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The role of mitochondria in stem cell fate and aging

The role of mitochondria in stem cell fate and aging © 2018. Published by The Company of Biologists Ltd | Development (2018) 145, dev143420. doi:10.1242/dev.143420 REVIEW 1,2 3 2, Hongbo Zhang , Keir J. Menzies and Johan Auwerx * ABSTRACT certain parts of the nervous system (Maslov et al., 2004) and hair follicles of epithelial tissue (Nishimura et al., 2005). In other tissues, The importance of mitochondria in energy metabolism, signal stem cells can maintain their population, or even increase in transduction and aging in post-mitotic tissues has been well numbers with aging, as seen for hematopoietic stem cells (HSCs) established. Recently, the crucial role of mitochondrial-linked (Rossi et al., 2005). However, despite the expansion of HSCs during signaling in stem cell function has come to light and the importance aging, there is still a decline in cell function (Morrison et al., 1996) of mitochondria in mediating stem cell activity is becoming and altered cell fate decisions (Rossi et al., 2005; Sudo et al., 2000). increasingly recognized. Despite the fact that many stem cells Similarly, an increase of cell number and decline in cell function is exhibit low mitochondrial content and a reliance on mitochondrial- also seen in intestinal stem cell aging (Biteau et al., 2008; Choi et al., independent glycolytic metabolism for energy, accumulating 2008; Martin et al., 1998). Understanding the diversity of stem cell evidence has implicated the importance of mitochondrial function in responses to aging within different stem cell niches requires stem cell activation, fate decisions and defense against senescence. comprehensive mechanistic studies of the molecular events that In this Review, we discuss the recent advances that link mitochondrial influence stem cells during aging. metabolism, homeostasis, stress responses, and dynamics to stem Mitochondria are bioenergetic organelles that produce ATP via cell function, particularly in the context of disease and aging. This oxidative phosphorylation (OXPHOS), a process driven by the Review will also highlight some recent progress in mitochondrial formation of reducing equivalents NADH and FADH . The therapeutics that may present attractive strategies for improving stem importance of mitochondria in mediating stem cell activity has cell function as a basis for regenerative medicine and healthy aging. been largely neglected owing to the low abundance of mitochondria KEY WORDS: Stem cell, Mitochondria, Cell fate, Aging in many types of stem cells, and their widely recognized dependence on glycolysis for energy (Rafalski et al., 2012). Recent findings have Introduction revealed how mitochondria influence stem cell fate and function, In adults, tissue-specific stem cells maintain tissue homeostasis and whether it be in healthy tissue or during aging and disease (Ansó provide committed progenitors for regeneration after tissue injury. et al., 2017; Buck et al., 2016; Jin et al., 2018; Khacho et al., 2016; To maintain the stem cell pool and provide progenitors for tissue- Mohrin et al., 2015; Zhang et al., 2016). Besides their known role in specific cell differentiation, stem cells must undergo a process of energy harvesting, mitochondria have a signaling function and self-renewal. The balance between the preservation of stem cells and various forms of stress in the mitochondria can generate retrograde tissue regeneration relies on the maintenance of cell fate decisions, signals, for example reactive oxygen species (ROS), that affect other which is under precise regulation by many different factors: growth cellular sites and are known to influence stem cell activity and factors, inflammatory mediators, the extracellular environment, cell- function (Sun et al., 2016). Mitochondria also compartmentalize cell signaling, cellular metabolism and so on. It is now well known several key metabolic pathways, such as the tricarboxylic acid (TCA) that an imbalance towards cell lineage commitment at the expense cycle, fatty acid β-oxidation and the one-carbon cycle. Metabolites of self-renewal can have detrimental effects under certain generated by these pathways can also act as retrograde signals, at least circumstances, for example in disease or during aging. in post-mitotic tissues. Protein lysine modifications by malonylation, Over time, stem cells progressively lose plasticity in response to succinylation and glutarylation all utilize substrates from chronological and replicative senescence. This has important mitochondrial fatty acid and amino acid metabolism (Hirschey and consequences for the maintenance of tissue function; slower Zhao, 2015). Interestingly, the sirtuin enzymes can catalyze the wound healing, muscle weakness, decreased immunity and hair cleavage of the above-mentioned post-translational modifications graying or loss all appear with age as a result of changes in tissue- (PTMs) using the mitochondrial metabolite NAD as a co-factor specific stem cell activity (Signer and Morrison, 2013; Van Zant and (Menzies et al., 2016). Furthermore, the TCA cycle intermediate α- Liang, 2003). Despite a general decline in stem cell function during ketoglutarate (α-KG) is a substrate for enzymes with DNA and aging, the specific changes in the stem cell phenotype depend on histone demethylation activity (Teperino et al., 2010). Although most their local tissue niche. During aging, tissues with low stem cell of these mitochondrial metabolism-mediated PTMs were discovered turnover rates often exhibit an accentuated depletion of the stem cell in post-mitotic adult tissue, similar cases have been described in stem pool, as is commonly seen in skeletal muscle (Bengal et al., 2017), cells during health, disease and aging (Chandel et al., 2016). As mitochondria play an important role in regulating stem cell activity, it follows that a decline in stem cell mitochondrial function Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Sun- might underpin age-related deterioration in stem cell function and self- Yat Sen University, 510080, Guangzhou, China. Laboratory of Integrative and Systems Physiology, École Polytechnique Fédérale de Lausanne, CH-1015, renewal in multiple different tissues (Ahlqvist et al., 2012; Ansó et al., Switzerland. Interdisciplinary School of Health Sciences, University of Ottawa 2017; Khacho et al., 2017; Rera et al., 2011; Stoll et al., 2011; Zhang Brain and Mind Research Institute and Centre for Neuromuscular Disease, Ottawa, et al., 2016) (Fig. 1). In this Review, we discuss the emerging role of Canada, K1H 8M5. mitochondrial energy metabolism, mitochondrial proteostasis, *Author for correspondence (admin.auwerx@epfl.ch) mitophagy and key mitochondrial signaling events in stem cell function and how this relates to tissue homeostasis in disease and aging. J.A., 0000-0002-5065-5393 DEVELOPMENT REVIEW Development (2018) 145, dev143420. doi:10.1242/dev.143420 Quiescent stem cells Aged stem cells Fig. 1. Mitochondrial influence on stem cell fate. Asymmetric division generates two daughter cells with different mitochondrial properties. The Premature daughter cell that received a greater proportion of commitment new mitochondria maintains its stem cell traits whereas the daughter cell that received more older Self-renewal mitochondria tends to differentiate. Other mitochondrial signaling mechanisms, such as ROS and mitochondrial dynamics, are also involved in the balance between stem cell self-renewal and Commitment Commitment commitment. Mitochondrial reduction and dysfunction can further lead to stem cell aging, Key ROS which is typically characterized by a reduction in stem cell renewal and premature commitment. Self-renewal New mitochondria Older mitochondria Dysfunctional mitochondria ROS Fragmented mitochondria Differentiation Energy metabolism in stem cells peroxisome proliferator-activated receptor δ (PPAR-δ) induces a Different types of stem cells have different metabolic properties loss of HSC maintenance, whereas treatment with PPAR-δ agonists (Table 1); however, most reported data describe stem cells as improves HSC maintenance by promoting asymmetric HSC glycolytic (reviewed by Rafalski et al., 2012). Human and murine division (Ito et al., 2012). Lipid metabolism is also important for HSCs (Miharada et al., 2011; Piccoli et al., 2005; Simsek et al., maintenance of NSC proliferation (Knobloch et al., 2013). 2010; Takubo et al., 2013; Yu et al., 2013), murine neural stem cells Conditional deletion of fatty acid synthase (FASN), the key (NSCs) (Lange et al., 2016; Wang et al., 2010), human embryonic enzyme of de novo lipogenesis, in mouse NSCs impairs adult stem cells (ESCs) (St John et al., 2005; Zhang et al., 2011) and neurogenesis (Knobloch et al., 2013). Similar to HSCs and NSCs, human bone marrow-derived mesenchymal stem cells (MSCs) cancer cells are generally considered to be glycolytic, a result of the (Chen et al., 2008) are all highly dependent on glycolytic Warburg effect; however, glioma stem cells have been reported to metabolism for stem cell maintenance and/or self-renewal. contain higher levels of ATP and rely mainly on OXPHOS as an Consistent with a reliance on glycolysis and low rates of energy source (Vlashi et al., 2011). Moreover, several types of mitochondrial oxidative respiration, human HSCs (Piccoli et al., tumor-initiating stem cells exhibit mitochondrial FAO as a 2005), MSCs (Chen et al., 2008) and ESCs (Chung et al., 2007) mechanism for self-renewal and resistance to chemotherapy have few mitochondria and an immature inner structure. (Chen et al., 2016; Samudio et al., 2010). Thus, the combination Furthermore, stem cell self-renewal and/or multi- or pluripotency of mitochondrial FAO and glycolysis might play a role in self- are promoted by hypoxia in murine HSCs, MSCs and NSCs and preservation in some types of CSCs. Related to this, intestinal stem human ESCs (D’Ippolito et al., 2006; Ezashi et al., 2005; Jeong cells (ISCs) exhibit an interesting phenomenon whereby their et al., 2007; Morrison et al., 2000). proper function depends both on their own mitochondrial activity, Several explanations have been proposed to account for the relative and on Paneth cells in their surrounding niche that are reliant on importance of glycolysis over mitochondrial OXPHOS activity in glycolysis (Rodríguez-Colman et al., 2017). stem cells. For instance, dependence on anaerobic metabolism may Consistent with the importance of mitochondrial OXPHOS be a long-term evolutionary adaption of stem cells to their low oxygen activity in stem cell function and maintenance, the clearance of niche. An example of this is the hypoxic bone marrow environment of ‘older’ mitochondria away from stem cells during asymmetric cell HSCs (Miharada et al., 2011; Simsek et al., 2010), as well as the rates division seems to be essential for retaining stemness in mammary of glycolysis in cancer stem cells (CSCs) within solid tumors (Zu and stem-like cells (Katajisto et al., 2015) (Fig. 1). Calorie restriction Guppy, 2004). Another explanation might be the benefit of a (CR), which is known to improve mitochondrial function in post- glycolytic metabolism in providing intermediates necessary for mitotic tissues, increases the abundance of muscle stem cells supporting anabolic pathways that are essential for stem cell self- (MuSCs) (Cerletti et al., 2012) and improves the self-renewal of renewal and the generation of progeny (reviewed by Suda et al., many stem cell populations, such as germline stem cells (GSCs) in 2011). Anaerobic metabolism can also help to avoid oxidative flies (Mair et al., 2010) and HSCs (Chen et al., 2003; Cheng et al., damage from mitochondria-generated ROS [reviewed by Suda et al. 2014) and ISCs (Igarashi and Guarente, 2016; Yilmaz et al., 2012) (2011) and further discussed in the next sections]. in mice. Conversely, caloric excess reduces mitochondrial function Recent studies have demonstrated that stem cells also utilize (Bournat and Brown, 2010) and impairs stem cell function: in mitochondrial fatty acid oxidation (FAO) in addition to glycolysis mouse models of high fat feeding or obesity and type 2 diabetes (ob/ during self-renewal (Ito et al., 2012). Inhibition of FAO in HSCs ob and db/db mice, respectively) muscle regeneration is blunted results in the loss of the asymmetric division of HSC daughter cells, with a reduction in