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ATP5B regulates mitochondrial fission and fusion in mammalian cells ATP5B regulates mitochondrial fission and fusion in mammalian cells
Seo, Hyemin; Lee, Icksoo; Chung, Hak Suk; Bae, Gyu-Un; Chang, Minsun; Song, Eunsook; Kim, Min Jung
2016-05-03 00:00:00
MOLECULAR & CELLULAR BIOLOGY ANIMAL CELLS AND SYSTEMS, 2016 VOL. 20, NO. 3, 157–164 http://dx.doi.org/10.1080/19768354.2016.1188855 ATP5B regulates mitochondrial fission and fusion in mammalian cells a† b† c,d e a a‡ Hyemin Seo , Icksoo Lee , Hak Suk Chung , Gyu-Un Bae , Minsun Chang , Eunsook Song and a‡ Min Jung Kim a b Department of Biological Sciences, Sookmyung Women’s University, Seoul, Korea; College of Medicine, Dankook University, Cheonan, South Korea; Center for Theragnosis, Biomedical Research Institute, Korea Institute of Science and Technology, Seoul, South Korea; Department of Biological Chemistry, Korea University of Science and Technology (UST), Seoul, South Korea; College of Pharmacy, Sookmyung Women’s University, Seoul, South Korea ABSTRACT ARTICLE HISTORY Received 18 April 2016 Mitochondria are essential organelles that produce ATP and regulate cell growth, proliferation, and Accepted 3 May 2016 cell death. To maintain homeostasis, fusion and fission of mitochondria must be strictly regulated. Even though oligomerization of ATP synthase could affect the mitochondrial morphology, the exact KEYWORDS: mechanism is not clear. We confirmed that structure and function of ATP5B, which is a major Mitochondria ATP5B fission component of the catalytic center of ATP synthase complexes, are closely connected to the fusion mitochondrial morphology. ATP5B itself can enhance elongation of mitochondria. Moreover, mutations of the threonine residue at β-barrel domain, and the serine residue at nucleotide- binding domain of ATP5B, produce the opposite effect on the fission and fusion of mitochondrial networks. Here, we demonstrate that ATP5B is clearly involved in the mechanism of regulation for mitochondrial fusion and fission in mammalian cells. Introduction Many human diseases are related to mitochondrial dynamics deficiencies (Westermann 2010). Evidence In the complete cycle from embryogenesis to senescence, shows the implication of mitochondrial dynamics in mitochondria play crucial roles in a broad range of events. various pathologies like NARP (Neuropathy, Ataxia and They are dynamic organelles which constantly undergo Retinitis Pigmentosa) and MILS (Maternally Inherited fission and fusion (Chan 2006). The balance of mitochon- Leigh Syndrome) (Alexeyev et al. 2008; Rojo et al. 2006; drial fission and fusion leads to the quality control of mito- Sciacco et al. 2003). However, it is still unknown chondria in cellular repair processes which are involved in whether altered mitochondrial shape and size are a the regulation of signaling mechanism, control of cell cause or a consequence of these pathologies. Disturb- ances of essential genes related to mitochondrial cycle, cell growth, as well as apoptosis (Margineantu dynamics result in mitochondrial dysfunction (Chen et al. 2002; Chandel 2014; Zorofchian Moghadamtousi et al. 2003; Chen et al. 2006; Waterham et al. 2007). The et al. 2014). Cells in the fission state contain small mito- mutation of OPA1, as a main component of the inner chondria, whereas cells in the fusion state have large, membrane fusion process, was identified as a major tabulated mitochondria (Li et al. 2015). Fragmented mito- cause in autosomal dominant optic atrophy, a common chondria impair the integration of the mitochondrial form of inherited childhood blindness (Baburamani network and release cytochrome c to activate the apopto- et al. 2015). Among the outer membrane fusion machin- tic pathway. Fusion of mitochondria extends the internal ery, the mutation of MFN2 is well known to be related to mitochondrial networks and produce ATP even in remote a neurodegenerative disorder, Charcot-Marie-Tooth parts of the cells. Therefore, fragmented mitochondria disease type 2A, which is characterized by the gradual display early signs of apoptosis, and fused mitochondria degeneration of peripheral neurons (Ching et al. 2010; are shown to have anti-apoptotic