Disorders of ATP synthase, the key enzyme in mitochondrial energy supply, belong to the most severe metabolic diseases, manifesting as early-onset mitochondrial encephalo-cardiomyopathies. Since ATP synthase subunits are encoded by both mitochondrial and nuclear DNA, pathogenic variants can be found in either genome. In addition, the biogenesis of ATP synthase requires several assembly factors, some of which are also hotspots for pathogenic variants. While variants of MT-ATP6 and TMEM70 represent the most common cases of mitochondrial and nuclear DNA mutations respectively, the advent of next-generation sequencing has revealed new pathogenic variants in a number of structural genes and TMEM70, sometimes with truly peculiar genetics. Here we present a systematic review of the reported cases and discuss biochemical mechanisms, through which they are affecting ATP synthase. We explore how the knowledge of pathophysiology can improve our understanding of enzyme biogenesis and function. Keywords: Mitochondrial diseases o ATP synthase o Nuclear DNA o Mitochondrial DNA o TMEM70.

Laboratory of Bioenergetics Institute of Physiology of the Czech Academy of Sciences Prague Czech Republic

Zobrazit více v PubMed

Kobayashi R, Ueno H, Li CB, Noji H. Rotary catalysis of bovine mitochondrial F(1)-ATPase studied by single-molecule experiments. Proc Natl Acad Sci U S A. 2020;117:1447–1456. doi: 10.1073/pnas.1909407117. PubMed DOI PMC

Lai Y, Zhang Y, Zhou S, Xu J, Du Z, Feng Z, Yu L, Zhao Z, Wang W, Tang Y, Yang X, Guddat LW, Liu F, Gao Y, Rao Z, Gong H. Structure of the human ATP synthase. Mol Cell. 2023;83:2137–2147e2134. doi: 10.1016/j.molcel.2023.04.029. PubMed DOI

Green DW, Grover GJ. The IF(1) inhibitor protein of the mitochondrial F(1)F(0)-ATPase. Biochim Biophys Acta. 2000;1458:343–355. doi: 10.1016/S0005-2728(00)00085-2. PubMed DOI

Wittig I, Meyer B, Heide H, Steger M, Bleier L, Wumaier Z, Karas M, Schagger H. Assembly and oligomerization of human ATP synthase lacking mitochondrial subunits a and A6L. Biochim Biophys Acta. 2010;1797:1004–1011. doi: 10.1016/j.bbabio.2010.02.021. PubMed DOI

Wang ZG, White PS, Ackerman SH. Atp11p and Atp12p are assembly factors for the F(1)-ATPase in human mitochondria. J Biol Chem. 2001;276:30773–30778. doi: 10.1074/jbc.M104133200. PubMed DOI

Li Y, Jourdain AA, Calvo SE, Liu JS, Mootha VK. CLIC, a tool for expanding biological pathways based on co-expression across thousands of datasets. PLoS Comput Biol. 2017;13:e1005653. doi: 10.1371/journal.pcbi.1005653. PubMed DOI PMC

Kovalcikova J, Vrbacky M, Pecina P, Tauchmannova K, Nuskova H, Kaplanova V, Brazdova A, Alan L, Elias J, Cunatova K, Korinek V, Sedlacek R, Mracek T, Houstek J. TMEM70 facilitates biogenesis of mammalian ATP synthase by promoting subunit c incorporation into the rotor structure of the enzyme. FASEB J. 2019;33:14103–14117. doi: 10.1096/fj.201900685RR. PubMed DOI

Carroll J, He J, Ding S, Fearnley IM, Walker JE. TMEM70 and TMEM242 help to assemble the rotor ring of human ATP synthase and interact with assembly factors for complex I. Proc Natl Acad Sci U S A. 2021:118. doi: 10.1073/pnas.2100558118. PubMed DOI PMC

Yu J, Liang X, Ji Y, Ai C, Liu J, Zhu L, Nie Z, Jin X, Wang C, Zhang J, Zhao F, Mei S, Zhao X, Zhou X, Zhang M, Wang M, Huang T, Jiang P, Guan MX. PRICKLE3 linked to ATPase biogenesis manifested Leber's hereditary optic neuropathy. J Clin Invest. 2020;130:4935–4946. doi: 10.1172/JCI134965. PubMed DOI PMC

Harrington JS, Ryter SW, Plataki M, Price DR, Choi AMK. Mitochondria in health, disease, and aging. Physiol Rev. 2023;103:2349–2422. doi: 10.1152/physrev.00058.2021. PubMed DOI PMC

Rahman S. Mitochondrial disease in children. J Intern Med. 2020;287:609–633. doi: 10.1111/joim.13054. PubMed DOI

Ng YS, Bindoff LA, Gorman GS, Klopstock T, Kornblum C, Mancuso M, McFarland R, Sue CM, Suomalainen A, Taylor RW, Thorburn DR, Turnbull DM. Mitochondrial disease in adults: recent advances and future promise. Lancet Neurol. 2021;20:573–584. doi: 10.1016/S1474-4422(21)00098-3. PubMed DOI

Al-Kafaji G, Bakheit HF, AlAli F, Fattah M, Alhajeri S, Alharbi MA, Daif A, Alsabbagh MM, Alwehaidah MS, Bakhiet M. Next-generation sequencing of the whole mitochondrial genome identifies functionally deleterious mutations in patients with multiple sclerosis. PLoS One. 2022;17:e0263606. doi: 10.1371/journal.pone.0263606. PubMed DOI PMC

de Mello AH, Costa AB, Engel JDG, Rezin GT. Mitochondrial dysfunction in obesity. Life Sci. 2018;192:26–32. doi: 10.1016/j.lfs.2017.11.019. PubMed DOI

Yaribeygi H, Sathyapalan T, Atkin SL, Sahebkar A. Molecular mechanisms linking oxidative stress and diabetes mellitus. Oxid Med Cell Longev. 2020;2020:8609213. doi: 10.1155/2020/8609213. PubMed DOI PMC

Prasun P. Mitochondrial dysfunction in metabolic syndrome. Biochim Biophys Acta Mol Basis Dis. 2020;1866:165838. doi: 10.1016/j.bbadis.2020.165838. PubMed DOI

Wallace DC. Mitochondria and cancer. Nat Rev Cancer. 2012;12:685–698. doi: 10.1038/nrc3365. PubMed DOI PMC

Park CB, Larsson NG. Mitochondrial DNA mutations in disease and aging. J Cell Biol. 2011;193:809–818. doi: 10.1083/jcb.201010024. PubMed DOI PMC

Lott MT, Leipzig JN, Derbeneva O, Xie HM, Chalkia D, Sarmady M, Procaccio V, Wallace DC. mtDNA Variation and Analysis Using Mitomap and Mitomaster. Curr Protoc Bioinformatics. 2013;44:1 23 21–26. doi: 10.1002/0471250953.bi0123s44. PubMed DOI PMC

DiMauro S, Mancuso M. Mitochondrial diseases: therapeutic approaches. Biosci Rep. 2007;27:125–137. doi: 10.1007/s10540-007-9041-4. PubMed DOI

Ardissone A, Ferrera G, Lamperti C, Tiranti V, Ghezzi D, Moroni I, Lamantea E. Phenotyping mitochondrial DNA-related diseases in childhood: A cohort study of 150 patients. Eur J Neurol. 2023;30:2079–2091. doi: 10.1111/ene.15814. PubMed DOI

Galber C, Carissimi S, Baracca A, Giorgio V. The ATP Synthase Deficiency in Human Diseases. Life (Basel) 2021:11. doi: 10.3390/life11040325. PubMed DOI PMC