injury-induced MuSC proliferation (Hu et al., which is an essential process for maintaining the ‘reserve’ stem cell 2010; Nguyen et al., 2011). Similarly, a high fat diet dysregulates pool during the simultaneous expansion of stem cell differentiation ISCs and their daughter cells, resulting in an increased incidence of (Ito et al., 2012). Indeed, loss of the mitochondrial FAO activator intestinal tumors (Beyaz et al., 2016). DEVELOPMENT REVIEW Development (2018) 145, dev143420. doi:10.1242/dev.143420 Table 1. Metabolic properties of different stem cells instance, several glycolytic adult stem cells require OXPHOS activity for differentiation, including NSCs (Zheng et al., 2016), Stem cell type Metabolic properties References MSCs (Tang et al., 2016; Tormos et al., 2011; Zhang et al., 2013), Human embryonic High glycolysis Zhou et al. (2012) HSCs (Inoue et al., 2010) and ESCs (Yanes et al., 2010). The stem cells reverse transition, from OXPHOS to glycolysis, is required for the Mouse embryonic Glycolysis, pentose Zhou et al. (2012), induction of pluripotency from somatic cells (Folmes et al., 2012), stem cells phosphate pathway Takehara et al. (2012) and OXPHOS which is consistent with the fact that induced pluripotent stem cells Induced pluripotent High glycolysis Folmes et al. (2011), (iPSCs) generally exhibit an immature mitochondrial morphology stem cells Yoshida et al. (2009), and reliance on glycolytic metabolism (Prigione et al., 2010). Prigione et al. (2010) Interestingly, it was later reported that the reprogramming of human Long-term High glycolysis, low Simsek et al. (2010), Ito and mouse iPSCs from fibroblasts requires a transient increase of hematopoietic OXPHOS and fatty et al. (2012) OXPHOS (Kida et al., 2015; Prigione et al., 2014). The switch stem cells acid oxidation Hematopoietic Both anabolic glycolysis Piccoli et al. (2005), between glycolysis and OXPHOS appears to also causally affect progenitors and OXPHOS Simsek et al. (2010), HSC fate decisions, as electron transport chain (ETC) uncoupling Takubo et al. (2013), Ito facilitates the self-renewal of cultured HSCs, even under et al. (2012) differentiation-inducing conditions (Vannini et al., 2016). NSCs Mesenchymal stem High glycolysis Chen et al. (2008) exhibit changes in mitochondrial morphology and metabolic cells properties throughout various stages of differentiation in vivo and, Neural stem cells High glycolysis; Lange et al. (2016), Wang in general, activated proliferating NSCs and committed neural OXPHOS may be et al. (2010) important in progenitors rely more on OXPHOS (Khacho et al., 2016). differentiation Intriguingly, mouse epidermal stem cells undergo diurnal metabolic Muscle stem cells Glycolysis; OXPHOS is Bracha et al. (2010), + oscillations such that a higher NADH/NAD ratio matched by an also important Cerletti et al. (2012), increased glycolysis/OXPHOS ratio is observed during the night Zhang et al., (2016) compared with the daytime. Moreover, this metabolic oscillation is Intestinal stem cells Relatively high Rodriguez-Colman et al. coupled to the stem cell cycle (Stringari et al., 2015). It is not yet OXPHOS compared (2017) with niche Paneth known whether the change in stem cell metabolism in circadian phase cells also occurs for other stem cell types. Interfollicular stem Oscillates between Stringari et al. (2015) cells glycolysis and Mitochondrial metabolites and stem cell fate decisions OXPHOS The generation of mitochondrial metabolites represents a possible Cancer stem cells Glycolysis; fatty acid Chen et al. (2016), means by which mitochondria could regulate stem cell activity. Key oxidation Samudio et al. (2010) enzymes that regulate chromatin (both DNA and histones) and protein modifications (i.e. acetylation and methylation) rely on Interestingly, mouse and human ESCs have different metabolic mitochondrial metabolic intermediates as co-factors (Matilainen properties (reviewed by Mathieu and Ruohola-Baker, 2017). In et al., 2017; Menzies et al., 2016). Hence, mitochondrial mice, despite the more immature appearance of mitochondria and metabolism is inextricably coupled to gene expression and protein lower mitochondrial content, basal and maximal mitochondrial activity. Despite the fact that many of these findings were made respiration are substantially higher in ESCs compared with the more using post-mitotic tissues, there are several emerging lines of differentiated (primed) epiblast stem cells (EpiSCs), which are evidence that suggest similar mechanisms may be at play in derived from a post-implantation epiblast at a later stage of regulating stem cell fate decisions. development (Zhou et al., 2012). Conventional human ESCs Several metabolites in the TCA cycle participate in additional (hESCs) do not appear to be naïve like mouse ESCs (mESCs) but pathways that regulate stem cell function and fate decisions (Fig. 2). more similar to primed mouse EpiSCs with regards to their gene Export of citrate from mitochondria to the cytoplasm provides acetyl expression profile and epigenetic state. In addition, hESCs are also coenzyme A (acetyl-CoA) for nucleo-cytoplasmic acetylation more metabolically similar to rodent EpiSCs as they display a higher reactions (Wellen et al., 2009). In addition to acetylation, other rate of glycolysis than do mouse ESCs (Sperber et al., 2015; Zhou protein PTMs, such as malonylation, succinylation and et al., 2012). Ectopic expression of HIF1α or exposure to hypoxia glutarylation, also use mitochondrial intermediates, including can promote the conversion of mESCs to the primed state by malonyl-CoA, succinyl-CoA and glutaryl-CoA, respectively, for favoring glycolysis, thereby suggesting an important role for the regulation of protein function (Matilainen et al., 2017; Sabari mitochondrial metabolism in the maintenance of mESCs (Zhou et al., 2017). α-KG is not only a substrate for the family of ten- et al., 2012). Indeed, upregulated mitochondrial transcripts and eleven translocation (TET) dioxygenases, enzymes with DNA increased mitochondrial oxidative metabolism by STAT3 activation demethylation function, but also for the Jumonji-C (JMJC) domain- supports the enhanced proliferation of mESCs and the containing histone demethylase (JHDMs) family of proteins that reprogramming of EpiSCs back to a naïve pluripotent state catalyze histone demethylation (Su et al., 2016; Teperino et al., (Carbognin et al., 2016). In the human context, conventional, 2010). Furthermore, S-adenosyl-methionine (SAM) is a co-factor primed ESCs can transition to a more naïve state in vitro by for histone methyltransferases connecting histone methylation to treatment with histone deacetylase (HDAC) inhibitors (Ware et al., one-carbon metabolism (Mentch et al., 2015) and threonine 2014). The fact that HDACs are largely NAD dependent (further metabolism (Shyh-Chang et al., 2013). discussed below) supports the role of metabolism in stem cell maintenance. Acetylation and deacetylation In addition to its role in stem cell self-renewal, metabolism is also Both histones and other proteins, such as the transcriptional factors/ an important regulator of stem cell identity and fate decisions. For co-factors peroxisome proliferator-activated receptor-γ coactivator 1α DEVELOPMENT REVIEW Development (2018) 145, dev143420. doi:10.1242/dev.143420 Glucose/FFA Mitochondrion Nucleus Acetyl-CoA Acetyl-CoA Acetyl-CoA CoA KA KA A AT T T Ts s Oxaloacetate Citrate Citrate Citrate SIR SIRT T T Ts s NAM NAD TCA cycle α-KG/ Succinate/ Succinate αα-KG α-KG FAD FADH JHDMs JHDMs NADH NAD FADH FAD Met HMTs SAM SAM SAH cycle α-KG Succinate One-C TET TET T Ts s Folate cycle cycle DNMTs SAM SAH Key Acetylation Methylation Fig. 2. Mitochondrial metabolism and epigenetic regulation in stem cells. Mitochondrial TCA cycle intermediate metabolites, such as acetyl-CoA, citrate and α-KG, can be transported to the cytosol and nucleus where they may potentially control stem cell fate via the epigenetic regulation of histones and DNA. Acetyl-CoA is a co-factor of lysine acetyltransferases (KATs), which reverse the activity of the NAD -dependent sirtuins (SIRTs) by catalyzing the acetylation of histones and other proteins. α-KG is the substrate for both histone (JHDMs) and DNA (TETs) demethylases. Mitochondrial one-carbon (One-C) metabolism coupled with cytosolic folate and methionine (Met) cycles generates SAM, which serves as the co-factor of histone (HMTs) and DNA (DNMTs) methyltransferases. FFA, free fatty acid; NAM, nicotinamide; SAH, S-adenosylhomocysteine. (PPARGC1α), forkhead box protein O 1 (FOXO1) and tumor protein reported to decline with age and lead to HSC dysfunction (Brown p53 (TP53/TRP53), can be acetylated on the ε-amino groups of site- et al., 2013; Mohrin et al., 2015). Protein acetylation has been specific lysine residues through N-ε-acetylation. This is a reversible shown to modulate ESC function too. KDAC inhibitors, such as PTM reaction catalyzed by lysine acetyltransferases (KATs) and butyrate, support the extensive self-renewal of mouse and human lysine deacetylases (KDACs, such as sirtuins). KATs and sirtuins are ESCs and promotes their convergence toward an earlier highly sensitive to the concentration of acetyl-CoA and NAD as developmental (more naïve) stage (Ware et al., 2014, 2009). substrates that tightly connect energy metabolism to gene expression The evidence linking KAT activity or acetyl-CoA levels to stem cell (Box 1 and reviewed by Menzies et al., 2016). Recently, control of function is mostly indirect. Recently, in Drosophila, acetyl-CoA levels such PTMs has been found to influence stem cell activity and were found to increase during aging. This increase is accompanied by senescence across a range of different stem cell types. an elevation in global histone acetylation, notably the acetylation of In MuSCs, NAD levels have been linked to myogenic lysine 12 on histone H4 (H4K12ac). Consistent with this notion, a differentiation. Decreased levels of cellular NAD , a co-factor for mutation in the gene encoding the H4K12-specific acetyltransferase the sirtuin deacetylases (Cantó et al., 2015), leads to elevated Chameau extends lifespan in Drosophila (Peleg et al., 2016). Whether H4K16 acetylation (H4K16ac), an activating modification that the effect of acetyl-CoA on Drosophila aging is related to stem cell induces myogenic gene expression (Ryall et al., 2015). In aged function has yet to be investigated. In human and mouse ESCs, mice, a decline in NAD levels in MuSCs leads to cell senescence, glycolysis-generated acetyl-coA has been reported to promote histone and boosting NAD levels with the dietary precursor nicotinamide acetylation during pluripotency (Moussaieff et al., 2015). Inhibition of riboside alleviates MuSCs senescence and extends mouse lifespan acetyl-coA production by blocking glycolysis causes a significant loss (Zhang et al., 2016). These effects are mediated, at least in part, by in pluripotency markers in human and mouse ESCs. It would be the sirtuin family of enzymes. NAD levels have also been shown to interesting to investigate whether cellular acetyl-CoA levels are also be limiting during aging in NSCs and can drive the decline in NSC coupled with stem cell function in mammals in vivo. oligodendrogenesis after cuprizone-induced brain demyelination (Stein and Imai, 2014). In HSCs, the level of H4K16ac decreases Methylation and demethylation with age (Florian et al., 2012) and inhibition of the RhoGTPase The methylation of nucleic acids and proteins can significantly CDC42 restores H4K16ac levels and reverses phenotypes of HSC change their stability and transcription/translation efficiency and aging in transplantation assays (Florian et al., 2012). It is less likely activity. Protein methylation can occur on both lysines and arginines that the decrease of H4K16ac levels in aged HSCs is due to the and generate either mono- or di-methylated forms, and lysine can activation of the NAD -sirtuin signaling axis as the expression of also be tri-methylated. The most well-studied protein methylation is two NAD -dependent sirtuins, SIRT3 and SIRT7, have been histone N-terminal tail methylation, which can either negatively or DEVELOPMENT REVIEW Development (2018) 145, dev143420. doi:10.1242/dev.143420 Box 1. Principal enzymes involved in protein acetylation and methylation Protein acetylation and methylation are two very common post-transcriptional protein modifications involved in the epigenetic regulation of stem