effect. The switching Marchesi et al. 2011). Moreover, recent studies showed behavior of mitochondria is intimately linked to their that neurodegenerative diseases, including Parkinson’s various functions, and the balance between fusion and (Arduino et al. 2013; Osellame & Duchen 2013) and Alz- heimer’s disease, were characterized by alteration of fission determines the survival of mitochondria as well mitochondrial dynamics (Cai & Tammineni 2016). as whole cells (Zhao et al. 2010). CONTACT Min Jung Kim minkim@sookmyung.ac.kr Equally contributed as first author Equally contributed as corresponding author © 2016 Korean Society for Integrative Biology 158 H. SEO ET AL. The electron transport chain complexes (complex I to Materials and methods IV) and F F ATP synthase (ATP synthase) carry out the 1 0 Reagents oxidative phosphorylation (OXPHOS) process in the inner membrane of mitochondria. The ATP synthase All chemicals were purchased from Sigma-Aldrich (USA) complex is constituted by F part (subunits unless otherwise specified. a, b, g, d, and 1) and F parts (subunits b, F6, d, f, a, A6L, and OSCP), and uses the electrochemical proton gra- Plasmid DNA construction dient produced by the electron transport chain com- plexes, to synthesize ATP (Habersetzer et al. 2013). For site-directed mutagenesis, AGT at 529 bp was replaced Dimerization of ATP synthase to form oligomers could by GCT to substitute Ala177 for Ser177, and ACC at 391 bp be responsible for the formation of cristae and mitochon- to GCT to substitute Ala107 for Thr107, from rat ATP drial morphology (Paumard et al. 2002). In yeast, the synthase β subunit gene. To construct the FLAG and alteration of mitochondrial morphology was observed EGFP vector that contains the wild-type and the mutant after the disruption of ATP synthase oligomerization β subunit gene, each gene was cloned into pCMV-Taq2b (Arnold et al. 1998). Moreover, deletion of subunit e and and pCMV-EGFP-N1 vector (Invitrogen, USA). g of ATP synthase F1 in yeast leads to no dimerization and oligomerization where the classical cristae shape did not exist; this was replaced by onion-shape mitochon- Cell culture and transfection dria, although the enzyme activity is fully functional. These HEK 293 T cells (CRL-11268, ATCC, USA) were grown in data support the idea of the correlation between the DMEM with 10% fetal bovine serum (Invitrogen, USA), organization of ATP synthase and mitochondrial mor- 100 units/mL penicillin, and 100 µg/mL streptomycin, phology (Habersetzer et al. 2013). Two previous publi- under standard conditions. Cells were seeded into 6- cations suggested that ATP5B might be involved in well plates and grown for 24 h prior to transfection. mitochondrial dynamics. Wang et al. demonstrated that HEK cells were transfected with 1 µg of plasmids using small molecule M1 promotes the mitochondrial fusion the Turbofect™ transfection reagent (QIAGEN, USA), by increasing ATP5A/B (Wang et al. 2012) and Jonckheere according to the manufacturer’s instructions. et al. have reported mitochondrial fragmentation and dys- function from a mitochondrial complex V (ATP5B included) deficient mutations in patient fibroblasts (Jonc- Western blotting kheere et al. 2011; Jonckheere et al. 2012). Such changes in mitochondrial shape have been shown to directly impact Whole-cell lysates were prepared with CETi lysis buffer cell differentiation and proliferation (Ahn & Metallo 2015); (Translab, Korea); protein lysate samples were quantified however, little is known as to how ATP5B regulates the with a Bradford assay (Bio-Rad, USA), and 20–30 µg of the phenotype and metabolic characteristics of mitochondria. protein lysates were separated on 10–15% sodium The goal of this study was to determine how ATP5B dodecyl sulfate–polyacrylamide gels. The proteins were affects the mitochondrial shape and metabolism in HEK then transferred onto polyvinylidene difluoride mem- cells, and to identify whether such changes regulate the cel- branes (BD Biosciences, USA). The membranes were lular maintenance and energy levels. Here, we report that blocked with ProNA Phospho-block solution (Translab, ATP5B is accompanied by mitochondrial fusion and Korea) and incubated with primary antibodies against