D'Aurelio M, Vives-Bauza C, Davidson MM, Manfredi G. Mitochondrial DNA background modifies the bioenergetics of NARP/MILS ATP6 mutant cells. Hum Mol Genet. 2010;19:374–386. doi: 10.1093/hmg/ddp503. PubMed DOI PMC

Mkaouar-Rebai E, Chaari W, Younes S, Bousoffara R, Sfar MT, Fakhfakh F. Maternally inherited Leigh syndrome: T8993G mutation in a Tunisian family. Pediatr Neurol. 2009;40:437–442. doi: 10.1016/j.pediatrneurol.2009.01.004. PubMed DOI

Rossignol R, Faustin B, Rocher C, Malgat M, Mazat JP, Letellier T. Mitochondrial threshold effects. Biochem J. 2003;370:751–762. doi: 10.1042/bj20021594. PubMed DOI PMC

Bugiardini E, Bottani E, Marchet S, Poole OV, Beninca C, Horga A, Woodward C, Lam A, Hargreaves I, Chalasani A, Valerio A, Lamantea E, Venner K, Holton JL, Zeviani M, Houlden H, Quinlivan R, Lamperti C, Hanna MG, Pitceathly RDS. Expanding the molecular and phenotypic spectrum of truncating MT-ATP6 mutations. Neurol Genet. 2020;6:e381. doi: 10.1212/NXG.0000000000000381. PubMed DOI PMC

Lopez-Gallardo E, Solano A, Herrero-Martin MD, Martinez-Romero I, Castano-Perez MD, Andreu AL, Herrera A, Lopez-Perez MJ, Ruiz-Pesini E, Montoya J. NARP syndrome in a patient harbouring an insertion in the MT-ATP6 gene that results in a truncated protein. J Med Genet. 2009;46:64–67. doi: 10.1136/jmg.2008.060616. PubMed DOI

Seneca S, Abramowicz M, Lissens W, Muller MF, Vamos E, de Meirleir L. A mitochondrial DNA microdeletion in a newborn girl with transient lactic acidosis. J Inherit Metab Dis. 1996;19:115–118. doi: 10.1007/BF01799407. PubMed DOI

Jesina P, Tesarova M, Fornuskova D, Vojtiskova A, Pecina P, Kaplanova V, Hansikova H, Zeman J, Houstek J. Diminished synthesis of subunit a (ATP6) and altered function of ATP synthase and cytochrome c oxidase due to the mtDNA 2 bp microdeletion of TA at positions 9205 and 9206. Biochem J. 2004;383:561–571. doi: 10.1042/BJ20040407. PubMed DOI PMC

Hejzlarova K, Kaplanova V, Nuskova H, Kovarova N, Jesina P, Drahota Z, Mracek T, Seneca S, Houstek J. Alteration of structure and function of ATP synthase and cytochrome c oxidase by lack of Fo-a and Cox3 subunits caused by mitochondrial DNA 9205delTA mutation. Biochem J. 2015;466:601–611. doi: 10.1042/BJ20141462. PubMed DOI

Ware SM, El-Hassan N, Kahler SG, Zhang Q, Ma YW, Miller E, Wong B, Spicer RL, Craigen WJ, Kozel BA, Grange DK, Wong LJ. Infantile cardiomyopathy caused by a mutation in the overlapping region of mitochondrial ATPase 6 and 8 genes. J Med Genet. 2009;46:308–314. doi: 10.1136/jmg.2008.063149. PubMed DOI

Imai A, Fujita S, Kishita Y, Kohda M, Tokuzawa Y, Hirata T, Mizuno Y, Harashima H, Nakaya A, Sakata Y, Takeda A, Mori M, Murayama K, Ohtake A, Okazaki Y. Rapidly progressive infantile cardiomyopathy with mitochondrial respiratory chain complex V deficiency due to loss of ATPase 6 and 8 protein. Int J Cardiol. 2016;207:203–205. doi: 10.1016/j.ijcard.2016.01.026. PubMed DOI

Imai-Okazaki A, Kishita Y, Kohda M, Mizuno Y, Fushimi T, Matsunaga A, Yatsuka Y, Hirata T, Harashima H, Takeda A, Nakaya A, Sakata Y, Kogaki S, Ohtake A, Murayama K, Okazaki Y. Cardiomyopathy in children with mitochondrial disease: Prognosis and genetic background. Int J Cardiol. 2019;279:115–121. doi: 10.1016/j.ijcard.2019.01.017. PubMed DOI

Zigman T, Sikic K, Petkovic Ramadza D, Mayr J, Wortmann S, Prokisch H, Ninkovic D, Dilber D, Saric D, Rubic F, Galic S, Slavicek J, Belina D, Fumic K, Baric I. ATP synthase deficiency due to m.8528T>C mutation - a novel cause of severe neonatal hyperammonemia requiring hemodialysis. J Pediatr Endocrinol Metab. 2021;34:389–393. doi: 10.1515/jpem-2020-0396. PubMed DOI

Jonckheere AI, Hogeveen M, Nijtmans LG, van den Brand MA, Janssen AJ, Diepstra JH, van den Brandt FC, van den Heuvel LP, Hol FA, Hofste TG, Kapusta L, Dillmann U, Shamdeen MG, Smeitink JA, Rodenburg RJ. A novel mitochondrial ATP8 gene mutation in a patient with apical hypertrophic cardiomyopathy and neuropathy. J Med Genet. 2008;45:129–133. doi: 10.1136/jmg.2007.052084. PubMed DOI

Kytovuori L, Lipponen J, Rusanen H, Komulainen T, Martikainen MH, Majamaa K. A novel mutation m.8561C>G in MT-ATP6/8 causing a mitochondrial syndrome with ataxia, peripheral neuropathy, diabetes mellitus, and hypergonadotropic hypogonadism. J Neurol. 2016;263:2188–2195. doi: 10.1007/s00415-016-8249-2. PubMed DOI

Fragaki K, Chaussenot A, Serre V, Acquaviva C, Bannwarth S, Rouzier C, Chabrol B, Paquis-Flucklinger V. A novel variant m.8561C>T in the overlapping region of MT-ATP6 and MT-ATP8 in a child with early-onset severe neurological signs. Mol Genet Metab Rep. 2019;21:100543. doi: 10.1016/j.ymgmr.2019.100543. PubMed DOI PMC

Ronchi D, Bordoni A, Cosi A, Rizzuti M, Fassone E, Di Fonzo A, Servida M, Sciacco M, Collotta M, Ronzoni M, Lucchini V, Mattioli M, Moggio M, Bresolin N, Corti S, Comi GP. Unusual adult-onset Leigh syndrome presentation due to the mitochondrial m.9176T>C mutation. Biochem Biophys Res Commun. 2011;412:245–248. doi: 10.1016/j.bbrc.2011.07.076. PubMed DOI

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

de Vries DD, van Engelen BG, Gabreels FJ, Ruitenbeek W, van Oost BA. A second missense mutation in the mitochondrial ATPase 6 gene in Leigh's syndrome. Ann Neurol. 1993;34:410–412. doi: 10.1002/ana.410340319. PubMed DOI

Wong LC, Chen T, Schmitt ES, Wang J, Tang S, Landsverk M, Li F, Zhang S, Wang Y, Zhang VW, Craigen WJ. Clinical and laboratory interpretation of mitochondrial mRNA variants. Hum Mutat. 2020;41:1783–1796. doi: 10.1002/humu.24082. PubMed DOI