cells (reviewed by Aloia et al., 2013; Oh et al., 2014; Portela and Esteller, 2010). The main enzymes in the class of lysine acetyltransferases (KATs) and lysine deacetylases (KDACs), which catalyze histone acetylation (red stars) and deacetylation, respectively, are given on the left. The main enzymes in the class of histone methytransferases (HMTs) and histone demethylases (HDMs), which catalyze histone methylation (purple stars) and demethylation, respectively, are given on the right. SRCs, steroid receptor co-activators. KDACs HMTs Class I: HDAC1, 2, 3, 8 H3K4: KMT2A-E, SETD1A/B, ASCL1, SMYD1-3, SETD7 Class IIA: HDAC4, 5, 7, 9 H3K9: SUV39H1/2, EHMT2, EHMT1, SETDB1-2, PRDM2 Class IIB: HDAC6, 10 H3K27: EZH2 Class III: SIRT1-7 H3K36: SETD2, NSD1-3, SMYD2, SETMAR Class IV: HDAC11 H3K79: DOT1L H4K20: KMT5A-C, NSD1 KDACs HMTs KATs HDMs KATs HDMs GNAT: KAT2A, KAT2B, HAT1, ATF2 H3K4: KDM1A/B, KDM2A/B, KDM5A-D, RIOX1 MYST: KAT5, KAT6A, KAT6B, KAT7 H3K9: KDM1A, KDM3A/B, KDM4A-D, SRCs: NCoA-1, NCoA-2, NCoA-3 KDM7A, PHF8 p300/CBP: EP300, CREBBP H3K27: KDM6A/B, PHF8 TAF1 H3K36: KDM2A/B, KDM4A-C GTF3C-α H3K79: not described CLOCK H4K20: not described positively affect gene transcriptional efficiency (Booth and Brunet, involved in stem cell aging. H3K4me3 (histone trimethylation) is a 2016; Teperino et al., 2010). DNA methylation and demethylation marker of gene activation and increases across HSC identity and PTMs are catalyzed reversibly by DNA methyltransferases self-renewal genes with age, which might explain the observed (DNMTs) and TET enzymes, respectively. Reversible histone increase of HSC numbers in mouse aging (Sun et al., 2014). In methylation can be catalyzed by histone methyltransferases (HMTs) contrast, H3K4me3 in MuSCs decreases with age, as the repressive and histone demethylases (HDMs, such as JHDMs). Importantly, histone methylation H3K27me3 increases (Liu et al., 2013). both DNA and histone methyltransferases use SAM as a substrate, Metabolites that modulate HMT and HDM activity can also impact whereas demethylases use α-KG (Fig. 2, Box 1). Therefore, these on stem cell function and fate decisions. Reductions in α-KG levels in modifications are strictly dependent on the availability of response to the knockdown of phosphoserine aminotransferase 1 mitochondrial metabolites (reviewed by Matilainen et al., 2017). (PSAT1) impairs mESC self-renewal and induces differentiation, Both DNA and histone methylation regulate stem cell function. mediated by lower DNA 5′-hydroxymethylcytosine levels and For instance, deficiency in DNA methyltransferase 3A and/or 3B increased histone methylation (Hwang et al., 2016). In fact, there is (DNMT3A/B) impairs the differentiation potential of HSCs evidence to suggest that pluripotency in mESCs might be regulated (Challen et al., 2014; Mayle et al., 2015). Conversely, reducing by the ratio of α-KG to succinate by virtue of its effect on H3K27me3 the function of the DNA demethylase TET2 by ascorbate depletion levels (Carey et al., 2015). Both α-KG and succinate are metabolites in mice increases HSC frequency and function, which leads to generated as a result of TCA metabolism in the mitochondrial matrix the acceleration of leukemogenesis (Agathocleous et al., 2017). (Fig. 2). Similarly, regulation of DNA and histone methylation by TET2 restoration, or vitamin C treatment, promotes HSC DNA SAM is also important in maintaining hESC and iPSC function. demethylation, promotes differentiation, and blocks leukemia Methionine deprivation rapidly decreases intracellular SAM, progression (Cimmino et al., 2017). Maintenance of the preventing hESC and iPSC self-renewal and increasing overall euchromatic transcriptional state by inhibition of the euchromatic differentiation potency, and eventually leading to cell apoptosis histone-lysine N-methyltransferase 2 (EHMT2, also known as (Shiraki et al., 2014). Depletion of intracellular SAM is also seen after G9A), delays HSC differentiation (Ugarte et al., 2015). However, in threonine deprivation in mouse ESCs, where it leads to slowed stem MuSCs, an H4K20 dimethyltransferase, lysine methyltransferase cell growth and increased differentiation (Fig. 2) (Shyh-Chang et al., 5B (KMT5B), maintains stem cell quiescence by promoting the 2013). formation of facultative heterochromatin. Deletion of KMT5B induces transcriptional activation, further resulting in abnormal The mitochondrial unfolded protein response and stem cell MuSC activation and differentiation. This leads to stem cell aging depletion and impaired long-term muscle regeneration Maintenance of mitochondrial function relies on the coordinated (Boonsanay et al., 2016). Histone methylation also appears to be expression of mitochondrial- and nuclear-encoded mitochondrial Acetylation Methylation DEVELOPMENT REVIEW Development (2018) 145, dev143420. doi:10.1242/dev.143420 proteins. An altered balance between protein expressions from 2005). Mitochondrial DNA (mtDNA) integrity plays an important these genomes can result in proteotoxic stress and the subsequent role in stem cell fate decisions; NSCs isolated from mice deficient accumulation of misfolded proteins within the mitochondria. for 8-oxoguanine DNA glycosylase (OGG1; the enzyme essential When this occurs, a mitochondrial unfolded protein response, for mtDNA damage repair) accumulate mtDNA damage and shift mt termed the UPR , is triggered (reviewed by Jovaisaite et al., 2014). their differentiation trajectory toward an astrocytic lineage at the This response likely synchronizes mitochondrial function to expense of neurogenesis (Wang et al., 2011). mtDNA defects have cellular homeostasis through the activation of a mitochondrion-to- also been observed in human stem cell aging (McDonald et al., nucleus retrograde signaling pathway, such as through prohibitin 1 2008; Taylor et al., 2003) and age-associated mitochondrial DNA (PHB) and 2 (PHB2) and/or c-Jun N-terminal protein kinase mutations have been reported to lead to abnormal cell proliferation (JNK2; MAPK9) and the protein kinase RNA-activated (PKR; and apoptosis in human colonic crypts (Taylor et al., 2003). The EIF2AK2)-activating transcription factor 4 (ATF4) pathway frequency of mtDNA defects is also greater in iPSCs generated from mt (Quirós et al., 2017). Overall, the UPR increases the expression aged compared with young people (Kang et al., 2016). However, of mitochondrial chaperones and proteases, and allows for a owing to limitations in the availability of human tissue and a lack of compensatory restoration of mitochondrial function following robust stem cell markers, the direct link between mtDNA mutations cellular stress (Jensen and Jasper, 2014; Jovaisaite et al., 2014; and stem cell function in vivo remains to be fully elucidated. Lin and Haynes, 2016). Clear evidence for a causal relationship between mtDNA mt Activation of the UPR response has been shown to have mutations and aging is provided by the nuclear-encoded mtDNA beneficial effects in multiple species (Jovaisaite and Auwerx, polymerase γ (POLG) knockout mouse model in which 2015). For instance, disrupting subunits of the mitochondrial ETC, spontaneous mutations or replication errors lead to the which stimulates the imbalance of the mito- and nuclear-encoded accumulation of mtDNA mutations, severe OXPHOS deficiency mt OXPHOS proteins and the induction of UPR , leads to overall and premature aging (Kujoth et al., 2005; Trifunovic et al., 2004). lifespan extension in yeast, worms, flies and mice (Durieux et al., Similar to the situation in physiological aging, stem cell deficiencies 2011; Houtkooper et al., 2013; Lee et al., 2003; Liu et al., 2005; were observed in multiple tissues of the POLG mice. mtDNA mt Owusu-Ansah et al., 2013). Recently, the UPR pathway was mutations inhibit early differentiation of HSCs (Norddahl et al., shown to regulate stem cell function, and the lifespan-extending 2011), resulting in abnormal myeloid lineages in the mutant mice mt effects of UPR stimulators such as nicotinamide riboside was (Ahlqvist et al., 2012; Chen et al., 2009). POLG mice have fewer linked in part to the improvement of stem cell function in aged mice quiescent NSCs (Ahlqvist et al., 2012), as well as increased levels of (Zhang et al., 2016). apoptosis, decreased cell proliferation and impaired SC-derived Mitochondrial stress, which can be stimulated by treating NSCs intestinal organoid formation (Fox et al., 2012). Moreover, POLG- with the bile acid tauro-ursodeoxycholic acid (TUDCA), generates a mutant cells have a markedly impaired capacity for reprogramming mitochondrial ROS-dependent retrograde signal that modulates during the generation of iPSCs (Hämäläinen et al., 2015). Although NSC proliferation and differentiation (Xavier et al., 2014). these studies link mtDNA mutations to stem cell dysfunction and However, because of the implication of TUDCA in endoplasmic aging, the stem cell defects in POLG mice do not appear to reticulum (ER) stress (Malo et al., 2010), it was unclear until recapitulate accurately the pace of physiological aging, as the level recently whether a mitochondrial-specific retrograde signal exists in of mtDNA mutations seen in these models is much higher than that stem cells and, if so, whether it regulates stem cell function. seen during the normal aging process (Norddahl et al., 2011). Supplementing mouse chow with nicotinamide riboside has been Therefore, although the levels of mtDNA mutations increase in aged mt shown to induce the UPR to prevent MuSC, NSC and melanocyte stem cells, it remains unclear whether this increase in mtDNA stem cell (McSC) senescence (Zhang et al., 2016). In MuSCs of mutations plays a fundamental role in stem cell aging. aged mice, nicotinamide riboside rescues cellular NAD depletion mt and thereby activates a SIRT1-dependent UPR signal to improve Influence of mitochondrial ROS on stem cell fate mitochondrial function and attenuate senescence (Zhang et al., Mitochondrial ROS are primarily generated from electron leakage 2016). Similarly, increased levels of NAD achieved via the from the mitochondrial OXPHOS complexes I and III (Box 2), overexpression of NAMPT, the rate-limiting NAD salvage which damages all components of the cell, including DNA, lipids enzyme, reduced cell senescence in aged MSCs (Ma et al., 2017). and proteins. Dysfunction of the mitochondrial respiratory chain In HSCs, SIRT7 has been shown to mediate a regulatory branch of and inefficient OXPHOS may lead to more electron leakage and mt the UPR and to maintain HSC function in aging (Mohrin et al., further increases in ROS generation, resulting in a detrimental cycle mt 2015). Therefore, some level of UPR signaling may help maintain that causes eventual, irreversible damage to cells and contributes to stem cell function during aging, possibly by preventing senescence. aging (Harman, 1972). mt However, constitutive activation of the UPR , with tissue-specific One of the first observations that suggested a role for ROS in cell loss of the mitochondrial chaperone protein HSP60 (HSPD1), can aging was that the replicative lifespans of in vitro cultured cells were also have detrimental effects, and lead to the loss of stemness in significantly extended by culturing the cells in a low-oxygen ISCs (Berger et al., 2016). Further studies will be needed to address environment, which might be due to less ROS generation (Packer mt how the relative level of UPR signaling affects stem cells and the and Fuehr, 1977; Parrinello et al., 2003). Mice with mutations in the extent to which this is context dependent (Fig. 3). DNA damage sensor ataxia telangiectasia (ATM) show a defect in HSC function that is associated with elevated ROS production, and Mitochondrial DNA mutations and stem cell function treatment with the anti-oxidant N-acetyl-L-cysteine (NAC) restored The mitochondrial genome encodes 37 genes, including 13 of the HSC function in these mice (Ito et al., 2004). A similar increase in OXPHOS subunits, two rRNAs and 22 tRNAs. The accumulation ROS production and DNA damage was seen in Bmi1-deficient of mitochondrial mutations has been observed in both rodent and mice, which were also rescued by NAC treatment (Liu et al., 2009). human tissues in vivo during aging (Cortopassi and Arnheim, 1990; Furthermore, FOXO proteins, which are key mediators in ROS Pikó et al., 1988), as well as in in vitro cell culture (Coller et al., signaling, may play essential roles in the response to physiological