fission, and these phenotypes are dependent on the anti-β tubulin (Sigma, USA), anti-Drp1 (Santa Cruz, domains of ATP5B which might bind the key regulators of USA), anti-mitofusin2 (Santa Cruz, USA), anti-FLAG mitochondrial dynamics. Our results demonstrate that the (Sigma, USA), and anti-GFP (Invitrogen, USA) (AbFrontier, β-barrel domain, which is highly conserved, plays a vital Korea) overnight at 4°C. The membranes were washed role in the mitochondrial fusion, and the point mutation five times with 10 mM Tris-HCl (pH 7.5) containing 150 at T107 within this motif can produce profound changes mM of NaCl and 0.1% Tween-20 (TBST), and further incu- like short and fragmented mitochondrial phenotypes bated with horseradish peroxidase-conjugated goat anti- which lead to apoptosis. However, the effects of S177 rabbit IgG and anti-mouse IgG (Thermo Scientific, USA) mutation in the nucleotide-binding domain differ from for 1 h at room temperature. After the removal of T107, demonstrating elongated mitochondrial networks excess secondary antibodies, the membranes were and attenuating apoptosis. These data indicate that the washed six times with TBST, and specific binding was phenotypic changes can be dependent on the context of detected with SuperSignal West Pico Chemiluminescent the mutations from the differential interaction with regulat- Substrate (Thermo Scientific, USA) according to the man- ory protein in mitochondrial dynamics. ufacturer’s instructions using LI-COR (LI-COR, USA). ANIMAL CELLS AND SYSTEMS 159 Cell viability assay Statistical analysis HEK cells were cultured in 24-well plates and transfected with The data are presented as the mean and standard deviation ATP synthase β subunit DNA plasmid for 24 h. Cell viability of the results from three independent experiments (n =3). was assessed with 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl- The statistical significance of the experimental differences 2H-tetrazolium bromide (MTT; AMRESCO, USA). The culture was determined with two-way analysis of variance. P medium was carefully removed from each well, replaced values less than .05 were considered statistically significant, with 0.4 mg/mL of MTT solution, and the cells were incubated and significance is indicated on the graphs with an asterisk. P for 2 h at 37°C. The MTT solution was removed and 500 µL of values less than .01 are indicated with two asterisks. DMSO was then added to each well to dissolve the formazan crystals. Absorbance was measured at 550 nm with a Spectra- Results and discussion Max® M5 microplate reader (VWR, USA). Structure of ATP5B reveals the importance of β- barrel and nucleotide-binding domain Mitochondrial respiration measurement During mitochondrial ATP synthesis, F -ATPase under- Mitochondrial respiration was measured as described, with goes a series of conformational changes to produce a modifications (Huttemann et al. 2012). Cells were permea- high level of ATP for cellular function. Through BLAST bilized using digitonin (6 µg/mg protein) and mitochon- analysis for ATP5B, we retrieved rat ATP5B sequences drial respiration was measured in the presence of (BC099743), which has the 94% homology to human substrates for electron transport chain complexes I and II protein, to identify the conserved domain and structure. (10 mM pyruvate + 3 mM malate and 10 mM succinate, Protein sequences were analyzed using the web-based respectively) at 30°C using a Clark-type oxygen electrode InterPro software program and NCBI-conserved domain (Oxygraph Plus System, Hansatech Instruments, UK). The server (Figure 1(a)). ATP5B contains a β-barrel domain, mitochondria were activated by addition of 1 mM ADP fol- a nucleotide-binding domain, and an ATP synthase α/β lowing the addition of ATP synthase inhibitor oligomycin chain domain. The phosphorylation sites were searched (200 µM) and oxidative phosphorylation uncoupler FCCP for regulation of the activity of ATP5B. The web-based (200 µM, carbonyl cyanide 4-(trifluoromethoxyphenylhy- NetPHOS2 phosphorylated site prediction program was drazone). Non-mitochondrial oxygen consumption, as applied to identify the putative phosphorylation site in determined after addition of KCN, was subtracted from ATP5B. Serine at 106 