Top

Published in:

Open Access 01-03-2012 | Review

Mitochondrial ATP synthase: architecture, function and pathology

Authors: An I. Jonckheere, Jan A. M. Smeitink, Richard J. T. Rodenburg

Published in: Journal of Inherited Metabolic Disease | Issue 2/2012

Abstract

Human mitochondrial (mt) ATP synthase, or complex V consists of two functional domains: F₁, situated in the mitochondrial matrix, and F_o, located in the inner mitochondrial membrane. Complex V uses the energy created by the proton electrochemical gradient to phosphorylate ADP to ATP. This review covers the architecture, function and assembly of complex V. The role of complex V di-and oligomerization and its relation with mitochondrial morphology is discussed. Finally, pathology related to complex V deficiency and current therapeutic strategies are highlighted. Despite the huge progress in this research field over the past decades, questions remain to be answered regarding the structure of subunits, the function of the rotary nanomotor at a molecular level, and the human complex V assembly process. The elucidation of more nuclear genetic defects will guide physio(patho)logical studies, paving the way for future therapeutic interventions.

Abu-Amero KK, Bosley TM (2006) Mitochondrial abnormalities in patients with LHON-like optic neuropathies. Invest Ophthalmol Vis Sci 47:4211–4220PubMed

Ackerman SH (2002) Atp11p and Atp12p are chaperones for F(1)-ATPase biogenesis in mitochondria. Biochim Biophys Acta 1555:101–105PubMed

Ackerman SH, Tzagoloff A (1990) Identification of two nuclear genes (ATP11, ATP12) required for assembly of the yeast F1-ATPase. Proc Natl Acad Sci USA 87:4986–4990PubMed

Adachi K, Oiwa K, Nishizaka T et al. (2007) Coupling of rotation and catalysis in F(1)-ATPase revealed by single-molecule imaging and manipulation. Cell 130:309–321PubMed

Alexeyev MF, Venediktova N, Pastukh V, Shokolenko I, Bonilla G, Wilson GL (2008) Selective elimination of mutant mitochondrial genomes as therapeutic strategy for the treatment of NARP and MILS syndromes. Gene Ther 15:516–523PubMed

Allen RD (1995) Membrane tubulation and proton pumps. Protoplasma 189:1–8

Anderson S, Bankier AT, Barrell BG et al. (1981) Sequence and organization of the human mitochondrial genome. Nature 290:457–465PubMed

Arechaga I, Butler PJ, Walker JE (2002) Self-assembly of ATP synthase subunit c rings. FEBS Lett 515:189–193PubMed

Arnold I, Pfeiffer K, Neupert W, Stuart RA, Schagger H (1998) Yeast mitochondrial F1F0-ATP synthase exists as a dimer: identification of three dimer-specific subunits. EMBO J 17:7170–7178PubMed

Arnold RS, Sun CQ, Richards JC et al. (2009) Mitochondrial DNA mutation stimulates prostate cancer growth in bone stromal environment. Prostate 69:1–11PubMed

Arselin G, Giraud MF, Dautant A et al. (2003) The GxxxG motif of the transmembrane domain of subunit e is involved in the dimerization/oligomerization of the yeast ATP synthase complex in the mitochondrial membrane. Eur J Biochem 270:1875–1884PubMed

Baracca A, Barogi S, Carelli V, Lenaz G, Solaini G (2000) Catalytic activities of mitochondrial ATP synthase in patients with mitochondrial DNA T8993G mutation in the ATPase 6 gene encoding subunit a. J Biol Chem 275:4177–4182PubMed

Belogrudov GI (2009) Recent advances in structure-functional studies of mitochondrial factor B. J Bioenerg Biomembr 41:137–143PubMed

Belogrudov GI, Hatefi Y (2002) Factor B and the mitochondrial ATP synthase complex. J Biol Chem 277:6097–6103PubMed

Bisetto E, Picotti P, Giorgio V, Alverdi V, Mavelli I, Lippe G (2008) Functional and stoichiometric analysis of subunit e in bovine heart mitochondrial F(0)F(1)ATP synthase. J Bioenerg Biomembr 40:257–267PubMed

Blok RB, Gook DA, Thorburn DR, Dahl HH (1997) Skewed segregation of the mtDNA nt 8993 (T– > G) mutation in human oocytes. Am J Hum Genet 60:1495–1501PubMed

Boyer PD (1975) A model for conformational coupling of membrane potential and proton translocation to ATP synthesis and to active transport. FEBS Lett 58:1–6PubMed

Boyer PD (1997) The ATP synthase–a splendid molecular machine. Annu Rev Biochem 66:717–749PubMed