DEVELOPMENT REVIEW Development (2018) 145, dev143420. doi:10.1242/dev.143420 NAD boosters Mitochondrion Nucleus (e.g. NR and NMN) ETC + + + NAD NAD NAD SIR SIRT T1 1 T Transcr ranscription iption Mitochondrial dynamics ??? ??? ??? Mitogenesis ??? A A A ATF4 TF4 Mitonuclear mt JNK2, PKR UPR protein imbalance T Transcr ranscription iption ETC ??? PHB/PHB2 Mito-translation Unfolded proteins Chaperones and proteases Proteotoxic stress Cell cycle regulators, Proliferation, e.g. cyclin-CDKs, CDKNs delayed senescence mt Fig. 3. UPR and stem cell regulation. Mitochondrial electron transport chain proteins are encoded by both the nuclear (green) and mitochondrial (red) genomes. Mitonuclear protein imbalance and proteotoxic stress, mitochondrial dynamics, and mitogenesis can all lead to mitochondrial stress, which activates mt mt the mitochondrial unfolded protein response (UPR ). Retrograde UPR signaling, through prohibitin 1 and 2 (PHB and PHB2) and/or c-Jun N-terminal protein kinase (JNK2) and the protein kinase RNA-activated (PKR)-activating transcription factor 4 (ATF4) pathway (Quiros et al., 2017) can specifically regulate mt nuclear gene expression to generate more chaperones and proteases to alleviate proteotoxic stress. UPR -induced gene expression changes also lead to stem cell proliferation and a delayed senescence response. Pathways with the question marks are speculative and require further experimental confirmation. Solid and dashed arrows indicate direct and indirect pathway/links, respectively. NR, nicotinamide riboside; NMN, nicotinamide mononucleotide. oxidative stress and thereby preserve HSC function by upregulating phenotypes in mtDNA mutant mice by affecting mechanisms antioxidant gene expression (Tothova et al., 2007). beyond redox status. Finally, there are an increasing number of In POLG mice, the deficiencies of NSC and HSC function were examples in which ROS appears to play a positive and necessary also rescued by supplementation with NAC (Ahlqvist et al., 2012). signaling role in stem cell biology (Bigarella et al., 2014; Hameed NAC also restored the ROS-mediated deficiency of POLG-mutant et al., 2015; Maryanovich et al., 2015). Altogether, the effect and cells to be reprogrammed into iPSCs (Hämäläinen et al., 2015), detailed mechanism of ROS in stem cell function still needs further again suggesting the effects of ROS signaling in mediating the investigation. balance between quiescent and active status of stem cells. Some studies suggest that mtDNA mutations might cause slight alterations Role of mitophagy and mitochondrial dynamics on stem cell in redox status, thus affecting stem cell fate decisions (Ahlqvist fate et al., 2012). Indeed, physiological ROS appears to be important for Mitochondria have been shown to be asymmetrically segregated mediating NSC fate decisions (reviewed by Bigarella et al., 2014). during stem cell division (Katajisto et al., 2015). This asymmetric In NSCs, mitochondrial fusion and fission (further discussed allocation of mitochondria appears to be a unique feature of below) triggers ROS signaling to moderate self-renewal and adult stem cells that enables the exclusion of older mitochondria. differentiation via NRF2 (also known as nuclear factor, erythroid Beyond cell division, mitochondria in quiescent stem cells are 2 like 2, NFE2L2)-mediated mito-nuclear retrograde signaling subject to mitochondrial dynamics, involving fusion/fission and (Khacho et al., 2016). mitochondria-specific autophagy, termed mitophagy. Recently, Similar to the role of the mtDNA mutations as previously mitochondrial dynamics has been linked to stem cell function and discussed, there is much controversy regarding the effect of aging. mitochondrial ROS on stem cell dysfunction and aging due to a In general, compared with post-mitotic cells, mitochondrial number of observations. First, long-lived species do not always networks are fragmented in stem cells of various types, including demonstrate lower levels of ROS and the accompanying oxidative ESCs (Folmes et al., 2011; Zhou et al., 2012). This normally damage (Andziak et al., 2006; Chen et al., 2007). For example, a rise suggests a high level of mitochondrial fission and a low level of in ROS increases the lifespan of worms (Yang and Hekimi, 2010; mitochondrial fusion events. Indeed, DRP1 (dynamin-related Zarse et al., 2012). Second, it is known that the widely used anti- protein 1; also known as DNM1L)-dependent mitochondrial oxidative reagent NAC affects physiological processes beyond ROS fission has been shown to be necessary for cell reprogramming scavenging. Therefore, NAC treatment could benefit stem cell (Prieto et al., 2016). However, two studies also illustrate the DEVELOPMENT *– O O 2 2 QH H III Cyt c II I IV ½O *– H O FADH O O 2 2 2 NADH ADP TCA *– 2 ATP Acetyl-CoA REVIEW Development (2018) 145, dev143420. doi:10.1242/dev.143420 Box 2. Reactive oxygen species generation The mitochondrial ETC consists of five respiratory complexes (I-V), which are composed of proteins encoded by both nuclear (green) and mitochondrial (red) genomes. Mitochondrial ROS (blue lightning bolt) are mainly generated from complex I and III of the ETC. Cyt c, cytochrome c;QH , ubiquinol. potential importance of mitochondrial fusion proteins in renewal of HSCs (Vannini et al., 2016). Furthermore, autophagy maintaining stem cell function. In HSCs, mitofusin 2 (MFN2), a maintains HSC function in aged mice (Ho et al., 2017), and is also protein involved in promoting mitochondrial fusion and likely to be involved in the metabolic switch during iPSC mitochondria-ER tethering, increases the buffering capacity for reprogramming (Ma et al., 2015). 2+ intracellular Ca and thereby inhibits the translocation and Interestingly, SIRT1, FOXO and mTORC1 signaling have all transcriptional activity of the nuclear factor of activated T cells been implicated in the regulation of autophagy during stem cell (NFAT) (Luchsinger et al., 2016). The inhibition of NFAT is activation, reprogramming and survival under stress (Tang and essential for the maintenance of lymphoid potential of HSCs. In Rando, 2014; Warr et al., 2013; Wu et al., 2015). Whether these NSCs, mitochondrial dynamics (fusion and fission) regulates NSC proteins and signaling pathways are also linked to mitophagy, and identity, proliferation, and fate decisions by orchestrating nuclear play a similar role to autophagy, in stem cells still needs transcriptional programs. NSC-specific deletion of either OPA1 or confirmation, yet mitophagy and mitochondrial metabolic MFN1/2 induces ROS and NRF2-dependent retrograde signaling, pathways might be tightly conjugated and are likely to regulate which suppresses NSC self-renewal and promotes differentiation, stem cell function and aging in a coordinated manner. leading to age-dependent NSC depletion, defects in neurogenesis, and cognitive impairment (Khacho et al., 2016) (Fig. 1). Conclusions and perspective When mitochondrial damage or unfolded protein accumulates in In many early studies, the evidence for an association between mt the mitochondria, the UPR activates mitochondrial chaperones mitochondria and stem cell function and especially aging was and proteases to help protein folding and cleavage. Mitochondrial mostly correlative, such as the increase of mtDNA mutations, ROS fusion/fission might then be activated to dilute or separate damaged levels and the decline in stem cell function with aging. Increasingly, proteins for further degradation. Simultaneously, the clearance of however, causative connections are being established. Mitochondria mitochondria through mitophagy may help to dispose of damaged regulate stem cell function and fate decision through different proteins. In fact, evidence for the importance of autophagy/ strategies: mitochondrial metabolism generates metabolites that mitophagy for the maintenance of stem cell homeostasis is serve as DNA and protein modification substrates, such as NAD , accumulating. For instance, autophagy levels are higher in HSCs acetyl-CoA, citrate, α-KG and fatty acids. Through epigenetic and skin stem cells compared with the surrounding cells (Salemi modulation of gene expression, the availability of these key et al., 2012). In the dentate gyrus of the mouse brain, areas enriched mitochondrial metabolites directly regulates stem cell fate mt for NSCs appear to have higher rate of autophagy (Sun et al., 2015). decisions and aging. Moreover, UPR , mitochondrial dynamics Moreover, several recent studies suggest a causative link between and stress can generate retrograde signals from the mitochondria to mitophagy and the prevention of stem cell aging (García-Prat et al., control nuclear gene expression. With stem cell mitochondria- 2016; Ho et al., 2017; Vazquez-Martin et al., 2016). Failure of nuclear cross-talk, mitochondria not only exert a strict quality autophagy in aged MuSCs, or the genetic impairment of autophagy control but may also impact gene expression patterns in order to in young MuSCs, causes entry into senescence by loss of alter cell fate decisions and physiological functions during aging. proteostasis, increased mitochondrial dysfunction and oxidative Despite much progress, this field of research is still in its infancy, stress, resulting in a decline in the function and number of MuSCs and there are many research questions that should now be answered. (García-Prat et al., 2016). However, MuSC senescence can be Importantly, we know that metabolism and mitochondrial function reversed through the re-establishment of autophagy (García-Prat are different amongst stem cell types and can change with stem cell et al., 2016). Loss of autophagy in HSCs causes the accumulation of dynamics. However, it is still not clear to what extent mitochondria mitochondria and an activated metabolic state that drives determine stem cell properties and fate decisions. Also, the accelerated myeloid differentiation and impairs HSC self-renewal mechanisms that underpin the heterogeneity of metabolic and activity and regenerative potential (Ho et al., 2017; Mortensen et al., mitochondrial properties in different stem cell types remains 2011). In agreement with this, lowering the mitochondrial activity undefined. Another interesting topic is stem cell aging, as it by uncoupling the ETC stimulates autophagy and drives self- represents not only a fundamental scientific issue but is also directly DEVELOPMENT REVIEW Development (2018) 145, dev143420. doi:10.1242/dev.143420 organismal level by extending lifespan (Rera et al., 2011; Zhang et al., 2016). This is an exciting prospect, and one that puts the Box 3. Mitochondrial therapeutics in stem cells Targeting mitochondrial function represents a possible treatment interplay between mitochondria and stem cells at the center stage of strategy for some inherited genetic diseases, metabolic syndromes the aging field. and neurodegenerative diseases. There are several ways to improve mitochondrial function, for example by targeting sirtuins, AMP-activated Competing interests protein kinase (AMPK), mTOR, NAD metabolism, nuclear receptors The authors declare no competing or financial interests. (such as PPARs and estrogen-related receptors), transcriptional factors/ co-factors (such as PPARGC1α, FOXO, NCORs), along with activators Funding mt of UPR and mitochondrial fusion/fission or mitophagy (reviewed by H.Z. is the recipient of a fellowship from the CARIGEST SA and his research is Sorrentino et al., 2017). Among these, however, there are very few supported by Sun Yat-sen University. K.J.M. is supported by the Canadian Institutes descriptions of how these treatment strategies affect stem cells of Health Research and Kidney Foundation of Canada. The research of J.A. is specifically. It was recently shown that PPARδ agonists improve supported by the École Polytechnique Fédérale de Lausanne, the National Institutes hematopoietic stem cell function by improving fatty acid oxidation (Ito of Health (R01AG043930), SystemsX (SySX.ch 2013/153), the Velux Stiftung et al., 2012). This finding highlights the therapeutic potential of PPARδ (Switzerland), and the Swiss National Science Foundation (Schweizerischer Nationalfonds zur Fö rderung der Wissenschaftlichen Forschung; 31003A-140780). agonists in improving the efficacy of bone marrow transplantation and the Deposited in PMC for release after 12 months. treatment of hematological malignancies. 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The role of mitochondria in stem cell fate and aging