and threonine at 107 identified in the respiration data. The mitochondrial respiration rate is the β-barrel domain, S177 in the α subunit interaction defined as consumed O (nmol)/min × total protein (mg). interface of nucleotide-binding domain, and T140 in the nucleotide-binding domain have been identified as Cellular ATP level measurement potential targets for several protein kinases. Specially, previous studies showed that phosphorylation at S106 The cells were collected by scraping and immediately and T107 site is associated with iron uptake in rat heart frozen in liquid nitrogen to prevent ATP degradation. mitochondria (Min et al. 2013). From crystal structures ATP concentration was determined by emitted lumines- (PDB # 1MAB, Bianchet et al. 1998), S177 is closely cence using ATP bioluminescence assay kit HS II (Roche, located between α and β subunits, and this location USA) according to the manufacturer’s recommendations implies the importance of the nucleotide-binding site (Lee et al. 2010). The ATP concentration is defined as (Figure 1(b)). Therefore, we chose T107 site for β-barrel nmol of ATP/total protein (mg). domain, and S177 site for nucleotide-binding domain, to reveal the regulatory mechanism of ATP5B function Confocal live imaging and measurement of in mitochondria. The gray flags are indicative of the mitochondrial length mutated residues at T107A and S177A in Figure 1(a). For the mitochondria imaging, DsRed2-mito cells and DsRed2-mito/ATP5B-WT, ATP5B-S177A, ATP5B-T107A co- Overexpression of S177A and T107A displays expressing HEK cells were seeded onto 0.1% poly-D- different phenotypes in mitochondrial fusion and lysine-coated 24-mm round coverslips and incubated for fission 24 h. Images were obtained with a LSM-710 confocal microscope (Carl Zeiss AG, Germany). Mitochondrial To characterize the implication of ATP5B in the function length was measured as previously described (Park et al. and organization of ATP synthase in mammalian cells, 2014). FLAG- or EGFP-tagged vector was generated for serine 160 H. SEO ET AL. Figure 1. Analysis of the structure of ATP5B. (a) A schematic representation of ATP5B proteins. Protein sequences were analyzed using the web-based InterPro software program. The gray flags are indicative of the mutated residues at T107A and S177A. The β-barrel domain is shown in black line, the nucleotide binding domain is shown in light orange line, and the ATP synthase α/β chain domain is shown in light green line. (b) Ribbon representation of the crystal structure of ATP5B (PDB # 1MAB, Bianchet et al. 1998). The F -ATP synthase α subunit is shown as pale green ribbon, the F -ATP synthase β subunit as light pink, and the F -ATP synthase 1 1 1 γ subunit as light orange. The serine residues at position 106 and 177, and threonine residue at 107 in ATP5B, are shown as light green in the yellow ovals. substitution at 177 to alanine (S177A), and threonine at other hand, in T107A-overexpressed conditions, mito- 107 to alanine of ATP5B (T107A). T107A and S177A chondrial organization was inverse. Most cells in T107A vectors were transfected into HEK cells. We then cells had fragmented (70%) and punctuated (20%) mito- assayed whether the mitochondrial network morphology chondrial morphology (Figure 2(d), d’). in HEK cells mutated or not in ATP5B using mitochondrial- Point mutation-induced overexpression in ATP5B led targeted dsRed. Mitochondrial network morphology was to the different phenotypes based on the region of classified into four categories. The classical and normal mutation. S177A led to the hyper-fused morphology, mitochondrial morphology is filamentous. Hyper-fused which implies strong mitochondrial elongation activity. morphology is when the mitochondrial tubules are con- Besides, T107A exhibited mitochondrial network frag- nected and traverse the entire cells. Fragmented mor- mentation which occurs with multiple different stress phology is for the short mitochondria (less than 2 μm). factors, including programmed cell death. Small and Punctuated morphology is when the tubular structure is fragmented mitochondria were found to be physically no more visible and is displayed as dots. A statistical and functionally impaired during cell