Boyer PD, Kohlbrenner WE (1981) The present status of the binding-change mechanism and its relation to ATP formation by chloroplasts. In: Selman BR, Selman-Peimer S (eds) Energy coupling in photosynthesis. Elsevier, Amsterdam, pp 231–240

Brown DT, Herbert M, Lamb VK et al. (2006) Transmission of mitochondrial DNA disorders: possibilities for the future. Lancet 368:87–89PubMed

Cabezon E, Butler PJ, Runswick MJ, Walker JE (2000) Modulation of the oligomerization state of the bovine F1-ATPase inhibitor protein, IF1, by pH. J Biol Chem 275:25460–25464PubMed

Cabezon E, Runswick MJ, Leslie AG, Walker JE (2001) The structure of bovine IF(1), the regulatory subunit of mitochondrial F-ATPase. EMBO J 20:6990–6996PubMed

Cabezon E, Montgomery MG, Leslie AG, Walker JE (2003) The structure of bovine F1-ATPase in complex with its regulatory protein IF1. Nat Struct Biol 10:744–750PubMed

Calvo S, Jain M, Xie X et al. (2006) Systematic identification of human mitochondrial disease genes through integrative genomics. Nat Genet 38:576–582PubMed

Cameron JM, Levandovskiy V, Mackay N et al. (2011) Complex V TMEM70 deficiency results in mitochondrial nucleoid disorganization. Mitochondrion 11:191–199PubMed

Campanella M, Casswell E, Chong S et al. (2008) Regulation of mitochondrial structure and function by the F1Fo-ATPase inhibitor protein, IF1. Cell Metab 8:13–25PubMed

Campanella M, Parker N, Tan CH, Hall AM, Duchen MR (2009) IF(1): setting the pace of the F(1)F(o)-ATP synthase. Trends Biochem Sci 34:343–350PubMed

Capaldi RA, Aggeler R, Turina P, Wilkens S (1994) Coupling between catalytic sites and the proton channel in F1F0-type ATPases. Trends Biochem Sci 19:284–289PubMed

Carelli V, Baracca A, Barogi S et al. (2002) Biochemical-clinical correlation in patients with different loads of the mitochondrial DNA T8993G mutation. Arch Neurol 59:264–270PubMed

Carrozzo R, Tessa A, Vazquez-Memije ME et al. (2001) The T9176G mtDNA mutation severely affects ATP production and results in Leigh syndrome. Neurology 56:687–690PubMed

Childs AM, Hutchin T, Pysden K et al. (2007) Variable phenotype including Leigh syndrome with a 9185T>C mutation in the MTATP6 gene. Neuropediatrics 38:313–316PubMed

Chinnery P, Majamaa K, Turnbull D, Thorburn D (2006) Treatment for mitochondrial disorders. Cochrane Database Syst Rev: CD004426.

Cizkova A, Stranecky V, Mayr JA et al. (2008) TMEM70 mutations cause isolated ATP synthase deficiency and neonatal mitochondrial encephalocardiomyopathy. Nat Genet 40:1288–1290PubMed

Cooperstein SJ, Lazarow A (1951) A microspectrophotometric method for the determination of cytochrome oxidase. J Biol Chem 189:665–670PubMed

Cortes-Hernandez P, Vazquez-Memije ME, Garcia JJ (2007) ATP6 homoplasmic mutations inhibit and destabilize the human F1F0-ATP synthase without preventing enzyme assembly and oligomerization. J Biol Chem 282:1051–1058PubMed

Cox GB, Jans DA, Fimmel AL, Gibson F, Hatch L (1984) Hypothesis. The mechanism of ATP synthase. Conformational change by rotation of the beta-subunit. Biochim Biophys Acta 768:201–208PubMed

Craven L, Tuppen HA, Greggains GD et al. (2010) Pronuclear transfer in human embryos to prevent transmission of mitochondrial DNA disease. Nature 465:82–85PubMed

Cross RL, Muller V (2004) The evolution of A-, F-, and V-type ATP synthases and ATPases: reversals in function and changes in the H+/ATP coupling ratio. FEBS Lett 576:1–4PubMed

Dahl HH, Thorburn DR, White SL (2000) Towards reliable prenatal diagnosis of mtDNA point mutations: studies of nt8993 mutations in oocytes, fetal tissues, children and adults. Hum Reprod 15(Suppl 2):246–255PubMed

D'Aurelio M, Vives-Bauza C, Davidson MM, Manfredi G (2010) Mitochondrial DNA background modifies the bioenergetics of NARP/MILS ATP6 mutant cells. Hum Mol Genet 19:374–386PubMed