Development , Volume 145 (8) – Apr 15, 2018

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© 2018. Published by The Company of Biologists Ltd | Development (2018) 145, dev143420. doi:10.1242/dev.143420 REVIEW 1,2 3 2, Hongbo Zhang , Keir J. Menzies and Johan Auwerx * ABSTRACT certain parts of the nervous system (Maslov et al., 2004) and hair follicles of epithelial tissue (Nishimura et al., 2005). In other tissues, The importance of mitochondria in energy metabolism, signal stem cells can maintain their population, or even increase in transduction and aging in post-mitotic tissues has been well numbers with aging, as seen for hematopoietic stem cells (HSCs) established. Recently, the crucial role of mitochondrial-linked (Rossi et al., 2005). However, despite the expansion of HSCs during signaling in stem cell function has come to light and the importance aging, there is still a decline in cell function (Morrison et al., 1996) of mitochondria in mediating stem cell activity is becoming and altered cell fate decisions (Rossi et al., 2005; Sudo et al., 2000). increasingly recognized. Despite the fact that many stem cells Similarly, an increase of cell number and decline in cell function is exhibit low mitochondrial content and a reliance on mitochondrial- also seen in intestinal stem cell aging (Biteau et al., 2008; Choi et al., independent glycolytic metabolism for energy, accumulating 2008; Martin et al., 1998). Understanding the diversity of stem cell evidence has implicated the importance of mitochondrial function in responses to aging within different stem cell niches requires stem cell activation, fate decisions and defense against senescence. comprehensive mechanistic studies of the molecular events that In this Review, we discuss the recent advances that link mitochondrial influence stem cells during aging. metabolism, homeostasis, stress responses, and dynamics to stem Mitochondria are bioenergetic organelles that produce ATP via cell function, particularly in the context of disease and aging. This oxidative phosphorylation (OXPHOS), a process driven by the Review will also highlight some recent progress in mitochondrial formation of reducing equivalents NADH and FADH . The therapeutics that may present attractive strategies for improving stem importance of mitochondria in mediating stem cell activity has cell function as a basis for regenerative medicine and healthy aging. been largely neglected owing to the low abundance of mitochondria KEY WORDS: Stem cell, Mitochondria, Cell fate, Aging in many types of stem cells, and their widely recognized dependence on glycolysis for energy (Rafalski et al., 2012). Recent findings have Introduction revealed how mitochondria influence stem cell fate and function, In adults, tissue-specific stem cells maintain tissue homeostasis and whether it be in healthy tissue or during aging and disease (Ansó provide committed progenitors for regeneration after tissue injury. et al., 2017; Buck et al., 2016; Jin et al., 2018; Khacho et al., 2016; To maintain the stem cell pool and provide progenitors for tissue- Mohrin et al., 2015; Zhang et al., 2016). Besides their known role in specific cell differentiation, stem cells must undergo a process of energy harvesting, mitochondria have a signaling function and self-renewal. The balance between the preservation of stem cells and various forms of stress in the mitochondria can generate retrograde tissue regeneration relies on the maintenance of cell fate decisions, signals, for example reactive oxygen species (ROS), that affect other which is under precise regulation by many different factors: growth cellular sites and are known to influence stem cell activity and factors, inflammatory mediators, the extracellular environment, cell- function (Sun et al., 2016). Mitochondria also compartmentalize cell signaling, cellular metabolism and so on. It is now well known several key metabolic pathways, such as the tricarboxylic acid (TCA) that an imbalance towards cell lineage commitment at the expense cycle, fatty acid β-oxidation and the one-carbon cycle. Metabolites of self-renewal can have detrimental effects under certain generated by these pathways can also act as retrograde signals, at least circumstances, for example in disease or during aging. in post-mitotic tissues. Protein lysine modifications by malonylation, Over time, stem cells progressively lose plasticity in response to succinylation and glutarylation all utilize substrates from chronological and replicative senescence. This has important mitochondrial fatty acid and amino acid metabolism (Hirschey and consequences for the maintenance of tissue function; slower Zhao, 2015). Interestingly, the sirtuin enzymes can catalyze the wound healing, muscle weakness, decreased immunity and hair cleavage of the above-mentioned post-translational modifications graying or loss all appear with age as a result of changes in tissue- (PTMs) using the mitochondrial metabolite NAD as a co-factor specific stem cell activity (Signer and Morrison, 2013; Van Zant and (Menzies et al., 2016). Furthermore, the TCA cycle intermediate α- Liang, 2003). Despite a general decline in stem cell function during ketoglutarate (α-KG) is a substrate for enzymes with DNA and aging, the specific changes in the stem cell phenotype depend on histone demethylation activity (Teperino et al., 2010). Although most their local tissue niche. During aging, tissues with low stem cell of these mitochondrial metabolism-mediated PTMs were discovered turnover rates often exhibit an accentuated depletion of the stem cell in post-mitotic adult tissue, similar cases have been described in stem pool, as is commonly seen in skeletal muscle (Bengal et al., 2017), cells during health, disease and aging (Chandel et al., 2016). As mitochondria play an important role in regulating stem cell activity, it follows that a decline in stem cell mitochondrial function Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Sun- might underpin age-related deterioration in stem cell function and self- Yat Sen University, 510080, Guangzhou, China. Laboratory of Integrative and Systems Physiology, École Polytechnique Fédérale de Lausanne, CH-1015, renewal in multiple different tissues (Ahlqvist et al., 2012; Ansó et al., Switzerland. Interdisciplinary School of Health Sciences, University of Ottawa 2017; Khacho et al., 2017; Rera et al., 2011; Stoll et al., 2011; Zhang Brain and Mind Research Institute and Centre for Neuromuscular Disease, Ottawa, et al., 2016) (Fig. 1). In this Review, we discuss the emerging role of Canada, K1H 8M5. mitochondrial energy metabolism, mitochondrial proteostasis, *Author for correspondence (admin.auwerx@epfl.ch) mitophagy and key mitochondrial signaling events in stem cell function and how this relates to tissue homeostasis in disease and aging. J.A., 0000-0002-5065-5393 DEVELOPMENT REVIEW Development (2018) 145, dev143420. doi:10.1242/dev.143420 Quiescent stem cells Aged stem cells Fig. 1. Mitochondrial influence on stem cell fate. Asymmetric division generates two daughter cells with different mitochondrial properties. The Premature daughter cell that received a greater proportion of commitment new mitochondria maintains its stem cell traits whereas the daughter cell that received more older Self-renewal mitochondria tends to differentiate. Other mitochondrial signaling mechanisms, such as ROS and mitochondrial dynamics, are also involved in the balance between stem cell self-renewal and Commitment Commitment commitment. Mitochondrial reduction and dysfunction can further lead to stem cell aging, Key ROS which is typically characterized by a reduction in stem cell renewal and premature commitment. Self-renewal New mitochondria Older mitochondria Dysfunctional mitochondria ROS Fragmented mitochondria Differentiation Energy metabolism in stem cells peroxisome proliferator-activated receptor δ (PPAR-δ) induces a Different types of stem cells have different metabolic properties loss of HSC maintenance, whereas treatment with PPAR-δ agonists (Table 1); however, most reported data describe stem cells as improves HSC maintenance by promoting asymmetric HSC glycolytic (reviewed by Rafalski et al., 2012). Human and murine division (Ito et al., 2012). Lipid metabolism is also important for HSCs (Miharada et al., 2011; Piccoli et al., 2005; Simsek et al., maintenance of NSC proliferation (Knobloch et al., 2013). 2010; Takubo et al., 2013; Yu et al., 2013), murine neural stem cells Conditional deletion of fatty acid synthase (FASN), the key (NSCs) (Lange et al., 2016; Wang et al., 2010), human embryonic enzyme of de novo lipogenesis, in mouse NSCs impairs adult stem cells (ESCs) (St John et al., 2005; Zhang et al., 2011) and neurogenesis (Knobloch et al., 2013). Similar to HSCs and NSCs, human bone marrow-derived mesenchymal stem cells (MSCs) cancer cells are generally considered to be glycolytic, a result of the (Chen et al., 2008) are all highly dependent on glycolytic Warburg effect; however, glioma stem cells have been reported to metabolism for stem cell maintenance and/or self-renewal. contain higher levels of ATP and rely mainly on OXPHOS as an Consistent with a reliance on glycolysis and low rates of energy source (Vlashi et al., 2011). Moreover, several types of mitochondrial oxidative respiration, human HSCs (Piccoli et al., tumor-initiating stem cells exhibit mitochondrial FAO as a 2005), MSCs (Chen et al., 2008) and ESCs (Chung et al., 2007) mechanism for self-renewal and resistance to chemotherapy have few mitochondria and an immature inner structure. (Chen et al., 2016; Samudio et al., 2010). Thus, the combination Furthermore, stem cell self-renewal and/or multi- or pluripotency of mitochondrial FAO and glycolysis might play a role in self- are promoted by hypoxia in murine HSCs, MSCs and NSCs and preservation in some types of CSCs. Related to this, intestinal stem human ESCs (D’Ippolito et al., 2006; Ezashi et al., 2005; Jeong cells (ISCs) exhibit an interesting phenomenon whereby their et al., 2007; Morrison et al., 2000). proper function depends both on their own mitochondrial activity, Several explanations have been proposed to account for the relative and on Paneth cells in their surrounding niche that are reliant on importance of glycolysis over mitochondrial OXPHOS activity in glycolysis (Rodríguez-Colman et al., 2017). stem cells. For instance, dependence on anaerobic metabolism may Consistent with the importance of mitochondrial OXPHOS be a long-term evolutionary adaption of stem cells to their low oxygen activity in stem cell function and maintenance, the clearance of niche. An example of this is the hypoxic bone marrow environment of ‘older’ mitochondria away from stem cells during asymmetric cell HSCs (Miharada et al., 2011; Simsek et al., 2010), as well as the rates division seems to be essential for retaining stemness in mammary of glycolysis in cancer stem cells (CSCs) within solid tumors (Zu and stem-like cells (Katajisto et al., 2015) (Fig. 1). Calorie restriction Guppy, 2004). Another explanation might be the benefit of a (CR), which is known to improve mitochondrial function in post- glycolytic metabolism in providing intermediates necessary for mitotic tissues, increases the abundance of muscle stem cells supporting anabolic pathways that are essential for stem cell self- (MuSCs) (Cerletti et al., 2012) and improves the self-renewal of renewal and the generation of progeny (reviewed by Suda et al., many stem cell populations, such as germline stem cells (GSCs) in 2011). Anaerobic metabolism can also help to avoid oxidative flies (Mair et al., 2010) and HSCs (Chen et al., 2003; Cheng et al., damage from mitochondria-generated ROS [reviewed by Suda et al. 2014) and ISCs (Igarashi and Guarente, 2016; Yilmaz et al., 2012) (2011) and further discussed in the next sections]. in mice. Conversely, caloric excess reduces mitochondrial function Recent studies have demonstrated that stem cells also utilize (Bournat and Brown, 2010) and impairs stem cell function: in mitochondrial fatty acid oxidation (FAO) in addition to glycolysis mouse models of high fat feeding or obesity and type 2 diabetes (ob/ during self-renewal (Ito et al., 2012). Inhibition of FAO in HSCs ob and db/db mice, respectively) muscle regeneration is blunted results in the loss of the asymmetric division of HSC daughter cells, with a reduction in injury-induced