Tatuch Y, Christodoulou J, Feigenbaum A, Clarke JT, Wherret J, Smith C, Rudd N, Petrova-Benedict R, Robinson BH. Heteroplasmic mtDNA mutation (T----G) at 8993 can cause Leigh disease when the percentage of abnormal mtDNA is high. Am J Hum Genet. 1992;50:852–858. PubMed PMC

Fryer A, Appleton R, Sweeney MG, Rosenbloom L, Harding AE. Mitochondrial DNA 8993 (NARP) mutation presenting with a heterogeneous phenotype including 'cerebral palsy'. Arch Dis Child. 1994;71:419–422. doi: 10.1136/adc.71.5.419. PubMed DOI PMC

Houstek J, Klement P, Hermanska J, Houstkova H, Hansikova H, Van den Bogert C, Zeman J. Altered properties of mitochondrial ATP-synthase in patients with a T-->G mutation in the ATPase 6 (subunit a) gene at position 8993 of mtDNA. Biochim Biophys Acta. 1995;1271:349–357. doi: 10.1016/0925-4439(95)00063-A. PubMed DOI

Uziel G, Moroni I, Lamantea E, Fratta GM, Ciceri E, Carrara F, Zeviani M. Mitochondrial disease associated with the T8993G mutation of the mitochondrial ATPase 6 gene: a clinical, biochemical, and molecular study in six families. J Neurol Neurosurg Psychiatry. 1997;63:16–22. doi: 10.1136/jnnp.63.1.16. PubMed DOI PMC

Carelli V, Baracca A, Barogi S, Pallotti F, Valentino ML, Montagna P, Zeviani M, Pini A, Lenaz G, Baruzzi A, Solaini G. Biochemical-clinical correlation in patients with different loads of the mitochondrial DNA T8993G mutation. Arch Neurol. 2002;59:264–270. doi: 10.1001/archneur.59.2.264. PubMed DOI

Wei Y, Cui L, Peng B. Mitochondrial DNA mutations in late-onset Leigh syndrome. J Neurol. 2018;265:2388–2395. doi: 10.1007/s00415-018-9014-5. PubMed DOI

Hu C, Li X, Zhao L, Shi Y, Zhou S, Wu B, Wang Y. Clinical and molecular characterization of pediatric mitochondrial disorders in south of China. Eur J Med Genet. 2020;63:103898. doi: 10.1016/j.ejmg.2020.103898. PubMed DOI

Mori M, Mytinger JR, Martin LC, Bartholomew D, Hickey S. m.8993T>G-Associated Leigh Syndrome with Hypocitrullinemia on Newborn Screening. JIMD Rep. 2014;17:47–51. doi: 10.1007/8904_2014_332. PubMed DOI PMC

Morava E, Rodenburg RJ, Hol F, de Vries M, Janssen A, van den Heuvel L, Nijtmans L, Smeitink J. Clinical and biochemical characteristics in patients with a high mutant load of the mitochondrial T8993G/C mutations. Am J Med Genet A. 2006;140:863–868. doi: 10.1002/ajmg.a.31194. PubMed DOI

Ng YS, Martikainen MH, Gorman GS, Blain A, Bugiardini E, Bunting A, Schaefer AM, Alston CL, Blakely EL, Sharma S, Hughes I, Lim A, de Goede C, McEntagart M, Spinty S, Horrocks I, Roberts M, Woodward CE, Chinnery PF, Horvath R, Nesbitt V, Fratter C, Poulton J, Hanna MG, Pitceathly RDS, Taylor RW, Turnbull DM, McFarland R. Pathogenic variants in MT-ATP6: A United Kingdom-based mitochondrial disease cohort study. Ann Neurol. 2019;86:310–315. doi: 10.1002/ana.25525. PubMed DOI PMC

Yu XL, Yan CZ, Ji KQ, Lin PF, Xu XB, Dai TJ, Li W, Zhao YY. Clinical, Neuroimaging, and Pathological Analyses of 13 Chinese Leigh Syndrome Patients with Mitochondrial DNA Mutations. Chin Med J (Engl) 2018;131:2705–2712. doi: 10.4103/0366-6999.245265. PubMed DOI PMC

Stendel C, Neuhofer C, Floride E, Yuqing S, Ganetzky RD, Park J, Freisinger P, Kornblum C, Kleinle S, Schols L, Distelmaier F, Stettner GM, Buchner B, Falk MJ, Mayr JA, Synofzik M, Abicht A, Haack TB, Prokisch H, Wortmann SB, Murayama K, Fang F, Klopstock T, Group ATPS. Delineating MT-ATP6-associated disease: From isolated neuropathy to early onset neurodegeneration. Neurol Genet. 2020;6:e393. doi: 10.1212/NXG.0000000000000393. PubMed DOI PMC

Tsao CY, Mendell JR, Bartholomew D. High mitochondrial DNA T8993G mutation (<90%) without typical features of Leigh's and NARP syndromes. J Child Neurol. 2001;16:533–535. https://doi.org/10.1177/088307380101600716, https://doi.org/10.2310/7010.2001.16972. PubMed DOI

Aure K, Dubourg O, Jardel C, Clarysse L, Sternberg D, Fournier E, Laforet P, Streichenberger N, Petiot P, Gervais-Bernard H, Vial C, Bedat-Millet AL, Drouin-Garraud V, Bouillaud F, Vandier C, Fontaine B, Lombes A. Episodic weakness due to mitochondrial DNA MT-ATP6/8 mutations. Neurology. 2013;81:1810–1818. doi: 10.1212/01.wnl.0000436067.43384.0b. PubMed DOI

Claeys KG, Abicht A, Hausler M, Kleinle S, Wiesmann M, Schulz JB, Horvath R, Weis J. Novel genetic and neuropathological insights in neurogenic muscle weakness, ataxia, and retinitis pigmentosa (NARP) Muscle Nerve. 2016;54:328–333. doi: 10.1002/mus.25125. PubMed DOI

Larson AA, Balasubramaniam S, Christodoulou J, Burrage LC, Marom R, Graham BH, Diaz GA, Glamuzina E, Hauser N, Heese B, Horvath G, Mattman A, van Karnebeek C, Lane Rutledge S, Williamson A, Estrella L, Van Hove JKL, Weisfeld-Adams JD. Biochemical signatures mimicking multiple carboxylase deficiency in children with mutations in MT-ATP6. Mitochondrion. 2019;44:58–64. doi: 10.1016/j.mito.2018.01.001. PubMed DOI PMC

Porto FB, Mack G, Sterboul MJ, Lewin P, Flament J, Sahel J, Dollfus H. Isolated late-onset cone-rod dystrophy revealing a familial neurogenic muscle weakness, ataxia, and retinitis pigmentosa syndrome with the T8993G mitochondrial mutation. Am J Ophthalmol. 2001;132:935–937. doi: 10.1016/S0002-9394(01)01187-4. PubMed DOI

Puddu P, Barboni P, Mantovani V, Montagna P, Cerullo A, Bragliani M, Molinotti C, Caramazza R. Retinitis pigmentosa, ataxia, and mental retardation associated with mitochondrial DNA mutation in an Italian family. Br J Ophthalmol. 1993;77:84–88. doi: 10.1136/bjo.77.2.84. PubMed DOI PMC

Rantamaki MT, Soini HK, Finnila SM, Majamaa K, Udd B. Adult-onset ataxia and polyneuropathy caused by mitochondrial 8993T-->C mutation. Ann Neurol. 2005;58:337–340. doi: 10.1002/ana.20555. PubMed DOI