De Meirleir L, Seneca S, Lissens W, Schoentjes E, Desprechins B (1995) Bilateral striatal necrosis with a novel point mutation in the mitochondrial ATPase 6 gene. Pediatr Neurol 13:242–246PubMed

De Meirleir L, Seneca S, Lissens W et al. (2004) Respiratory chain complex V deficiency due to a mutation in the assembly gene ATP12. J Med Genet 41:120–124PubMed

de Vries DD, van Engelen BG, Gabreels FJ, Ruitenbeek W, van Oost BA (1993) A second missense mutation in the mitochondrial ATPase 6 gene in Leigh's syndrome. Ann Neurol 34:410–412PubMed

Dean NL, Battersby BJ, Ao A et al. (2003) Prospect of preimplantation genetic diagnosis for heritable mitochondrial DNA diseases. Mol Hum Reprod 9:631–638PubMed

Debray FG, Lambert M, Lortie A, Vanasse M, Mitchell GA (2007) Long-term outcome of Leigh syndrome caused by the NARP-T8993C mtDNA mutation. Am J Med Genet A 143A:2046–2051PubMed

Devenish RJ, Prescott M, Boyle GM, Nagley P (2000) The oligomycin axis of mitochondrial ATP synthase: OSCP and the proton channel. J Bioenerg Biomembr 32:507–515PubMed

Devenish RJ, Prescott M, Rodgers AJ (2008) The structure and function of mitochondrial F1F0-ATP synthases. Int Rev Cell Mol Biol 267:1–58PubMed

Dickson VK, Silvester JA, Fearnley IM, Leslie AG, Walker JE (2006) On the structure of the stator of the mitochondrial ATP synthase. EMBO J 25:2911–2918PubMed

DiMauro S, Hirano M, Schon EA (2006) Approaches to the treatment of mitochondrial diseases. Muscle Nerve 34:265–283PubMed

Dionisi-Vici C, Seneca S, Zeviani M et al. (1998) Fulminant Leigh syndrome and sudden unexpected death in a family with the T9176C mutation of the mitochondrial ATPase 6 gene. J Inherit Metab Dis 21:2–8PubMed

Garcia JJ, Ogilvie I, Robinson BH, Capaldi RA (2000) Structure, functioning, and assembly of the ATP synthase in cells from patients with the T8993G mitochondrial DNA mutation. Comparison with the enzyme in Rho(0) cells completely lacking mtdna. J Biol Chem 275:11075–11081PubMed

Gibbons C, Montgomery MG, Leslie AG, Walker JE (2000) The structure of the central stalk in bovine F(1)-ATPase at 2.4 A resolution. Nat Struct Biol 7:1055–1061PubMed

Havlickova V, Kaplanova V, Nuskova H, Drahota Z, Houstek J (2010) Knockdown of F1 epsilon subunit decreases mitochondrial content of ATP synthase and leads to accumulation of subunit c. Biochim Biophys Acta 1797:1124–1129PubMed

Hejzlarova K, Tesarova M, Vrbacka-Cizkova A et al. (2011) Expression and processing of the TMEM70 protein. Biochim Biophys Acta 1807:144–149PubMed

Holt IJ, Harding AE, Petty RK, Morgan-Hughes JA (1990) A new mitochondrial disease associated with mitochondrial DNA heteroplasmy. Am J Hum Genet 46:428–433PubMed

Honzik T, Tesarova M, Mayr JA et al. (2010) Mitochondrial encephalocardio-myopathy with early neonatal onset due to TMEM70 mutation. Arch Dis Child 95:296–301PubMed

Houstek J, Pickova A, Vojtiskova A, Mracek T, Pecina P, Jesina P (2006) Mitochondrial diseases and genetic defects of ATP synthase. Biochim Biophys Acta 1757:1400–1405PubMed

Hung PC, Wang HS (2007) A previously undescribed leukodystrophy in Leigh syndrome associated with T9176C mutation of the mitochondrial ATPase 6 gene. Dev Med Child Neurol 49:65–67PubMed

Iino R, Hasegawa R, Tabata KV, Noji H (2009) Mechanism of inhibition by C-terminal alpha-helices of the epsilon subunit of Escherichia coli FoF1-ATP synthase. J Biol Chem 284:17457–17464PubMed

Janssen AJ, Smeitink JA, van den Heuvel LP (2003) Some practical aspects of providing a diagnostic service for respiratory chain defects. Ann Clin Biochem 40:3–8PubMed