MuSC proliferation (Hu et al., which is an essential process for maintaining the ‘reserve’ stem cell 2010; Nguyen et al., 2011). Similarly, a high fat diet dysregulates pool during the simultaneous expansion of stem cell differentiation ISCs and their daughter cells, resulting in an increased incidence of (Ito et al., 2012). Indeed, loss of the mitochondrial FAO activator intestinal tumors (Beyaz et al., 2016). DEVELOPMENT REVIEW Development (2018) 145, dev143420. doi:10.1242/dev.143420 Table 1. Metabolic properties of different stem cells instance, several glycolytic adult stem cells require OXPHOS activity for differentiation, including NSCs (Zheng et al., 2016), Stem cell type Metabolic properties References MSCs (Tang et al., 2016; Tormos et al., 2011; Zhang et al., 2013), Human embryonic High glycolysis Zhou et al. (2012) HSCs (Inoue et al., 2010) and ESCs (Yanes et al., 2010). The stem cells reverse transition, from OXPHOS to glycolysis, is required for the Mouse embryonic Glycolysis, pentose Zhou et al. (2012), induction of pluripotency from somatic cells (Folmes et al., 2012), stem cells phosphate pathway Takehara et al. (2012) and OXPHOS which is consistent with the fact that induced pluripotent stem cells Induced pluripotent High glycolysis Folmes et al. (2011), (iPSCs) generally exhibit an immature mitochondrial morphology stem cells Yoshida et al. (2009), and reliance on glycolytic metabolism (Prigione et al., 2010). Prigione et al. (2010) Interestingly, it was later reported that the reprogramming of human Long-term High glycolysis, low Simsek et al. (2010), Ito and mouse iPSCs from fibroblasts requires a transient increase of hematopoietic OXPHOS and fatty et al. (2012) OXPHOS (Kida et al., 2015; Prigione et al., 2014). The switch stem cells acid oxidation Hematopoietic Both anabolic glycolysis Piccoli et al. (2005), between glycolysis and OXPHOS appears to also causally affect progenitors and OXPHOS Simsek et al. (2010), HSC fate decisions, as electron transport chain (ETC) uncoupling Takubo et al. (2013), Ito facilitates the self-renewal of cultured HSCs, even under et al. (2012) differentiation-inducing conditions (Vannini et al., 2016). NSCs Mesenchymal stem High glycolysis Chen et al. (2008) exhibit changes in mitochondrial morphology and metabolic cells properties throughout various stages of differentiation in vivo and, Neural stem cells High glycolysis; Lange et al. (2016), Wang in general, activated proliferating NSCs and committed neural OXPHOS may be et al. (2010) important in progenitors rely more on OXPHOS (Khacho et al., 2016). differentiation Intriguingly, mouse epidermal stem cells undergo diurnal metabolic Muscle stem cells Glycolysis; OXPHOS is Bracha et al. (2010), + oscillations such that a higher NADH/NAD ratio matched by an also important Cerletti et al. (2012), increased glycolysis/OXPHOS ratio is observed during the night Zhang et al., (2016) compared with the daytime. Moreover, this metabolic oscillation is Intestinal stem cells Relatively high Rodriguez-Colman et al. coupled to the stem cell cycle (Stringari et al., 2015). It is not yet OXPHOS compared (2017) with niche Paneth known whether the change in stem cell metabolism in circadian phase cells also occurs for other stem cell types. Interfollicular stem Oscillates between Stringari et al. (2015) cells glycolysis and Mitochondrial metabolites and stem cell fate decisions OXPHOS The generation of mitochondrial metabolites represents a possible Cancer stem cells Glycolysis; fatty acid Chen et al. (2016), means by which mitochondria could regulate stem cell activity. Key oxidation Samudio et al. (2010) enzymes that regulate chromatin (both DNA and histones) and protein modifications (i.e. acetylation and methylation) rely on Interestingly, mouse and human ESCs have different metabolic mitochondrial metabolic intermediates as co-factors (Matilainen properties (reviewed by Mathieu and Ruohola-Baker, 2017). In et al., 2017; Menzies et al., 2016). Hence, mitochondrial mice, despite the more immature appearance of mitochondria and metabolism is inextricably coupled to gene expression and protein lower mitochondrial content, basal and maximal mitochondrial activity. Despite the fact that many of these findings were made respiration are substantially higher in ESCs compared with the more using post-mitotic tissues, there are several emerging lines of differentiated (primed) epiblast stem cells (EpiSCs), which are evidence that suggest similar mechanisms may be at play in derived from a post-implantation epiblast at a later stage of regulating stem cell fate decisions. development (Zhou et al., 2012). Conventional human ESCs Several metabolites in the TCA cycle participate in additional (hESCs) do not appear to be naïve like mouse ESCs (mESCs) but pathways that regulate stem cell function and fate decisions (Fig. 2). more similar to primed mouse EpiSCs with regards to their gene Export of citrate from mitochondria to the cytoplasm provides acetyl expression profile and epigenetic state. In addition, hESCs are also coenzyme A (acetyl-CoA) for nucleo-cytoplasmic acetylation more metabolically similar to rodent EpiSCs as they display a higher reactions (Wellen et al., 2009). In addition to acetylation, other rate of glycolysis than do mouse ESCs (Sperber et al., 2015; Zhou protein PTMs, such as malonylation, succinylation and et al., 2012). Ectopic expression of HIF1α or exposure to hypoxia glutarylation, also use mitochondrial intermediates, including can promote the conversion of mESCs to the primed state by malonyl-CoA, succinyl-CoA and glutaryl-CoA, respectively, for favoring glycolysis, thereby suggesting an important role for the regulation of protein function (Matilainen et al., 2017; Sabari mitochondrial metabolism in the maintenance of mESCs (Zhou et al., 2017). α-KG is not only a substrate for the family of ten- et al., 2012). Indeed, upregulated mitochondrial transcripts and eleven translocation (TET) dioxygenases, enzymes with DNA increased mitochondrial oxidative metabolism by STAT3 activation demethylation function, but also for the Jumonji-C (JMJC) domain- supports the enhanced proliferation of mESCs and the containing histone demethylase (JHDMs) family of proteins that reprogramming of EpiSCs back to a naïve pluripotent state catalyze histone demethylation (Su et al., 2016; Teperino et al., (Carbognin et al., 2016). In the human context, conventional, 2010). Furthermore, S-adenosyl-methionine (SAM) is a co-factor primed ESCs can transition to a more naïve state in vitro by for histone methyltransferases connecting histone methylation to treatment with histone deacetylase (HDAC) inhibitors (Ware et al., one-carbon metabolism (Mentch et al., 2015) and threonine 2014). The fact that HDACs are largely NAD dependent (further metabolism (Shyh-Chang et al., 2013). discussed below) supports the role of metabolism in stem cell maintenance. Acetylation and deacetylation In addition to its role in stem cell self-renewal, metabolism is also Both histones and other proteins, such as the transcriptional factors/ an important regulator of stem cell identity and fate decisions. For co-factors peroxisome proliferator-activated receptor-γ coactivator 1α DEVELOPMENT REVIEW Development (2018) 145, dev143420. doi:10.1242/dev.143420 Glucose/FFA Mitochondrion Nucleus Acetyl-CoA Acetyl-CoA Acetyl-CoA CoA KA KA A AT T T Ts s Oxaloacetate Citrate Citrate Citrate SIR SIRT T T Ts s NAM NAD TCA cycle α-KG/ Succinate/ Succinate αα-KG α-KG FAD FADH JHDMs JHDMs NADH NAD FADH FAD Met HMTs SAM SAM SAH cycle α-KG Succinate One-C TET TET T Ts s Folate cycle cycle DNMTs SAM SAH Key Acetylation Methylation Fig. 2. Mitochondrial metabolism and epigenetic regulation in stem cells. Mitochondrial TCA cycle intermediate metabolites, such as acetyl-CoA, citrate and α-KG, can be transported to the cytosol and nucleus where they may potentially control stem cell fate via the epigenetic regulation of histones and DNA. Acetyl-CoA is a co-factor of lysine acetyltransferases (KATs), which reverse the activity of the NAD -dependent sirtuins (SIRTs) by catalyzing the acetylation of histones and other proteins. α-KG is the substrate for both histone (JHDMs) and DNA (TETs) demethylases. Mitochondrial one-carbon (One-C) metabolism coupled with cytosolic folate and methionine (Met) cycles generates SAM, which serves as the co-factor of histone (HMTs) and DNA (DNMTs) methyltransferases. FFA, free fatty acid; NAM, nicotinamide; SAH, S-adenosylhomocysteine. (PPARGC1α), forkhead box protein O 1 (FOXO1) and tumor protein reported to decline with age and lead to HSC dysfunction (Brown p53 (TP53/TRP53), can be acetylated on the ε-amino groups of site- et al., 2013; Mohrin et al., 2015). Protein acetylation has been specific lysine residues through N-ε-acetylation. This is a reversible shown to modulate ESC function too. KDAC inhibitors, such as PTM reaction catalyzed by lysine acetyltransferases (KATs) and butyrate, support the extensive self-renewal of mouse and human lysine deacetylases (KDACs, such as sirtuins). KATs and sirtuins are ESCs and promotes their convergence toward an earlier highly sensitive to the concentration of acetyl-CoA and NAD as developmental (more naïve) stage (Ware et al., 2014, 2009). substrates that tightly connect energy metabolism to gene expression The evidence linking KAT activity or acetyl-CoA levels to stem cell (Box 1 and reviewed by Menzies et al., 2016). Recently, control of function is mostly indirect. Recently, in Drosophila, acetyl-CoA levels such PTMs has been found to influence stem cell activity and were found to increase during aging. This increase is accompanied by senescence across a range of different stem cell types. an elevation in global histone acetylation, notably the acetylation of In MuSCs, NAD levels have been linked to myogenic lysine 12 on histone H4 (H4K12ac). Consistent with this notion, a differentiation. Decreased levels of cellular NAD , a co-factor for mutation in the gene encoding the H4K12-specific acetyltransferase the sirtuin deacetylases (Cantó et al., 2015), leads to elevated Chameau extends lifespan in Drosophila (Peleg et al., 2016). Whether H4K16 acetylation (H4K16ac), an activating modification that the effect of acetyl-CoA on Drosophila aging is related to stem cell induces myogenic gene expression (Ryall et al., 2015). In aged function has yet to be investigated. In human and mouse ESCs, mice, a decline in NAD levels in MuSCs leads to cell senescence, glycolysis-generated acetyl-coA has been reported to promote histone and boosting NAD levels with the dietary precursor nicotinamide acetylation during pluripotency (Moussaieff et al., 2015). Inhibition of riboside alleviates MuSCs senescence and extends mouse lifespan acetyl-coA production by blocking glycolysis causes a significant loss (Zhang et al., 2016). These effects are mediated, at least in part, by in pluripotency markers in human and mouse ESCs. It would be the sirtuin family of enzymes. NAD levels have also been shown to interesting to investigate whether cellular acetyl-CoA levels are also be limiting during aging in NSCs and can drive the decline in NSC coupled with stem cell function in mammals in vivo. oligodendrogenesis after cuprizone-induced brain demyelination (Stein and Imai, 2014). In HSCs, the level of H4K16ac decreases Methylation and demethylation with age (Florian et al., 2012) and inhibition of the RhoGTPase The methylation of nucleic acids and proteins can significantly CDC42 restores H4K16ac levels and reverses phenotypes of HSC change their stability and transcription/translation efficiency and aging in transplantation assays (Florian et al., 2012). It is less likely activity. Protein methylation can occur on both lysines and arginines that the decrease of H4K16ac levels in aged HSCs is due to the and generate either mono- or di-methylated forms, and lysine can activation of the NAD -sirtuin signaling axis as the expression of also be tri-methylated. The most well-studied protein methylation is two NAD -dependent sirtuins, SIRT3 and SIRT7, have been histone N-terminal tail methylation, which can either negatively or DEVELOPMENT REVIEW Development (2018) 145, dev143420. doi:10.1242/dev.143420 Box 1. Principal enzymes involved in protein acetylation and methylation Protein acetylation and methylation are two very common post-transcriptional protein modifications involved in the epigenetic regulation of stem