death. Altogether, analysis of the mitochondrial morphology was performed our results suggest a requirement for ATP5B to regulate and is presented in Figure 2(e). mitochondrial fusion and fission events. In EGFP-N1 control conditions, 89% of the cells had Because of these remarkable morphological changes filamentous mitochondrial networks (Figure 2(a), a’). in mitochondrial structure, we examined the expression Cells with fragmented and punctuated mitochondria level of the proteins Mfn2 and Drp1, known to be involved were low (7.8% and 3.3%, respectively). In ATP5B wild- in regulating mitochondrial dynamics (Figure 2(f)). Since type overexpressed conditions, 85% of the mitochondria Mfn2 (mitofusin2) promotes mitochondrial fusion, level displayed filamentous, 8.5% of hyper-fused, and 6.5% of of Mfn2 expression was measured to confirm the highly fragmented morphology (Figure 2(b), b’). Overexpression interconnected mitochondrial networks for ATP5B-WT of ATP5B-WT was enough to induce mitochondrial and ATP5B-S177A. Compared to control cells which elongation activity. However, in S177A-overexpressed were expressed in FLAG-empty vector, Mfn2 was slightly conditions, 86% of the hyper-fused mitochondrial net- increased in ATP5B-WT- and S177A-expressed cells. Inter- works were observed, and 10% had filamentous mor- estingly, T107A-expressed cells reduced 30% of the level phology (Figure 2(c), c’). It is striking that one point of S177A-expressed cells. The fragmented mitochondrial mutation in ATP5B can result in a change to intercon- morphology of T107A-expressed cells seems to be associ- nected tubular mitochondrial morphology by promoting ated not only with decrease in the Mfn2, but also with a the elongation activity. Interconnected mitochondrial 50% increase in the Drp1, a mitochondrial fission networks are known to be beneficial for cell physiology protein that induces outer membrane ‘pinching’ in the and provide an escape from major dysfunction. On the division of tubular mitochondria. ANIMAL CELLS AND SYSTEMS 161 Figure 2. ATP5B is involved in mitochondrial fission and fusion. (a)–(d) and (a’)–(d’). Representative live-cell confocal images of mito- chondria in EGFP-N1 (control), ATP5B-WT-EGFP, ATP5B-S177A-EGFP, and ATP5B-T107A-EGFP expressed HEK cells. Cells were co-trans- fected with mito-dsRed and imaged with a Zeiss confocal 710 microscope. Data shown are representative of three independent experiments. The white box depicts higher magnification of each representative. Green = EGFP-N1 and ATP5B, Red = mito-dsRed. (e) Percentages of the different classes of mitochondrial morphology in control, ATP5B-WT-EGFP, ATP5B-S177A-EGFP, and ATP5B- T107A-EGFP expressed HEK cells. The mitochondria were manually classified on 100 randomly selected cells. Counts are the mean of three independent experiments. (f) Representative Western blots of mitofusin2 (Mfn2), dynamin-related protein 1 (Drp1), FLAG, and β tubulin. HEK cells were transfected with FLAG, ATP5B-WT-FLAG, ATP5B-S177A-FLAG, ATP5B-T107A-FLAG vectors for 24 h, and western blot analysis for Mfn2 and Drp1 levels was performed. Membranes were stripped and re-probed with anti-β tubulin and FLAG. The images are representative of three independent experiments. The amino acid mutations in different domains of apoptotic cell death assay using MTT showed that ATP5B resulted in remarkable mitochondrial remodeling ATP5B-WT attenuated apoptosis (Figure 3, 10% increase that is mediated by the changes in mitochondrial fission of cell viability over that of control, P < .05). As expected, and fusion protein levels. We speculated S177 in the ATP5B-T107A strongly induced apoptosis compared to nucleotide-binding domain and T107 in the β-barrel control (30% decrease of cell viability over that of domain are responsible for mitochondrial fission and control, P < .01), consistent with increased mitochondrial fusion, respectively, and they might provide platforms fragmentation to initiate apoptosis. Interestingly, the for the binding of important regulatory components expression of ATP5B-S177A which caused the hyper- for mitochondrial dynamics. fused mitochondrial phenotype failed to inhibit the process of apoptosis, but attenuated apoptosis com- pared to ATP5B-T107A. As