Janssen AJ, Trijbels FJ, Sengers RC et al. (2006) Measurement of the energy-generating capacity of human muscle mitochondria: diagnostic procedure and application to human pathology. Clin Chem 52:860–871PubMed

Jenuth JP, Peterson AC, Shoubridge EA (1997) Tissue-specific selection for different mtDNA genotypes in heteroplasmic mice. Nat Genet 16:93–95PubMed

Jonckheere AI, Hogeveen M, Nijtmans LG et al. (2008) A novel mitochondrial ATP8 gene mutation in a patient with apical hypertrophic cardiomyopathy and neuropathy. J Med Genet 45:129–133PubMed

Jonckheere AI, Huigsloot M, Janssen AJ, Kappen AJ, Smeitink JA, Rodenburg RJ (2010) High-throughput assay to measure oxygen consumption in digitonin-permeabilized cells of patients with mitochondrial disorders. Clin Chem 56:424–431PubMed

Junge W, Sielaff H, Engelbrecht S (2009) Torque generation and elastic power transmission in the rotary F(O)F(1)-ATPase. Nature 459:364–370PubMed

Kirby DM, Thorburn DR, Turnbull DM, Taylor RW (2007) Biochemical assays of respiratory chain complex activity. Methods Cell Biol 80:93–119PubMed

Koene S, Smeitink J (2009) Mitochondrial medicine: entering the era of treatment. J Intern Med 265:193–209PubMed

Koene S, Smeitink J (2010) Metabolic manipulators: a well founded strategy to combat mitochondrial dysfunction. J Inherit Metab Dis

Krause F, Reifschneider NH, Goto S, Dencher NA (2005) Active oligomeric ATP synthases in mammalian mitochondria. Biochem Biophys Res Commun 329:583–590PubMed

Kucharczyk R, Rak M, di Rago JP (2009a) Biochemical consequences in yeast of the human mitochondrial DNA 8993T>C mutation in the ATPase6 gene found in NARP/MILS patients. Biochim Biophys Acta 1793:817–824PubMed

Kucharczyk R, Salin B, di Rago JP (2009b) Introducing the human Leigh syndrome mutation T9176G into Saccharomyces cerevisiae mitochondrial DNA leads to severe defects in the incorporation of Atp6p into the ATP synthase and in the mitochondrial morphology. Hum Mol Genet 18:2889–2898PubMed

Kucharczyk R, Zick M, Bietenhader M et al. (2009c) Mitochondrial ATP synthase disorders: molecular mechanisms and the quest for curative therapeutic approaches. Biochim Biophys Acta 1793:186–199PubMed

Kucharczyk R, Ezkurdia N, Couplan E et al. (2010) Consequences of the pathogenic T9176C mutation of human mitochondrial DNA on yeast mitochondrial ATP synthase. Biochim Biophys Acta 1797:1105–1112PubMed

La Morgia C, Achilli A, Iommarini L et al. (2008) Rare mtDNA variants in Leber hereditary optic neuropathy families with recurrence of myoclonus. Neurology 70:762–770PubMed

Lamminen T, Majander A, Juvonen V et al. (1995) A mitochondrial mutation at nt 9101 in the ATP synthase 6 gene associated with deficient oxidative phosphorylation in a family with Leber hereditary optic neuroretinopathy. Am J Hum Genet 56:1238–1240PubMed

Lee LK, Stewart AG, Donohoe M, Bernal RA, Stock D (2010) The structure of the peripheral stalk of Thermus thermophilus H + -ATPase/synthase. Nat Struct Mol Biol 17:373–378PubMed

Lefebvre-Legendre L, Salin B, Schaeffer J et al. (2005) Failure to assemble the alpha 3 beta 3 subcomplex of the ATP synthase leads to accumulation of the alpha and beta subunits within inclusion bodies and the loss of mitochondrial cristae in Saccharomyces cerevisiae. J Biol Chem 280:18386–18392PubMed

Lenaz G, Baracca A, Carelli V, D'Aurelio M, Sgarbi G, Solaini G (2004) Bioenergetics of mitochondrial diseases associated with mtDNA mutations. Biochim Biophys Acta 1658:89–94PubMed

Manfredi G, Gupta N, Vazquez-Memije ME et al. (1999) Oligomycin induces a decrease in the cellular content of a pathogenic mutation in the human mitochondrial ATPase 6 gene. J Biol Chem 274:9386–9391PubMed

Manfredi G, Fu J, Ojaimi J et al. (2002) Rescue of a deficiency in ATP synthesis by transfer of MTATP6, a mitochondrial DNA-encoded gene, to the nucleus. Nat Genet 30:394–399PubMed