cells (reviewed by Aloia et al., 2013; Oh et al., 2014; Portela and Esteller, 2010). The main enzymes in the class of lysine acetyltransferases (KATs) and lysine deacetylases (KDACs), which catalyze histone acetylation (red stars) and deacetylation, respectively, are given on the left. The main enzymes in the class of histone methytransferases (HMTs) and histone demethylases (HDMs), which catalyze histone methylation (purple stars) and demethylation, respectively, are given on the right. SRCs, steroid receptor co-activators. KDACs HMTs Class I: HDAC1, 2, 3, 8 H3K4: KMT2A-E, SETD1A/B, ASCL1, SMYD1-3, SETD7 Class IIA: HDAC4, 5, 7, 9 H3K9: SUV39H1/2, EHMT2, EHMT1, SETDB1-2, PRDM2 Class IIB: HDAC6, 10 H3K27: EZH2 Class III: SIRT1-7 H3K36: SETD2, NSD1-3, SMYD2, SETMAR Class IV: HDAC11 H3K79: DOT1L H4K20: KMT5A-C, NSD1 KDACs HMTs KATs HDMs KATs HDMs GNAT: KAT2A, KAT2B, HAT1, ATF2 H3K4: KDM1A/B, KDM2A/B, KDM5A-D, RIOX1 MYST: KAT5, KAT6A, KAT6B, KAT7 H3K9: KDM1A, KDM3A/B, KDM4A-D, SRCs: NCoA-1, NCoA-2, NCoA-3 KDM7A, PHF8 p300/CBP: EP300, CREBBP H3K27: KDM6A/B, PHF8 TAF1 H3K36: KDM2A/B, KDM4A-C GTF3C-α H3K79: not described CLOCK H4K20: not described positively affect gene transcriptional efficiency (Booth and Brunet, involved in stem cell aging. H3K4me3 (histone trimethylation) is a 2016; Teperino et al., 2010). DNA methylation and demethylation marker of gene activation and increases across HSC identity and PTMs are catalyzed reversibly by DNA methyltransferases self-renewal genes with age, which might explain the observed (DNMTs) and TET enzymes, respectively. Reversible histone increase of HSC numbers in mouse aging (Sun et al., 2014). In methylation can be catalyzed by histone methyltransferases (HMTs) contrast, H3K4me3 in MuSCs decreases with age, as the repressive and histone demethylases (HDMs, such as JHDMs). Importantly, histone methylation H3K27me3 increases (Liu et al., 2013). both DNA and histone methyltransferases use SAM as a substrate, Metabolites that modulate HMT and HDM activity can also impact whereas demethylases use α-KG (Fig. 2, Box 1). Therefore, these on stem cell function and fate decisions. Reductions in α-KG levels in modifications are strictly dependent on the availability of response to the knockdown of phosphoserine aminotransferase 1 mitochondrial metabolites (reviewed by Matilainen et al., 2017). (PSAT1) impairs mESC self-renewal and induces differentiation, Both DNA and histone methylation regulate stem cell function. mediated by lower DNA 5′-hydroxymethylcytosine levels and For instance, deficiency in DNA methyltransferase 3A and/or 3B increased histone methylation (Hwang et al., 2016). In fact, there is (DNMT3A/B) impairs the differentiation potential of HSCs evidence to suggest that pluripotency in mESCs might be regulated (Challen et al., 2014; Mayle et al., 2015). Conversely, reducing by the ratio of α-KG to succinate by virtue of its effect on H3K27me3 the function of the DNA demethylase TET2 by ascorbate depletion levels (Carey et al., 2015). Both α-KG and succinate are metabolites in mice increases HSC frequency and function, which leads to generated as a result of TCA metabolism in the mitochondrial matrix the acceleration of leukemogenesis (Agathocleous et al., 2017). (Fig. 2). Similarly, regulation of DNA and histone methylation by TET2 restoration, or vitamin C treatment, promotes HSC DNA SAM is also important in maintaining hESC and iPSC function. demethylation, promotes differentiation, and blocks leukemia Methionine deprivation rapidly decreases intracellular SAM, progression (Cimmino et al., 2017). Maintenance of the preventing hESC and iPSC self-renewal and increasing overall euchromatic transcriptional state by inhibition of the euchromatic differentiation potency, and eventually leading to cell apoptosis histone-lysine N-methyltransferase 2 (EHMT2, also known as (Shiraki et al., 2014). Depletion of intracellular SAM is also seen after G9A), delays HSC differentiation (Ugarte et al., 2015). However, in threonine deprivation in mouse ESCs, where it leads to slowed stem MuSCs, an H4K20 dimethyltransferase, lysine methyltransferase cell growth and increased differentiation (Fig. 2) (Shyh-Chang et al., 5B (KMT5B), maintains stem cell quiescence by promoting the 2013). formation of facultative heterochromatin. Deletion of KMT5B induces transcriptional activation, further resulting in abnormal The mitochondrial unfolded protein response and stem cell MuSC activation and differentiation. This leads to stem cell aging depletion and impaired long-term muscle regeneration Maintenance of mitochondrial function relies on the coordinated (Boonsanay et al., 2016). Histone methylation also appears to be expression of mitochondrial- and nuclear-encoded mitochondrial Acetylation Methylation DEVELOPMENT REVIEW Development (2018) 145, dev143420. doi:10.1242/dev.143420 proteins. An altered balance between protein expressions from 2005). Mitochondrial DNA (mtDNA) integrity plays an important these genomes can result in proteotoxic stress and the subsequent role in stem cell fate decisions; NSCs isolated from mice deficient accumulation of misfolded proteins within the mitochondria. for 8-oxoguanine DNA glycosylase (OGG1; the enzyme essential When this occurs, a mitochondrial unfolded protein response, for mtDNA damage repair) accumulate mtDNA damage and shift mt termed the UPR , is triggered (reviewed by Jovaisaite et al., 2014). their differentiation trajectory toward an astrocytic lineage at the This response likely synchronizes mitochondrial function to expense of neurogenesis (Wang et al., 2011). mtDNA defects have cellular homeostasis through the activation of a mitochondrion-to- also been observed in human stem cell aging (McDonald et al., nucleus retrograde signaling pathway, such as through prohibitin 1 2008; Taylor et al., 2003) and age-associated mitochondrial DNA (PHB) and 2 (PHB2) and/or c-Jun N-terminal protein kinase mutations have been reported to lead to abnormal cell proliferation (JNK2; MAPK9) and the protein kinase RNA-activated (PKR; and apoptosis in human colonic crypts (Taylor et al., 2003). The EIF2AK2)-activating transcription factor 4 (ATF4) pathway frequency of mtDNA defects is also greater in iPSCs generated from mt (Quirós et al., 2017). Overall, the UPR increases the expression aged compared with young people (Kang et al., 2016). However, of mitochondrial chaperones and proteases, and allows for a owing to limitations in the availability of human tissue and a lack of compensatory restoration of mitochondrial function following robust stem cell markers, the direct link between mtDNA mutations cellular stress (Jensen and Jasper, 2014; Jovaisaite et al., 2014; and stem cell function in vivo remains to be fully elucidated. Lin and Haynes, 2016). Clear evidence for a causal relationship between mtDNA mt Activation of the UPR response has been shown to have mutations and aging is provided by the nuclear-encoded mtDNA beneficial effects in multiple species (Jovaisaite and Auwerx, polymerase γ (POLG) knockout mouse model in which 2015). For instance, disrupting subunits of the mitochondrial ETC, spontaneous mutations or replication errors lead to the which stimulates the imbalance of the mito- and nuclear-encoded accumulation of mtDNA mutations, severe OXPHOS deficiency mt OXPHOS proteins and the induction of UPR , leads to overall and premature aging (Kujoth et al., 2005; Trifunovic et al., 2004). lifespan extension in yeast, worms, flies and mice (Durieux et al., Similar to the situation in physiological aging, stem cell deficiencies 2011; Houtkooper et al., 2013; Lee et al., 2003; Liu et al., 2005; were observed in multiple tissues of the POLG mice. mtDNA mt Owusu-Ansah et al., 2013). Recently, the UPR pathway was mutations inhibit early differentiation of HSCs (Norddahl et al., shown to regulate stem cell function, and the lifespan-extending 2011), resulting in abnormal myeloid lineages in the mutant mice mt effects of UPR stimulators such as nicotinamide riboside was (Ahlqvist et al., 2012; Chen et al., 2009). POLG mice have fewer linked in part to the improvement of stem cell function in aged mice quiescent NSCs (Ahlqvist et al., 2012), as well as increased levels of (Zhang et al., 2016). apoptosis, decreased cell proliferation and impaired SC-derived Mitochondrial stress, which can be stimulated by treating NSCs intestinal organoid formation (Fox et al., 2012). Moreover, POLG- with the bile acid tauro-ursodeoxycholic acid (TUDCA), generates a mutant cells have a markedly impaired capacity for reprogramming mitochondrial ROS-dependent retrograde signal that modulates during the generation of iPSCs (Hämäläinen et al., 2015). Although NSC proliferation and differentiation (Xavier et al., 2014). these studies link mtDNA mutations to stem cell dysfunction and However, because of the implication of TUDCA in endoplasmic aging, the stem cell defects in POLG mice do not appear to reticulum (ER) stress (Malo et al., 2010), it was unclear until recapitulate accurately the pace of physiological aging, as the level recently whether a mitochondrial-specific retrograde signal exists in of mtDNA mutations seen in these models is much higher than that stem cells and, if so, whether it regulates stem cell function. seen during the normal aging process (Norddahl et al., 2011). Supplementing mouse chow with nicotinamide riboside has been Therefore, although the levels of mtDNA mutations increase in aged mt shown to induce the UPR to prevent MuSC, NSC and melanocyte stem cells, it remains unclear whether this increase in mtDNA stem cell (McSC) senescence (Zhang et al., 2016). In MuSCs of mutations plays a fundamental role in stem cell aging. aged mice, nicotinamide riboside rescues cellular NAD depletion mt and thereby activates a SIRT1-dependent UPR signal to improve Influence of mitochondrial ROS on stem cell fate mitochondrial function and attenuate senescence (Zhang et al., Mitochondrial ROS are primarily generated from electron leakage 2016). Similarly, increased levels of NAD achieved via the from the mitochondrial OXPHOS complexes I and III (Box 2), overexpression of NAMPT, the rate-limiting NAD salvage which damages all components of the cell, including DNA, lipids enzyme, reduced cell senescence in aged MSCs (Ma et al., 2017). and proteins. Dysfunction of the mitochondrial respiratory chain In HSCs, SIRT7 has been shown to mediate a regulatory branch of and inefficient OXPHOS may lead to more electron leakage and mt the UPR and to maintain HSC function in aging (Mohrin et al., further increases in ROS generation, resulting in a detrimental cycle mt 2015). Therefore, some level of UPR signaling may help maintain that causes eventual, irreversible damage to cells and contributes to stem cell function during aging, possibly by preventing senescence. aging (Harman, 1972). mt However, constitutive activation of the UPR , with tissue-specific One of the first observations that suggested a role for ROS in cell loss of the mitochondrial chaperone protein HSP60 (HSPD1), can aging was that the replicative lifespans of in vitro cultured cells were also have detrimental effects, and lead to the loss of stemness in significantly extended by culturing the cells in a low-oxygen ISCs (Berger et al., 2016). Further studies will be needed to address environment, which might be due to less ROS generation (Packer mt how the relative level of UPR signaling affects stem cells and the and Fuehr, 1977; Parrinello et al., 2003). Mice with mutations in the extent to which this is context dependent (Fig. 3). DNA damage sensor ataxia telangiectasia (ATM) show a defect in HSC function that is associated with elevated ROS production, and Mitochondrial DNA mutations and stem cell function treatment with the anti-oxidant N-acetyl-L-cysteine (NAC) restored The mitochondrial genome encodes 37 genes, including 13 of the HSC function in these mice (Ito et al., 2004). A similar increase in OXPHOS subunits, two rRNAs and 22 tRNAs. The accumulation ROS production and DNA damage was seen in Bmi1-deficient of mitochondrial mutations has been observed in both rodent and mice, which were also rescued by NAC treatment (Liu et al., 2009). human tissues in vivo during aging (Cortopassi and Arnheim, 1990; Furthermore, FOXO proteins, which are key mediators in ROS Pikó et al., 1988), as well as in in vitro cell culture (Coller et al., signaling, may play essential roles in the response to physiological