Craig K, Elliott HR, Keers SM, Lambert C, Pyle A, Graves TD, Woodward C, Sweeney MG, Davis MB, Hanna MG, Chinnery PF. Episodic ataxia and hemiplegia caused by the 8993T->C mitochondrial DNA mutation. J Med Genet. 2007;44:797–799. doi: 10.1136/jmg.2007.052902. PubMed DOI PMC

Lemoine S, Panaye M, Rabeyrin M, Errazuriz-Cerda E, Mousson de Camaret B, Petiot P, Juillard L, Guebre-Egziabher F. Renal Involvement in Neuropathy, Ataxia, Retinitis Pigmentosa (NARP) Syndrome: A Case Report. Am J Kidney Dis. 2018;71:754–757. doi: 10.1053/j.ajkd.2017.09.020. PubMed DOI

Santorelli FM, Tanji K, Shanske S, DiMauro S. Heterogeneous clinical presentation of the mtDNA NARP/T8993G mutation. Neurology. 1997;49:270–273. doi: 10.1212/WNL.49.1.270. PubMed DOI

Chinnery PF, Elliott C, Green GR, Rees A, Coulthard A, Turnbull DM, Griffiths TD. The spectrum of hearing loss due to mitochondrial DNA defects. Brain. 2000;123(Pt 1):82–92. doi: 10.1093/brain/123.1.82. PubMed DOI

Rucheton B, Jardel C, Filaut S, Amador MDM, Maisonobe T, Serre I, Romero NB, Leonard-Louis S, Haraux F, Lombes A. Homoplasmic deleterious MT-ATP6/8 mutations in adult patients. Mitochondrion. 2020;55:64–77. doi: 10.1016/j.mito.2020.08.004. PubMed DOI

Pastores GM, Santorelli FM, Shanske S, Gelb BD, Fyfe B, Wolfe D, Willner JP. Leigh syndrome and hypertrophic cardiomyopathy in an infant with a mitochondrial DNA point mutation (T8993G) Am J Med Genet. 1994;50:265–271. doi: 10.1002/ajmg.1320500310. PubMed DOI

Campos Y, Martin MA, Rubio JC, Solana LG, Garcia-Benayas C, Terradas JL, Arenas J. Leigh syndrome associated with the T9176C mutation in the ATPase 6 gene of mitochondrial DNA. Neurology. 1997;49:595–597. doi: 10.1212/WNL.49.2.595. PubMed DOI

Carrozzo R, Tessa A, Vazquez-Memije ME, Piemonte F, Patrono C, Malandrini A, Dionisi-Vici C, Vilarinho L, Villanova M, Schagger H, Federico A, Bertini E, Santorelli FM. The T9176G mtDNA mutation severely affects ATP production and results in Leigh syndrome. Neurology. 2001;56:687–690. doi: 10.1212/WNL.56.5.687. PubMed DOI

Akagi M, Inui K, Tsukamoto H, Sakai N, Muramatsu T, Yamada M, Matsuzaki K, Goto Y, Nonaka I, Okada S. A point mutation of mitochondrial ATPase 6 gene in Leigh syndrome. Neuromuscul Disord. 2002;12:53–55. doi: 10.1016/S0960-8966(01)00242-5. PubMed DOI

Castagna AE, Addis J, McInnes RR, Clarke JT, Ashby P, Blaser S, Robinson BH. Late onset Leigh syndrome and ataxia due to a T to C mutation at bp 9,185 of mitochondrial DNA. Am J Med Genet A. 2007;143A:808–816. doi: 10.1002/ajmg.a.31637. PubMed DOI

Childs AM, Hutchin T, Pysden K, Highet L, Bamford J, Livingston J, Crow YJ. Variable phenotype including Leigh syndrome with a 9185T>C mutation in the MTATP6 gene. Neuropediatrics. 2007;38:313–316. doi: 10.1055/s-2008-1065355. PubMed DOI

Saneto RP, Singh KK. Illness-induced exacerbation of Leigh syndrome in a patient with the MTATP6 mutation, m. 9185 T>C. Mitochondrion. 2010;10:567–572. doi: 10.1016/j.mito.2010.05.006. PubMed DOI PMC

Ogawa E, Shimura M, Fushimi T, Tajika M, Ichimoto K, Matsunaga A, Tsuruoka T, Ishige M, Fuchigami T, Yamazaki T, Mori M, Kohda M, Kishita Y, Okazaki Y, Takahashi S, Ohtake A, Murayama K. Clinical validity of biochemical and molecular analysis in diagnosing Leigh syndrome: a study of 106 Japanese patients. J Inherit Metab Dis. 2017;40:685–693. doi: 10.1007/s10545-017-0042-6. PubMed DOI PMC

Piekutowska-Abramczuk D, Rutyna R, Czyzyk E, Jurkiewicz E, Iwanicka-Pronicka K, Rokicki D, Stachowicz S, Strzemecka J, Guz W, Gawronski M, Kosierb A, Ligas J, Puchala M, Drelich-Zbroja A, Bednarska-Makaruk M, Dabrowski W, Ciara E, Ksiazyk JB, Pronicka E. Leigh syndrome in individuals bearing m.9185T>C MTATP6 variant. Is hyperventilation a factor which starts its development? Metab Brain Dis. 2018;33:191–199. doi: 10.1007/s11011-017-0122-1. PubMed DOI PMC

Takada R, Tozawa T, Kondo H, Kizaki Z, Kishita Y, Okazaki Y, Murayama K, Ohtake A, Chiyonobu T. Early infantile-onset Leigh syndrome complicated with infantile spasms associated with the m.9185 T > C variant in the MT-ATP6 gene: Expanding the clinical spectrum. Brain Dev. 2020;42:69–72. doi: 10.1016/j.braindev.2019.08.006. PubMed DOI

Moslemi AR, Darin N, Tulinius M, Oldfors A, Holme E. Two new mutations in the MTATP6 gene associated with Leigh syndrome. Neuropediatrics. 2005;36:314–318. doi: 10.1055/s-2005-872845. PubMed DOI

Synofzik M, Schicks J, Wilhelm C, Bornemann A, Schols L. Charcot-Marie-Tooth hereditary neuropathy due to a mitochondrial ATP6 mutation. Eur J Neurol. 2012;19:e114–116. doi: 10.1111/j.1468-1331.2012.03812.x. PubMed DOI

Pitceathly RD, Murphy SM, Cottenie E, Chalasani A, Sweeney MG, Woodward C, Mudanohwo EE, Hargreaves I, Heales S, Land J, Holton JL, Houlden H, Blake J, Champion M, Flinter F, Robb SA, Page R, Rose M, Palace J, Crowe C, Longman C, Lunn MP, Rahman S, Reilly MM, Hanna MG. Genetic dysfunction of MT-ATP6 causes axonal Charcot-Marie-Tooth disease. Neurology. 2012;79:1145–1154. doi: 10.1212/WNL.0b013e3182698d8d. PubMed DOI PMC

Bardakjian T, Scherer SS. A MT-ATP6 mutation causes a slowly progressive myeloneuropathy. J Neuromuscul Dis. 2019;6:385–387. doi: 10.3233/JND-190400. PubMed DOI PMC

Panosyan FB, Tawil R, Herrmann DN. Episodic weakness and Charcot-marie-tooth disease due to a mitochondrial MT-ATP6 mutation. Muscle Nerve. 2017;55:922–927. doi: 10.1002/mus.25453. PubMed DOI