Matsuno-Yagi A, Yagi T, Hatefi Y (1985) Studies on the mechanism of oxidative phosphorylation: effects of specific F0 modifiers on ligand-induced conformation changes of F1. Proc Natl Acad Sci USA 82:7550–7554PubMed

Mattiazzi M, Vijayvergiya C, Gajewski CD et al. (2004) The mtDNA T8993G (NARP) mutation results in an impairment of oxidative phosphorylation that can be improved by antioxidants. Hum Mol Genet 13:869–879PubMed

Mayr JA, Havlickova V, Zimmermann F et al. (2010) Mitochondrial ATP synthase deficiency due to a mutation in the ATP5E gene for the F1 epsilon subunit. Hum Mol Genet 19:3430–3439PubMed

Meulemans A, Seneca S, Pribyl T et al. (2010) Defining the pathogenesis of the human Atp12p W94R mutation using a Saccharomyces cerevisiae yeast model. J Biol Chem 285:4099–4109PubMed

Meyer B, Wittig I, Trifilieff E, Karas M, Schagger H (2007) Identification of two proteins associated with mammalian ATP synthase. Mol Cell Proteomics 6:1690–1699PubMed

Mkaouar-Rebai E, Chaari W, Younes S, Bousoffara R, Sfar MT, Fakhfakh F (2009) Maternally inherited Leigh syndrome: T8993G mutation in a Tunisian family. Pediatr Neurol 40:437–442PubMed

Mkaouar-Rebai E, Kammoun F, Chamkha I et al. (2010) A de novo mutation in the adenosine triphosphatase (ATPase) 8 gene in a patient with mitochondrial disorder. J Child Neurol 25:770–775PubMed

Mnatsakanyan N, Hook JA, Quisenberry L, Weber J (2009) ATP synthase with its gamma subunit reduced to the N-terminal helix can still catalyze ATP synthesis. J Biol Chem 284:26519–26525PubMed

Morava E, Rodenburg RJ, Hol F et al. (2006) Clinical and biochemical characteristics in patients with a high mutant load of the mitochondrial T8993G/C mutations. Am J Med Genet A 140:863–868PubMed

Moslemi AR, Darin N, Tulinius M, Oldfors A, Holme E (2005) Two new mutations in the MTATP6 gene associated with Leigh syndrome. Neuropediatrics 36:314–318PubMed

Niers L, van den Heuvel L, Trijbels F, Sengers R, Smeitink J (2003) Prerequisites and strategies for prenatal diagnosis of respiratory chain deficiency in chorionic villi. J Inherit Metab Dis 26:647–658PubMed

Nijtmans LG, Klement P, Houstek J, van den Bogert C (1995) Assembly of mitochondrial ATP synthase in cultured human cells: implications for mitochondrial diseases. Biochim Biophys Acta 1272:190–198PubMed

Nijtmans LG, Henderson NS, Holt IJ (2002) Blue Native electrophoresis to study mitochondrial and other protein complexes. Methods 26:327–334PubMed

Ohsakaya S, Fujikawa M, Hisabori T, Yoshida M (2011) Knockdown of DAPIT (diabetes-associated protein in insulin-sensitive tissue) results in loss of ATP synthase in mitochondria. J Biol Chem

Ojaimi J, Pan J, Santra S, Snell WJ, Schon EA (2002) An algal nucleus-encoded subunit of mitochondrial ATP synthase rescues a defect in the analogous human mitochondrial-encoded subunit. Mol Biol Cell 13:3836–3844PubMed

Pallotti F, Baracca A, Hernandez-Rosa E et al. (2004) Biochemical analysis of respiratory function in cybrid cell lines harbouring mitochondrial DNA mutations. Biochem J 384:287–293PubMed

Paumard P, Vaillier J, Coulary B et al. (2002) The ATP synthase is involved in generating mitochondrial cristae morphology. EMBO J 21:221–230PubMed

Penefsky HS (1985) Mechanism of inhibition of mitochondrial adenosine triphosphatase by dicyclohexylcarbodiimide and oligomycin: relationship to ATP synthesis. Proc Natl Acad Sci USA 82:1589–1593PubMed

Petros JA, Baumann AK, Ruiz-Pesini E et al. (2005) mtDNA mutations increase tumorigenicity in prostate cancer. Proc Natl Acad Sci USA 102:719–724PubMed

Poulton J, Marchington DR (2002) Segregation of mitochondrial DNA (mtDNA) in human oocytes and in animal models of mtDNA disease: clinical implications. Reproduction 123:751–755PubMed