DEVELOPMENT REVIEW Development (2018) 145, dev143420. doi:10.1242/dev.143420 NAD boosters Mitochondrion Nucleus (e.g. NR and NMN) ETC + + + NAD NAD NAD SIR SIRT T1 1 T Transcr ranscription iption Mitochondrial dynamics ??? ??? ??? Mitogenesis ??? A A A ATF4 TF4 Mitonuclear mt JNK2, PKR UPR protein imbalance T Transcr ranscription iption ETC ??? PHB/PHB2 Mito-translation Unfolded proteins Chaperones and proteases Proteotoxic stress Cell cycle regulators, Proliferation, e.g. cyclin-CDKs, CDKNs delayed senescence mt Fig. 3. UPR and stem cell regulation. Mitochondrial electron transport chain proteins are encoded by both the nuclear (green) and mitochondrial (red) genomes. Mitonuclear protein imbalance and proteotoxic stress, mitochondrial dynamics, and mitogenesis can all lead to mitochondrial stress, which activates mt mt the mitochondrial unfolded protein response (UPR ). Retrograde UPR signaling, through prohibitin 1 and 2 (PHB and PHB2) and/or c-Jun N-terminal protein kinase (JNK2) and the protein kinase RNA-activated (PKR)-activating transcription factor 4 (ATF4) pathway (Quiros et al., 2017) can specifically regulate mt nuclear gene expression to generate more chaperones and proteases to alleviate proteotoxic stress. UPR -induced gene expression changes also lead to stem cell proliferation and a delayed senescence response. Pathways with the question marks are speculative and require further experimental confirmation. Solid and dashed arrows indicate direct and indirect pathway/links, respectively. NR, nicotinamide riboside; NMN, nicotinamide mononucleotide. oxidative stress and thereby preserve HSC function by upregulating phenotypes in mtDNA mutant mice by affecting mechanisms antioxidant gene expression (Tothova et al., 2007). beyond redox status. Finally, there are an increasing number of In POLG mice, the deficiencies of NSC and HSC function were examples in which ROS appears to play a positive and necessary also rescued by supplementation with NAC (Ahlqvist et al., 2012). signaling role in stem cell biology (Bigarella et al., 2014; Hameed NAC also restored the ROS-mediated deficiency of POLG-mutant et al., 2015; Maryanovich et al., 2015). Altogether, the effect and cells to be reprogrammed into iPSCs (Hämäläinen et al., 2015), detailed mechanism of ROS in stem cell function still needs further again suggesting the effects of ROS signaling in mediating the investigation. balance between quiescent and active status of stem cells. Some studies suggest that mtDNA mutations might cause slight alterations Role of mitophagy and mitochondrial dynamics on stem cell in redox status, thus affecting stem cell fate decisions (Ahlqvist fate et al., 2012). Indeed, physiological ROS appears to be important for Mitochondria have been shown to be asymmetrically segregated mediating NSC fate decisions (reviewed by Bigarella et al., 2014). during stem cell division (Katajisto et al., 2015). This asymmetric In NSCs, mitochondrial fusion and fission (further discussed allocation of mitochondria appears to be a unique feature of below) triggers ROS signaling to moderate self-renewal and adult stem cells that enables the exclusion of older mitochondria. differentiation via NRF2 (also known as nuclear factor, erythroid Beyond cell division, mitochondria in quiescent stem cells are 2 like 2, NFE2L2)-mediated mito-nuclear retrograde signaling subject to mitochondrial dynamics, involving fusion/fission and (Khacho et al., 2016). mitochondria-specific autophagy, termed mitophagy. Recently, Similar to the role of the mtDNA mutations as previously mitochondrial dynamics has been linked to stem cell function and discussed, there is much controversy regarding the effect of aging. mitochondrial ROS on stem cell dysfunction and aging due to a In general, compared with post-mitotic cells, mitochondrial number of observations. First, long-lived species do not always networks are fragmented in stem cells of various types, including demonstrate lower levels of ROS and the accompanying oxidative ESCs (Folmes et al., 2011; Zhou et al., 2012). This normally damage (Andziak et al., 2006; Chen et al., 2007). For example, a rise suggests a high level of mitochondrial fission and a low level of in ROS increases the lifespan of worms (Yang and Hekimi, 2010; mitochondrial fusion events. Indeed, DRP1 (dynamin-related Zarse et al., 2012). Second, it is known that the widely used anti- protein 1; also known as DNM1L)-dependent mitochondrial oxidative reagent NAC affects physiological processes beyond ROS fission has been shown to be necessary for cell reprogramming scavenging. Therefore, NAC treatment could benefit stem cell (Prieto et al., 2016). However, two studies also illustrate the DEVELOPMENT *– O O 2 2 QH H III Cyt c II I IV ½O *– H O FADH O O 2 2 2 NADH ADP TCA *– 2 ATP Acetyl-CoA REVIEW Development (2018) 145, dev143420. doi:10.1242/dev.143420 Box 2. Reactive oxygen species generation The mitochondrial ETC consists of five respiratory complexes (I-V), which are composed of proteins encoded by both nuclear (green) and mitochondrial (red) genomes. Mitochondrial ROS (blue lightning bolt) are mainly generated from complex I and III of the ETC. Cyt c, cytochrome c;QH , ubiquinol. potential importance of mitochondrial fusion proteins in renewal of HSCs (Vannini et al., 2016). Furthermore, autophagy maintaining stem cell function. In HSCs, mitofusin 2 (MFN2), a maintains HSC function in aged mice (Ho et al., 2017), and is also protein involved in promoting mitochondrial fusion and likely to be involved in the metabolic switch during iPSC mitochondria-ER tethering, increases the buffering capacity for reprogramming (Ma et al., 2015). 2+ intracellular Ca and thereby inhibits the translocation and Interestingly, SIRT1, FOXO and mTORC1 signaling have all transcriptional activity of the nuclear factor of activated T cells been implicated in the regulation of autophagy during stem cell (NFAT) (Luchsinger et al., 2016). The inhibition of NFAT is activation, reprogramming and survival under stress (Tang and essential for the maintenance of lymphoid potential of HSCs. In Rando, 2014; Warr et al., 2013; Wu et al., 2015). Whether these NSCs, mitochondrial dynamics (fusion and fission) regulates NSC proteins and signaling pathways are also linked to mitophagy, and identity, proliferation, and fate decisions by orchestrating nuclear play a similar role to autophagy, in stem cells still needs transcriptional programs. NSC-specific deletion of either OPA1 or confirmation, yet mitophagy and mitochondrial metabolic MFN1/2 induces ROS and NRF2-dependent retrograde signaling, pathways might be tightly conjugated and are likely to regulate which suppresses NSC self-renewal and promotes differentiation, stem cell function and aging in a coordinated manner. leading to age-dependent NSC depletion, defects in neurogenesis, and cognitive impairment (Khacho et al., 2016) (Fig. 1). Conclusions and perspective When mitochondrial damage or unfolded protein accumulates in In many early studies, the evidence for an association between mt the mitochondria, the UPR activates mitochondrial chaperones mitochondria and stem cell function and especially aging was and proteases to help protein folding and cleavage. Mitochondrial mostly correlative, such as the increase of mtDNA mutations, ROS fusion/fission might then be activated to dilute or separate damaged levels and the decline in stem cell function with aging. Increasingly, proteins for further degradation. Simultaneously, the clearance of however, causative connections are being established. Mitochondria mitochondria through mitophagy may help to dispose of damaged regulate stem cell function and fate decision through different proteins. In fact, evidence for the importance of autophagy/ strategies: mitochondrial metabolism generates metabolites that mitophagy for the maintenance of stem cell homeostasis is serve as DNA and protein modification substrates, such as NAD , accumulating. For instance, autophagy levels are higher in HSCs acetyl-CoA, citrate, α-KG and fatty acids. Through epigenetic and skin stem cells compared with the surrounding cells (Salemi modulation of gene expression, the availability of these key et al., 2012). In the dentate gyrus of the mouse brain, areas enriched mitochondrial metabolites directly regulates stem cell fate mt for NSCs appear to have higher rate of autophagy (Sun et al., 2015). decisions and aging. Moreover, UPR , mitochondrial dynamics Moreover, several recent studies suggest a causative link between and stress can generate retrograde signals from the mitochondria to mitophagy and the prevention of stem cell aging (García-Prat et al., control nuclear gene expression. With stem cell mitochondria- 2016; Ho et al., 2017; Vazquez-Martin et al., 2016). Failure of nuclear cross-talk, mitochondria not only exert a strict quality autophagy in aged MuSCs, or the genetic impairment of autophagy control but may also impact gene expression patterns in order to in young MuSCs, causes entry into senescence by loss of alter cell fate decisions and physiological functions during aging. proteostasis, increased mitochondrial dysfunction and oxidative Despite much progress, this field of research is still in its infancy, stress, resulting in a decline in the function and number of MuSCs and there are many research questions that should now be answered. (García-Prat et al., 2016). However, MuSC senescence can be Importantly, we know that metabolism and mitochondrial function reversed through the re-establishment of autophagy (García-Prat are different amongst stem cell types and can change with stem cell et al., 2016). Loss of autophagy in HSCs causes the accumulation of dynamics. However, it is still not clear to what extent mitochondria mitochondria and an activated metabolic state that drives determine stem cell properties and fate decisions. Also, the accelerated myeloid differentiation and impairs HSC self-renewal mechanisms that underpin the heterogeneity of metabolic and activity and regenerative potential (Ho et al., 2017; Mortensen et al., mitochondrial properties in different stem cell types remains 2011). In agreement with this, lowering the mitochondrial activity undefined. Another interesting topic is stem cell aging, as it by uncoupling the ETC stimulates autophagy and drives self- represents not only a fundamental scientific issue but is also directly DEVELOPMENT REVIEW Development (2018) 145, dev143420. doi:10.1242/dev.143420 organismal level by extending lifespan (Rera et al., 2011; Zhang et al., 2016). This is an exciting prospect, and one that puts the Box 3. Mitochondrial therapeutics in stem cells Targeting mitochondrial function represents a possible treatment interplay between mitochondria and stem cells at the center stage of strategy for some inherited genetic diseases, metabolic syndromes the aging field. and neurodegenerative diseases. There are several ways to improve mitochondrial function, for example by targeting sirtuins, AMP-activated Competing interests protein kinase (AMPK), mTOR, NAD metabolism, nuclear receptors The authors declare no competing or financial interests. (such as PPARs and estrogen-related receptors), transcriptional factors/ co-factors (such as PPARGC1α, FOXO, NCORs), along with activators Funding mt of UPR and mitochondrial fusion/fission or mitophagy (reviewed by H.Z. is the recipient of a fellowship from the CARIGEST SA and his research is Sorrentino et al., 2017). Among these, however, there are very few supported by Sun Yat-sen University. K.J.M. is supported by the Canadian Institutes descriptions of how these treatment strategies affect stem cells of Health Research and Kidney Foundation of Canada. The research of J.A. is specifically. It was recently shown that PPARδ agonists improve supported by the École Polytechnique Fédérale de Lausanne, the National Institutes hematopoietic stem cell function by improving fatty acid oxidation (Ito of Health (R01AG043930), SystemsX (SySX.ch 2013/153), the Velux Stiftung et al., 2012). This finding highlights the therapeutic potential of PPARδ (Switzerland), and the Swiss National Science Foundation (Schweizerischer Nationalfonds zur Fö rderung der Wissenschaftlichen Forschung; 31003A-140780). agonists in improving the efficacy of bone marrow transplantation and the Deposited in PMC for release after 12 months. treatment of hematological malignancies. 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