Thyagarajan D, Shanske S, Vazquez-Memije M, De Vivo D, DiMauro S. A novel mitochondrial ATPase 6 point mutation in familial bilateral striatal necrosis. Ann Neurol. 1995;38:468–472. doi: 10.1002/ana.410380321. PubMed DOI

Verny C, Guegen N, Desquiret V, Chevrollier A, Prundean A, Dubas F, Cassereau J, Ferre M, Amati-Bonneau P, Bonneau D, Reynier P, Procaccio V. Hereditary spastic paraplegia-like disorder due to a mitochondrial ATP6 gene point mutation. Mitochondrion. 2011;11:70–75. doi: 10.1016/j.mito.2010.07.006. PubMed DOI

Brum M, Semedo C, Guerreiro R, Pinto Marques J. Motor Neuron Syndrome as a New Phenotypic Manifestation of Mutation 9185T>C in Gene MTATP6. Case Rep Neurol Med. 2014;2014:701761. doi: 10.1155/2014/701761. PubMed DOI PMC

Pfeffer G, Blakely EL, Alston CL, Hassani A, Boggild M, Horvath R, Samuels DC, Taylor RW, Chinnery PF. Adult-onset spinocerebellar ataxia syndromes due to MTATP6 mutations. J Neurol Neurosurg Psychiatry. 2012;83:883–886. doi: 10.1136/jnnp-2012-302568. PubMed DOI PMC

Nolte D, Kang JS, Hofmann A, Schwaab E, Kramer HH, Muller U. Mutations in MT-ATP6 are a frequent cause of adult-onset spinocerebellar ataxia. J Neurol. 2021;268:4866–4873. doi: 10.1007/s00415-021-10607-5. PubMed DOI PMC

Ganetzky RD, Stendel C, McCormick EM, Zolkipli-Cunningham Z, Goldstein AC, Klopstock T, Falk MJ. MT-ATP6 mitochondrial disease variants: Phenotypic and biochemical features analysis in 218 published cases and cohort of 14 new cases. Hum Mutat. 2019;40:499–515. doi: 10.1002/humu.23723. PubMed DOI PMC

Honzik T, Tesarova M, Vinsova K, Hansikova H, Magner M, Kratochvilova H, Zamecnik J, Zeman J, Jesina P. Different laboratory and muscle biopsy findings in a family with an m.8851T>C mutation in the mitochondrial MTATP6 gene. Mol Genet Metab. 2013;108:102–105. doi: 10.1016/j.ymgme.2012.11.002. PubMed DOI

Blanco-Grau A, Bonaventura-Ibars I, Coll-Canti J, Melia MJ, Martinez R, Martinez-Gallo M, Andreu AL, Pinos T, Garcia-Arumi E. Identification and biochemical characterization of the novel mutation m.8839G>C in the mitochondrial ATP6 gene associated with NARP syndrome. Genes Brain Behav. 2013;12:812–820. doi: 10.1111/gbb.12089. PubMed DOI

Duno M, Wibrand F, Baggesen K, Rosenberg T, Kjaer N, Frederiksen AL. A novel mitochondrial mutation m.8989G>C associated with neuropathy, ataxia, retinitis pigmentosa - the NARP syndrome. Gene. 2013;515:372–375. doi: 10.1016/j.gene.2012.12.066. PubMed DOI

Lopez-Gallardo E, Emperador S, Solano A, Llobet L, Martin-Navarro A, Lopez-Perez MJ, Briones P, Pineda M, Artuch R, Barraquer E, Jerico I, Ruiz-Pesini E, Montoya J. Expanding the clinical phenotypes of MT-ATP6 mutations. Hum Mol Genet. 2014;23:6191–6200. doi: 10.1093/hmg/ddu339. PubMed DOI

Mordel P, Schaeffer S, Dupas Q, Laville MA, Gerard M, Chapon F, Allouche S. A 2 bp deletion in the mitochondrial ATP 6 gene responsible for the NARP (neuropathy, ataxia, and retinitis pigmentosa) syndrome. Biochem Biophys Res Commun. 2017;494:133–137. doi: 10.1016/j.bbrc.2017.10.066. PubMed DOI

Jackson CB, Hahn D, Schroter B, Richter U, Battersby BJ, Schmitt-Mechelke T, Marttinen P, Nuoffer JM, Schaller A. A novel mitochondrial ATP6 frameshift mutation causing isolated complex V deficiency, ataxia and encephalomyopathy. Eur J Med Genet. 2017;60:345–351. doi: 10.1016/j.ejmg.2017.04.006. PubMed DOI

Panwala TF, Garcia-Santibanez R, Vizcarra JA, Garcia AG, Verma S. Childhood-Onset Hereditary Spastic Paraplegia (HSP): A Case Series and Review of Literature. Pediatr Neurol. 2022;130:7–13. doi: 10.1016/j.pediatrneurol.2022.02.007. PubMed DOI

De Meirleir L, Seneca S, Lissens W, Schoentjes E, Desprechins B. Bilateral striatal necrosis with a novel point mutation in the mitochondrial ATPase 6 gene. Pediatr Neurol. 1995;13:242–246. doi: 10.1016/0887-8994(95)00184-H. PubMed DOI

Sikorska M, Sandhu JK, Simon DK, Pathiraja V, Sodja C, Li Y, Ribecco-Lutkiewicz M, Lanthier P, Borowy-Borowski H, Upton A, Raha S, Pulst SM, Tarnopolsky MA. Identification of ataxia-associated mtDNA mutations (m.4052T>C and m.9035T>C) and evaluation of their pathogenicity in transmitochondrial cybrids. Muscle Nerve. 2009;40:381–394. doi: 10.1002/mus.21355. PubMed DOI

Capiau S, Smet J, De Paepe B, Yildiz Y, Arslan M, Stevens O, Verschoore M, Stepman H, Seneca S, Vanlander A. Clinical heterogeneity in MT-ATP6 pathogenic variants: same genotype-different onset. Cells. 2022:11. doi: 10.3390/cells11030489. PubMed DOI PMC

Knight KM, Shelkowitz E, Larson AA, Mirsky DM, Wang Y, Chen T, Wong LJ, Friederich MW, Van Hove JLK. The mitochondrial DNA variant m.9032T > C in MT-ATP6 encoding p.(Leu169Pro) causes a complex mitochondrial neurological syndrome. Mitochondrion. 2020;55:8–13. doi: 10.1016/j.mito.2020.08.009. PubMed DOI PMC

Burrage LC, Tang S, Wang J, Donti TR, Walkiewicz M, Luchak JM, Chen LC, Schmitt ES, Niu Z, Erana R, Hunter JV, Graham BH, Wong LJ, Scaglia F. Mitochondrial myopathy, lactic acidosis, and sideroblastic anemia (MLASA) plus associated with a novel de novo mutation (m.8969G>A) in the mitochondrial encoded ATP6 gene. Mol Genet Metab. 2014;113:207–212. doi: 10.1016/j.ymgme.2014.06.004. PubMed DOI PMC

Wen S, Niedzwiecka K, Zhao W, Xu S, Liang S, Zhu X, Xie H, Tribouillard-Tanvier D, Giraud MF, Zeng C, Dautant A, Kucharczyk R, Liu Z, di Rago JP, Chen H. Identification of G8969>A in mitochondrial ATP6 gene that severely compromises ATP synthase function in a patient with IgA nephropathy. Sci Rep. 2016;6:36313. doi: 10.1038/srep36313. PubMed DOI PMC