Povalko N, Zakharova E, Rudenskaia G et al. (2005) A new sequence variant in mitochondrial DNA associated with high penetrance of Russian Leber hereditary optic neuropathy. Mitochondrion 5:194–199PubMed

Pullman ME, Monroy GC (1963) A naturally occurring inhibitor of mitochondrial adenosine triphosphatase. J Biol Chem 238:3762–3769PubMed

Rabl R, Soubannier V, Scholz R et al. (2009) Formation of cristae and crista junctions in mitochondria depends on antagonism between Fcj1 and Su e/g. J Cell Biol 185:1047–1063PubMed

Rak M, Tzagoloff A (2009) F1-dependent translation of mitochondrially encoded Atp6p and Atp8p subunits of yeast ATP synthase. Proc Natl Acad Sci USA 106:18509–18514PubMed

Rak M, Tetaud E, Duvezin-Caubet S et al. (2007a) A yeast model of the neurogenic ataxia retinitis pigmentosa (NARP) T8993G mutation in the mitochondrial ATP synthase-6 gene. J Biol Chem 282:34039–34047PubMed

Rak M, Tetaud E, Godard F et al. (2007b) Yeast cells lacking the mitochondrial gene encoding the ATP synthase subunit 6 exhibit a selective loss of complex IV and unusual mitochondrial morphology. J Biol Chem 282:10853–10864PubMed

Rak M, Zeng X, Briere JJ, Tzagoloff A (2009) Assembly of F0 in Saccharomyces cerevisiae. Biochim Biophys Acta 1793:108–116PubMed

Rak M, Gokova S, Tzagoloff A (2011) Modular assembly of yeast mitochondrial ATP synthase. EMBO J 30:920–930PubMed

Rees DM, Leslie AG, Walker JE (2009) The structure of the membrane extrinsic region of bovine ATP synthase. Proc Natl Acad Sci USA 106:21597–21601PubMed

Rodenburg RJ (2011) Biochemical diagnosis of mitochondrial disorders. J Inherit Metab Dis 34:283–292PubMed

Sanchez-Cenizo L, Formentini L, Aldea M et al. (2010) Up-regulation of the ATPase inhibitory factor 1 (IF1) of the mitochondrial H + -ATP synthase in human tumors mediates the metabolic shift of cancer cells to a Warburg phenotype. J Biol Chem 285:25308–25313PubMed

Sato A, Kono T, Nakada K et al. (2005) Gene therapy for progeny of mito-mice carrying pathogenic mtDNA by nuclear transplantation. Proc Natl Acad Sci USA 102:16765–16770PubMed

Schagger H, Pfeiffer K (2000) Supercomplexes in the respiratory chains of yeast and mammalian mitochondria. EMBO J 19:1777–1783PubMed

Schagger H, von Jagow G (1991) Blue native electrophoresis for isolation of membrane protein complexes in enzymatically active form. Anal Biochem 199:223–231PubMed

Schapira AH (2006) Mitochondrial disease. Lancet 368:70–82PubMed

Schwimmer C, Lefebvre-Legendre L, Rak M et al. (2005) Increasing mitochondrial substrate-level phosphorylation can rescue respiratory growth of an ATP synthase-deficient yeast. J Biol Chem 280:30751–30759PubMed

Seneca S, Abramowicz M, Lissens W, Muller MF, Vamos E, de Meirleir L (1996) A mitochondrial DNA microdeletion in a newborn girl with transient lactic acidosis. J Inherit Metab Dis 19:115–118PubMed

Sgarbi G, Baracca A, Lenaz G, Valentino LM, Carelli V, Solaini G (2006) Inefficient coupling between proton transport and ATP synthesis may be the pathogenic mechanism for NARP and Leigh syndrome resulting from the T8993G mutation in mtDNA. Biochem J 395:493–500PubMed

Sgarbi G, Casalena GA, Baracca A, Lenaz G, DiMauro S, Solaini G (2009) Human NARP mitochondrial mutation metabolism corrected with alpha-ketoglutarate/aspartate: a potential new therapy. Arch Neurol 66:951–957PubMed

Shchelochkov OA, Li FY, Wang J et al. (2010) Milder clinical course of Type IV 3-methylglutaconic aciduria due to a novel mutation in TMEM70. Mol Genet Metab 101:282–285PubMed

Sikorska M, Sandhu JK, Simon DK et al. (2009) Identification of ataxia-associated mtDNA mutations (m.4052T>C and m.9035T>C) and evaluation of their pathogenicity in transmitochondrial cybrids. Muscle Nerve 40:381–394PubMed