mitochondrial fusion is Overexpression of ATP5B attenuates apoptosis in known to serve for mixing and unifying the mitochon- human HEK cells drial components, the cells with S177 mutation were Next, the cell viability of ATP5B and ATP5B mutant over- rescued from cell death to some extent. expressed HEK cells was determined to examine the These data suggest that ATP5B itself improves cell sur- apoptotic activity of these cells. The quantitative vival through increased mitochondria fusion, and the 162 H. SEO ET AL. ATP5B-WT cells (P < .05). Since the replacement of threo- nine to alanine residue at 107 of ATP5B was accompanied with the short mitochondrial phenotype and apoptosis, it was not surprising to obtain the lower respiratory activity. The structure of ATP5B demonstrates that residue 107 is located on the outside of β-barrel domain where a protein chaperone likely assists in appropriate target membranes. These characteristics could be disrupted by the mutation that leads to impaired mitochondrial dynamics in the mechanism of fusion, lower respiratory capacity, and enhanced apopto- sis. Unlike S107A, there was no significant change in the Figure 3. Cell viability of ATP5B transfected HEK cells. HEK cells respiration of ATP5B-S177A cells compared to the were transfected and incubated with FLAG (control), ATP5B-WT- ATP5B-WT cells. Since lower apoptotic activity and FLAG, ATP5B-S177A-FLAG, and ATP5B-T107A-FLAG for 24 h. The MTT absorbance value on control cells was considered as 100% hyper-fused mitochondrial morphology was detected of the number of viable cells. Each data were the mean of in S177A cells, it was not surprising to have rescued phe- three independent experiments. * denotes a value significantly notype compared to ATP5B-WT-overexpressed HEK cells. different from that of ATP5B-WT (*P < .05, **P < .01) The total ATP contents in the cells were examined in HEK cells (Figure 4(a)) to see whether ATP5B mutations changes in ATP5B can modulate not only the mitochon- cause any changes in cellular energy levels. ATP5B-WT drial morphology, but also apoptosis-related pathways. overexpression slightly augmented ATP level compared to control cells. However, the concentrations of ATP were significantly decreased (P < .05 in both) in S177A- Remodeling of mitochondrial networks sustains and T107A-induced cells compared to ATP5B-WT-over- mitochondrial respiratory activity and efficient expressed cells; also, there was no difference between cellular ATP levels both mutations. These results indicate that any defects on ATP5B could impair the cellular energy status that To determine if conversion of the phenotype affected might be caused by altered ATP synthesis activity or/ the ability of mitochondria to respire, we measured and by change in the consumption of ATP in the cells. the mitochondrial respiration in permeabilized cells In summary, we report here the novel and unexpected (Figure 4(a)). In HEK cells, ATP5B-WT significantly finding that ATP5B has an essential role in regulation of increased respiration compared to control cells in the mitochondrial remodeling, which is required to maintain presence of substrates and ADP, even when they were mitochondrial dynamics and homeostasis. We show that subsequently challenged by oligomycin and FCCP. The β-barrel motif and nucleotide-binding domain can con- point mutation at T107 of ATP5B does decrease the tribute to ATP5B function for fusion and fission, state 3 respiration (ADP added) compared to that of Figure 4. Mitochondrial respiration and cellular energy levels of ATP5B transfected HEK cells. (a) Mitochondrial respiration of the trans- fected cells with EGFP-N1 (control), ATP5B-WT-EGFP, ATP5B-S177A-EGFP, and ATP5B-T107A-EGFP was determined. Respiration was initiated by addition of complex I and II substrates, and state 3 respiration was induced by addition of ADP. Mitochondria were chal- lenged using oligomycin and FCCP subsequently. n =3, *P < .05. (b) Total cellular ATP content was determined with the bioluminescent method. ATP concentration was normalized to total cell protein concentration. n =6, *P < .05 compared to ATP5B-WT. ANIMAL CELLS AND SYSTEMS 163 Chan DC. 2006. 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