Honzik T, Tesarova M, Magner M, Mayr J, Jesina P, Vesela K, Wenchich L, Szentivanyi K, Hansikova H, Sperl W, Zeman J. Neonatal onset of mitochondrial disorders in 129 patients: clinical and laboratory characteristics and a new approach to diagnosis. J Inherit Metab Dis. 2012;35:749–759. doi: 10.1007/s10545-011-9440-3. PubMed DOI

Isohanni P, Carroll CJ, Jackson CB, Pohjanpelto M, Lonnqvist T, Suomalainen A. Defective mitochondrial ATPase due to rare mtDNA m.8969G>A mutation-causing lactic acidosis, intellectual disability, and poor growth. Neurogenetics. 2018;19:49–53. doi: 10.1007/s10048-018-0537-9. PubMed DOI

Berhe S, Heeney MM, Campagna DR, Thompson JF, White EJ, Ross T, Peake RWA, Hanrahan JD, Rodriguez V, Renaud DL, Patnaik MS, Chang E, Bottomley SS, Fleming MD. Recurrent heteroplasmy for the MT-ATP6 p.Ser148Asn (m.8969G>A) mutation in patients with syndromic congenital sideroblastic anemia of variable clinical severity. Haematologica. 2018;103:e561–e563. doi: 10.3324/haematol.2018.199109. PubMed DOI PMC

Adema AY, Janssen MC, van der Heijden JW. A novel mutation in mitochondrial DNA in a patient with diabetes, deafness and proteinuria. Neth J Med. 2016;74:455–457. PubMed

Bergs PMJ, Maas DM, Janssen MCH, Groothuis JT. Feasible and clinical relevant outcome measures for adults with mitochondrial disease. Mol Genet Metab. 2022;135:102–108. doi: 10.1016/j.ymgme.2021.12.010. PubMed DOI

Kumar M, Tanwar M, Saxena R, Sharma P, Dada R. Identification of novel mitochondrial mutations in Leber's hereditary optic neuropathy. Mol Vis. 2010;16:782–792. PubMed PMC

Abu-Amero KK, Bosley TM. Mitochondrial abnormalities in patients with LHON-like optic neuropathies. Invest Ophthalmol Vis Sci. 2006;47:4211–4220. doi: 10.1167/iovs.06-0295. PubMed DOI

Dawod PGA, Jancic J, Marjanovic A, Brankovic M, Jankovic M, Samardzic J, Potkonjak D, Djuric V, Mesaros S, Novakovic I, Abdel Motaleb FI, Kostic VS, Nikolic D. Whole Mitochondrial Genome Analysis in Serbian Cases of Leber's Hereditary Optic Neuropathy. Genes (Basel) 2020:11. doi: 10.3390/genes11091037. PubMed DOI PMC

Lamminen T, Majander A, Juvonen V, Wikstrom M, Aula P, Nikoskelainen E, Savontous ML. 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. 1995;56:1238–1240. PubMed PMC

Pinke G, Zhou L, Sazanov LA. Cryo-EM structure of the entire mammalian F-type ATP synthase. Nat Struct Mol Biol. 2020;27:1077–1085. doi: 10.1038/s41594-020-0503-8. PubMed DOI

Pallotti F, Baracca A, Hernandez-Rosa E, Walker WF, Solaini G, Lenaz G, Melzi D'Eril GV, Dimauro S, Schon EA, Davidson MM. Biochemical analysis of respiratory function in cybrid cell lines harbouring mitochondrial DNA mutations. Biochem J. 2004;384:287–293. doi: 10.1042/BJ20040561. PubMed DOI PMC

Sgarbi G, Baracca A, Lenaz G, Valentino LM, Carelli V, Solaini G. 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. 2006;395:493–500. doi: 10.1042/BJ20051748. PubMed DOI PMC

Baracca A, Sgarbi G, Mattiazzi M, Casalena G, Pagnotta E, Valentino ML, Moggio M, Lenaz G, Carelli V, Solaini G. Biochemical phenotypes associated with the mitochondrial ATP6 gene mutations at nt8993. Biochim Biophys Acta. 2007;1767:913–919. doi: 10.1016/j.bbabio.2007.05.005. PubMed DOI

Vazquez-Memije ME, Rizza T, Meschini MC, Nesti C, Santorelli FM, Carrozzo R. Cellular and functional analysis of four mutations located in the mitochondrial ATPase6 gene. J Cell Biochem. 2009;106:878–886. doi: 10.1002/jcb.22055. PubMed DOI

Baracca A, Barogi S, Carelli V, Lenaz G, Solaini G. Catalytic activities of mitochondrial ATP synthase in patients with mitochondrial DNA T8993G mutation in the ATPase 6 gene encoding subunit a. J Biol Chem. 2000;275:4177–4182. doi: 10.1074/jbc.275.6.4177. PubMed DOI

Tatuch Y, Pagon RA, Vlcek B, Roberts R, Korson M, Robinson BH. The 8993 mtDNA mutation: heteroplasmy and clinical presentation in three families. Eur J Hum Genet. 1994;2:35–43. doi: 10.1159/000472339. PubMed DOI

Vazquez-Memije ME, Shanske S, Santorelli FM, Kranz-Eble P, DeVivo DC, DiMauro S. Comparative biochemical studies of ATPases in cells from patients with the T8993G or T8993C mitochondrial DNA mutations. J Inherit Metab Dis. 1998;21:829–836. doi: 10.1023/A:1005418718299. PubMed DOI

Cortes-Hernandez P, Vazquez-Memije ME, Garcia JJ. ATP6 homoplasmic mutations inhibit and destabilize the human F1F0-ATP synthase without preventing enzyme assembly and oligomerization. J Biol Chem. 2007;282:1051–1058. doi: 10.1074/jbc.M606828200. PubMed DOI

Dautant A, Meier T, Hahn A, Tribouillard-Tanvier D, di Rago JP, Kucharczyk R. ATP Synthase Diseases of Mitochondrial Genetic Origin. Front Physiol. 2018;9:329. doi: 10.3389/fphys.2018.00329. PubMed DOI PMC

Del Dotto V, Musiani F, Baracca A, Solaini G. Variants in Human ATP Synthase Mitochondrial Genes: Biochemical Dysfunctions, Associated Diseases, and Therapies. Int J Mol Sci. 2024:25. doi: 10.3390/ijms25042239. PubMed DOI PMC

Stenton SL, Prokisch H. Genetics of mitochondrial diseases: Identifying mutations to help diagnosis. EBioMedicine. 2020;56:102784. doi: 10.1016/j.ebiom.2020.102784. PubMed DOI PMC

Dimauro S. A history of mitochondrial diseases. J Inherit Metab Dis. 2011;34:261–276. doi: 10.1007/s10545-010-9082-x. PubMed DOI

Holme E, Greter J, Jacobson CE, Larsson NG, Lindstedt S, Nilsson KO, Oldfors A, Tulinius M. Mitochondrial ATP-synthase deficiency in a child with 3-methylglutaconic aciduria. Pediatr Res. 1992;32:731–735. doi: 10.1203/00006450-199212000-00022. PubMed DOI

Houstek J, Klement P, Floryk D, Antonicka H, Hermanska J, Kalous M, Hansikova H, Hout'kova H, Chowdhury SK, Rosipal T, Kmoch S, Stratilova L, Zeman J. A novel deficiency of mitochondrial ATPase of nuclear origin. Hum Mol Genet. 1999;8:1967–1974. doi: 10.1093/hmg/8.11.1967. PubMed DOI