Spiegel R, Khayat M, Shalev SA et al. (2011) TMEM70 mutations are a common cause of nuclear encoded ATP synthase assembly defect: further delineation of a new syndrome. J Med Genet 48:177–182PubMed

Steffann J, Gigarel N, Corcos J et al. (2007) Stability of the m.8993T->G mtDNA mutation load during human embryofetal development has implications for the feasibility of prenatal diagnosis in NARP syndrome. J Med Genet 44:664–669PubMed

Stephens AN, Nagley P, Devenish RJ (2003) Each yeast mitochondrial F1F0-ATP synthase complex contains a single copy of subunit 8. Biochim Biophys Acta 1607:181–189PubMed

Stock D, Leslie AG, Walker JE (1999) Molecular architecture of the rotary motor in ATP synthase. Science 286:1700–1705PubMed

Strauss M, Hofhaus G, Schroder RR, Kuhlbrandt W (2008) Dimer ribbons of ATP synthase shape the inner mitochondrial membrane. EMBO J 27:1154–1160PubMed

Tachibana M, Sparman M, Sritanaudomchai H et al. (2009) Mitochondrial gene replacement in primate offspring and embryonic stem cells. Nature 461:367–372PubMed

Tanaka M, Borgeld HJ, Zhang J et al. (2002) Gene therapy for mitochondrial disease by delivering restriction endonuclease SmaI into mitochondria. J Biomed Sci 9:534–541PubMed

Tatuch Y, Robinson BH (1993) The mitochondrial DNA mutation at 8993 associated with NARP slows the rate of ATP synthesis in isolated lymphoblast mitochondria. Biochem Biophys Res Commun 192:124–128PubMed

Temperley RJ, Seneca SH, Tonska K et al. (2003) Investigation of a pathogenic mtDNA microdeletion reveals a translation-dependent deadenylation decay pathway in human mitochondria. Hum Mol Genet 12:2341–2348PubMed

Thomas D, Bron P, Weimann T et al. (2008) Supramolecular organization of the yeast F1Fo-ATP synthase. Biol Cell 100:591–601PubMed

Thyagarajan D, Shanske S, Vazquez-Memije M, De Vivo D, DiMauro S (1995) A novel mitochondrial ATPase 6 point mutation in familial bilateral striatal necrosis. Ann Neurol 38:468–472PubMed

Toei M, Saum R, Forgac M (2010) Regulation and isoform function of the V-ATPases. Biochemistry 49:4715–4723PubMed

Trounce I, Neill S, Wallace DC (1994) Cytoplasmic transfer of the mtDNA nt 8993T–>G (ATP6) point mutation associated with Leigh syndrome into mtDNA-less cells demonstrates cosegregation with a decrease in state III respiration and ADP/O ratio. Proc Natl Acad Sci USA 91:8334–8338PubMed

van der Walt JM, Nicodemus KK, Martin ER et al. (2003) Mitochondrial polymorphisms significantly reduce the risk of Parkinson disease. Am J Hum Genet 72:804–811PubMed

Van Heeke G, Deforce L, Schnizer RA et al. (1993) Recombinant bovine heart mitochondrial F1-ATPase inhibitor protein: overproduction in Escherichia coli, purification, and structural studies. Biochemistry 32:10140–10149PubMed

Vazquez-Memije ME, Shanske S, Santorelli FM, Kranz-Eble P, DeVivo DC, DiMauro S (1998) Comparative biochemical studies of ATPases in cells from patients with the T8993G or T8993C mitochondrial DNA mutations. J Inherit Metab Dis 21:829–836PubMed

Velours J, Arselin G (2000) The Saccharomyces cerevisiae ATP synthase. J Bioenerg Biomembr 32:383–390PubMed

Verny C, Guegen N, Desquiret V et al. (2011) Hereditary spastic paraplegia-like disorder due to a mitochondrial ATP6 gene point mutation. Mitochondrion 11:70–75PubMed

Vives-Bauza C, Magrane J, Andreu AL, Manfredi G (2010) Novel role of ATPase subunit C targeting peptides beyond mitochondrial protein import. Mol Biol Cell 21:131–139PubMed

Wagner K, Perschil I, Fichter CD, van der Laan M (2010) Stepwise assembly of dimeric F(1)F(o)-ATP synthase in mitochondria involves the small F(o)-subunits k and i. Mol Biol Cell 21:1494–1504PubMed

Walker JE, Dickson VK (2006) The peripheral stalk of the mitochondrial ATP synthase. Biochim Biophys Acta 1757:286–296PubMed

Wallace DC (2005) A mitochondrial paradigm of metabolic and degenerative diseases, aging, and cancer: a dawn for evolutionary medicine. Annu Rev Genet 39:359–407PubMed

Wang ZG, Sheluho D, Gatti DL, Ackerman SH (2000) The alpha-subunit of the mitochondrial F(1) ATPase interacts directly with the assembly factor Atp12p. EMBO J 19:1486–1493PubMed

Ware SM, El-Hassan N, Kahler SG et al. (2009) Infantile cardiomyopathy caused by a mutation in the overlapping region of mitochondrial ATPase 6 and 8 genes. J Med Genet 46:308–314PubMed

Watt IN, Montgomery MG, Runswick MJ, Leslie AG, Walker JE (2010) Bioenergetic cost of making an adenosine triphosphate molecule in animal mitochondria. Proc Natl Acad Sci USA 107:16823–16827PubMed

Wittig I, Schagger H (2005) Advantages and limitations of clear-native PAGE. Proteomics 5:4338–4346PubMed

Wittig I, Schagger H (2008) Structural organization of mitochondrial ATP synthase. Biochim Biophys Acta 1777:592–598PubMed

Wittig I, Schagger H (2009) Supramolecular organization of ATP synthase and respiratory chain in mitochondrial membranes. Biochim Biophys Acta 1787:672–680PubMed

Wittig I, Meyer B, Heide H et al. (2010) Assembly and oligomerization of human ATP synthase lacking mitochondrial subunits a and A6L. Biochim Biophys Acta 1797:1004–1011PubMed

Zeviani M, Di Donato S (2004) Mitochondrial disorders. Brain 127:2153–2172PubMed

Zick M, Rabl R, Reichert AS (2009) Cristae formation-linking ultrastructure and function of mitochondria. Biochim Biophys Acta 1793:5–19PubMed

Title: Mitochondrial ATP synthase: architecture, function and pathology
Authors: An I. Jonckheere
Jan A. M. Smeitink
Richard J. T. Rodenburg
Publication date: 01-03-2012
Publisher: Springer Netherlands
Published in: Journal of Inherited Metabolic Disease / Issue 2/2012
Print ISSN: 0141-8955
Electronic ISSN: 1573-2665
DOI: https://doi.org/10.1007/s10545-011-9382-9

Obesity Clinical Trial Summary

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine

Highlights from the ACC 2024 Congress

Year in Review: Pediatric cardiology

Pediatric Cardiology Video

Watch Dr. Anne Marie Valente present the last year's highlights in pediatric and congenital heart disease in the official ACC.24 Year in Review session.

Year in Review: Pulmonary vascular disease

Cardiopulmonary Comorbidity Video

The last year's highlights in pulmonary vascular disease are presented by Dr. Jane Leopold in this official video from ACC.24.

Year in Review: Valvular heart disease

Valvular Heart Disease Video

Watch Prof. William Zoghbi present the last year's highlights in valvular heart disease from the official ACC.24 Year in Review session.

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.

Watch now

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

16-04-2024 Type 2 Diabetes News

Incentivised to exercise

11-04-2024 Lifestyle Modifications News

New intervention for STEMI-related cardiogenic shock

10-04-2024 Myocardial Infarction News

» View more highlights on the ACC 2024 congress hub page

Image Credits

STEP AAG HeroTeaserCollection image/© Tarek / Generated with AI / Stock.adobe.com, ACC 2024 Pediatric and Congenital Heart Disease: Year in Review/© 2024 American College of Cardiology, ACC 2024 Pulmonary Vascular Disease: Year in Review/© 2024 American College of Cardiology, ACC 2024 Valvular Heart Disease: Year in Review/© 2024 American College of Cardiology, ACC 2024 HF and Cardiomyopathies: Year in Review/© 2024 American College of Cardiology, Woman out walking/© Seventyfour / stock.adobe.com (symbolic image with model), Woman checking smartwatch /© saltdium / stock.adobe.com (symbolic image with model), Cardiac catheterization/© Damian / stock.adobe.com

At a glance: The STEP trials

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 2/2012

Neurocognitive outcome in patients with hypertyrosinemia type I after long-term treatment with NTBC

Prediction of long-term outcome in glycine encephalopathy: a clinical survey

The adult galactosemic phenotype

VLCAD enzyme activity determinations in newborns identified by screening: a valuable tool for risk assessment

Erratum to: Urine analysis of glucose tetrasaccharide by HPLC; a useful marker for the investigation of patients with Pompe and other glycogen storage diseases

Effects of enzyme replacement therapy on five patients with advanced late-onset glycogen storage disease type II: a 2-year follow-up study

Highlights from the ACC 2024 Congress

ACC 2024 Congress Coverage