Sperl W, Jesina P, Zeman J, Mayr JA, Demeirleir L, VanCoster R, Pickova A, Hansikova H, Houst'kova H, Krejcik Z, Koch J, Smet J, Muss W, Holme E, Houstek J. Deficiency of mitochondrial ATP synthase of nuclear genetic origin. Neuromuscul Disord. 2006;16:821–829. doi: 10.1016/j.nmd.2006.08.008. PubMed DOI

De Meirleir L, Seneca S, Lissens W, De Clercq I, Eyskens F, Gerlo E, Smet J, Van Coster R. Respiratory chain complex V deficiency due to a mutation in the assembly gene ATP12. J Med Genet. 2004;41:120–124. doi: 10.1136/jmg.2003.012047. PubMed DOI PMC

Cizkova A, Stranecky V, Mayr JA, Tesarova M, Havlickova V, Paul J, Ivanek R, Kuss AW, Hansikova H, Kaplanova V, Vrbacky M, Hartmannova H, Noskova L, Honzik T, Drahota Z, Magner M, Hejzlarova K, Sperl W, Zeman J, Houstek J, Kmoch S. TMEM70 mutations cause isolated ATP synthase deficiency and neonatal mitochondrial encephalocardiomyopathy. Nat Genet. 2008;40:1288–1290. doi: 10.1038/ng.246. PubMed DOI

Mayr JA, Havlickova V, Zimmermann F, Magler I, Kaplanova V, Jesina P, Pecinova A, Nuskova H, Koch J, Sperl W, Houstek J. Mitochondrial ATP synthase deficiency due to a mutation in the ATP5E gene for the F1 epsilon subunit. Hum Mol Genet. 2010;19:3430–3439. doi: 10.1093/hmg/ddq254. PubMed DOI

Lieber DS, Calvo SE, Shanahan K, Slate NG, Liu S, Hershman SG, Gold NB, Chapman BA, Thorburn DR, Berry GT, Schmahmann JD, Borowsky ML, Mueller DM, Sims KB, Mootha VK. Targeted exome sequencing of suspected mitochondrial disorders. Neurology. 2013;80:1762–1770. doi: 10.1212/WNL.0b013e3182918c40. PubMed DOI PMC

Jonckheere AI, Renkema GH, Bras M, van den Heuvel LP, Hoischen A, Gilissen C, Nabuurs SB, Huynen MA, de Vries MC, Smeitink JA, Rodenburg RJ. A complex V ATP5A1 defect causes fatal neonatal mitochondrial encephalopathy. Brain. 2013;136:1544–1554. doi: 10.1093/brain/awt086. PubMed DOI

Lines MA, Cuillerier A, Chakraborty P, Naas T, Duque Lasio ML, Michaud J, Pileggi C, Harper ME, Burelle Y, Toler TL, Sondheimer N, Crawford HP, Millan F, Geraghty MT. A recurrent de novo ATP5F1A substitution associated with neonatal complex V deficiency. Eur J Hum Genet. 2021;29:1719–1724. doi: 10.1038/s41431-021-00956-0. PubMed DOI PMC

Zech M, Kopajtich R, Steinbrucker K, Bris C, Gueguen N, Feichtinger RG, Achleitner MT, Duzkale N, Perivier M, Koch J, Engelhardt H, Freisinger P, Wagner M, Brunet T, Berutti R, Smirnov D, Navaratnarajah T, Rodenburg RJT, Pais LS, Austin-Tse C, O' Leary M, Boesch S, Jech R, Bakhtiari S, Jin SC, Wilbert F, Kruer MC, Wortmann SB, Eckenweiler M, Mayr JA, Distelmaier F, Steinfeld R, Winkelmann J, Prokisch H. Variants in Mitochondrial ATP Synthase Cause Variable Neurologic Phenotypes. Ann Neurol. 2022;91:225–237. doi: 10.1002/ana.26293. PubMed DOI PMC

Ganetzky RD, Markhard AL, Yee I, Clever S, Cahill A, Shah H, Grabarek Z, To TL, Mootha VK. Congenital Hypermetabolism and Uncoupled Oxidative Phosphorylation. N Engl J Med. 2022;387:1395–1403. doi: 10.1056/NEJMoa2202949. PubMed DOI PMC

Nasca A, Mencacci NE, Invernizzi F, Zech M, Keller Sarmiento IJ, Legati A, Frascarelli C, Bustos BI, Romito LM, Krainc D, Winkelmann J, Carecchio M, Nardocci N, Zorzi G, Prokisch H, Lubbe SJ, Garavaglia B, Ghezzi D. Variants in ATP5F1B are associated with dominantly inherited dystonia. Brain. 2023;146:2730–2738. doi: 10.1093/brain/awad068. PubMed DOI PMC

Olahova M, Yoon WH, Thompson K, Jangam S, Fernandez L, Davidson JM, Kyle JE, Grove ME, Fisk DG, Kohler JN, Holmes M, Dries AM, Huang Y, Zhao C, Contrepois K, Zappala Z, Fresard L, Waggott D, Zink EM, Kim YM, Heyman HM, Stratton KG, Webb-Robertson BM, Snyder M, Merker JD, Montgomery SB, Fisher PG, Feichtinger RG, Mayr JA, Hall J, Barbosa IA, Simpson MA, Deshpande C, Waters KM, Koeller DM, Metz TO, Morris AA, Schelley S, Cowan T, Friederich MW, McFarland R, Van Hove JLK, Enns GM, Yamamoto S, Ashley EA, Wangler MF, Taylor RW, Bellen HJ, Bernstein JA, Wheeler MT Undiagnosed Diseases N. Biallelic Mutations in ATP5F1D, which Encodes a Subunit of ATP Synthase, Cause a Metabolic Disorder. Am J Hum Genet. 2018;102:494–504. doi: 10.1016/j.ajhg.2018.01.020. PubMed DOI PMC

Neilson DE, Zech M, Hufnagel RB, Slone J, Wang X, Homan S, Gutzwiller LM, Leslie EJ, Leslie ND, Xiao J, Hedera P, LeDoux MS, Gebelein B, Wilbert F, Eckenweiler M, Winkelmann J, Gilbert DL, Huang T. A novel variant of ATP5MC3 associated with both dystonia and spastic paraplegia. Mov Disord. 2022;37:375–383. doi: 10.1002/mds.28821. PubMed DOI PMC

Barca E, Ganetzky RD, Potluri P, Juanola-Falgarona M, Gai X, Li D, Jalas C, Hirsch Y, Emmanuele V, Tadesse S, Ziosi M, Akman HO, Chung WK, Tanji K, McCormick EM, Place E, Consugar M, Pierce EA, Hakonarson H, Wallace DC, Hirano M, Falk MJ. USMG5 Ashkenazi Jewish founder mutation impairs mitochondrial complex V dimerization and ATP synthesis. Hum Mol Genet. 2018;27:3305–3312. doi: 10.1093/hmg/ddy231. PubMed DOI PMC

Ganapathi M, Friocourt G, Gueguen N, Friederich MW, Le Gac G, Okur V, Loaec N, Ludwig T, Ka C, Tanji K, Marcorelles P, Theodorou E, Lignelli-Dipple A, Voisset C, Walker MA, Briere LC, Bourhis A, Blondel M, LeDuc C, Hagen J, Cooper C, Muraresku C, Ferec C, Garenne A, Lelez-Soquet S, Rogers CA, Shen Y, Strode DK, Bizargity P, Iglesias A, Goldstein A, High FA, Network UD, Sweetser DA, Ganetzky R, Van Hove JLK, Procaccio V, Le Marechal C, Chung WK. A homozygous splice variant in ATP5PO, disrupts mitochondrial complex V function and causes Leigh syndrome in two unrelated families. J Inherit Metab Dis. 2022;45:996–1012. doi: 10.1002/jimd.12526. PubMed DOI PMC

Waterham HR, Koster J, Ebberink MS, Jesina P, Zeman J, Noskova L, Kmoch S, Devic P, Cheillan D, Wanders RJA, Ferdinandusse S. Autosomal dominant Zellweger spectrum disorder caused by de novo variants in PEX14 gene. Genet Med. 2023;25:100944. doi: 10.1016/j.gim.2023.100944. PubMed DOI

Gilbert DL, Leslie EJ, Keddache M, Leslie ND. A novel hereditary spastic paraplegia with dystonia linked to chromosome 2q24–2q31. Mov Disord. 2009;24:364–370. doi: 10.1002/mds.22363. PubMed DOI

Luft R, Ikkos D, Palmieri G, Ernster L, Afzelius B. A case of severe hypermetabolism of nonthyroid origin with a defect in the maintenance of mitochondrial respiratory control: a correlated clinical, biochemical, and morphological study. J Clin Invest. 1962;41:1776–1804. doi: 10.1172/JCI104637. PubMed DOI PMC

DiMauro S, Bonilla E, Lee CP, Schotland DL, Scarpa A, Conn H, Jr, Chance B. Luft's disease. Further biochemical and ultrastructural studies of skeletal muscle in the second case. J Neurol Sci. 1976;27:217–232. doi: 10.1016/0022-510X(76)90063-0. PubMed DOI

Giorgio V, Fogolari F, Lippe G, Bernardi P. OSCP subunit of mitochondrial ATP synthase: role in regulation of enzyme function and of its transition to a pore. Br J Pharmacol. 2019;176:4247–4257. doi: 10.1111/bph.14513. PubMed DOI PMC

He J, Ford HC, Carroll J, Douglas C, Gonzales E, Ding S, Fearnley IM, Walker JE. Assembly of the membrane domain of ATP synthase in human mitochondria. Proc Natl Acad Sci U S A. 2018;115:2988–2993. doi: 10.1073/pnas.1722086115. PubMed DOI PMC

Wang Y, Singh U, Mueller DM. Mitochondrial genome integrity mutations uncouple the yeast Saccharomyces cerevisiae ATP synthase. J Biol Chem. 2007;282:8228–8236. doi: 10.1074/jbc.M609635200. PubMed DOI PMC

Kuhlbrandt W. Structure and Mechanisms of F-Type ATP Synthases. Annu Rev Biochem. 2019;88:515–549. doi: 10.1146/annurev-biochem-013118-110903. PubMed DOI

He J, Ford HC, Carroll J, Ding S, Fearnley IM, Walker JE. Persistence of the mitochondrial permeability transition in the absence of subunit c of human ATP synthase. Proc Natl Acad Sci U S A. 2017;114:3409–3414. https://doi.org/10.1073/pnas.1702357114, https://doi.org/10.1073/pnas.1711201114. PubMed DOI PMC

Calvo S, Jain M, Xie X, Sheth SA, Chang B, Goldberger OA, Spinazzola A, Zeviani M, Carr SA, Mootha VK. Systematic identification of human mitochondrial disease genes through integrative genomics. Nat Genet. 2006;38:576–582. doi: 10.1038/ng1776. PubMed DOI

Honzik T, Tesarova M, Mayr JA, Hansikova H, Jesina P, Bodamer O, Koch J, Magner M, Freisinger P, Huemer M, Kostkova O, van Coster R, Kmoch S, Houstek J, Sperl W, Zeman J. Mitochondrial encephalocardio-myopathy with early neonatal onset due to TMEM70 mutation. Arch Dis Child. 2010;95:296–301. doi: 10.1136/adc.2009.168096. PubMed DOI

Wortmann SB, Rodenburg RJ, Jonckheere A, de Vries MC, Huizing M, Heldt K, van den Heuvel LP, Wendel U, Kluijtmans LA, Engelke UF, Wevers RA, Smeitink JA, Morava E. Biochemical and genetic analysis of 3-methylglutaconic aciduria type IV: a diagnostic strategy. Brain. 2009;132:136–146. doi: 10.1093/brain/awn296. PubMed DOI

Tort F, Del Toro M, Lissens W, Montoya J, Fernandez-Burriel M, Font A, Bujan N, Navarro-Sastre A, Lopez-Gallardo E, Arranz JA, Riudor E, Briones P, Ribes A. Screening for nuclear genetic defects in the ATP synthase-associated genes TMEM70, ATP12 and ATP5E in patients with 3-methylglutaconic aciduria. Clin Genet. 2011;80:297–300. doi: 10.1111/j.1399-0004.2011.01650.x. PubMed DOI

Stojanovic V, Doronjski A. Mild form of 3-methylglutaconic aciduria type IV and mutation in the TMEM70 genes. J Pediatr Endocrinol Metab. 2013;26:151–154. doi: 10.1515/jpem-2012-0291. PubMed DOI

Catteruccia M, Verrigni D, Martinelli D, Torraco A, Agovino T, Bonafe L, D' Amico A, Donati MA, Adorisio R, Santorelli FM, Carrozzo R, Bertini E, Dionisi-Vici C. Persistent pulmonary arterial hypertension in the newborn (PPHN): a frequent manifestation of TMEM70 defective patients. Mol Genet Metab. 2014;111:353–359. doi: 10.1016/j.ymgme.2014.01.001. PubMed DOI

Torraco A, Verrigni D, Rizza T, Meschini MC, Vazquez-Memije ME, Martinelli D, Bianchi M, Piemonte F, Dionisi-Vici C, Santorelli FM, Bertini E, Carrozzo R. TMEM70: a mutational hot spot in nuclear ATP synthase deficiency with a pivotal role in complex V biogenesis. Neurogenetics. 2012;13:375–386. doi: 10.1007/s10048-012-0343-8. PubMed DOI

Magner M, Dvorakova V, Tesarova M, Mazurova S, Hansikova H, Zahorec M, Brennerova K, Bzduch V, Spiegel R, Horovitz Y, Mandel H, Eminoglu FT, Mayr JA, Koch J, Martinelli D, Bertini E, Konstantopoulou V, Smet J, Rahman S, Broomfield A, Stojanovic V, Dionisi-Vici C, van Coster R, Morava E, Sperl W, Zeman J, Honzik T. TMEM70 deficiency: long-term outcome of 48 patients. J Inherit Metab Dis. 2015;38:417–426. https://doi.org/10.1007/s10545-015-9833-9, https://doi.org/10.1007/s10545-014-9774-8. PubMed DOI

Braczynski AK, Vlaho S, Muller K, Wittig I, Blank AE, Tews DS, Drott U, Kleinle S, Abicht A, Horvath R, Plate KH, Stenzel W, Goebel HH, Schulze A, Harter PN, Kieslich M, Mittelbronn M. ATP synthase deficiency due to TMEM70 mutation leads to ultrastructural mitochondrial degeneration and is amenable to treatment. Biomed Res Int. 2015;2015:462592. doi: 10.1155/2015/462592. PubMed DOI PMC

Diodato D, Invernizzi F, Lamantea E, Fagiolari G, Parini R, Menni F, Parenti G, Bollani L, Pasquini E, Donati MA, Cassandrini D, Santorelli FM, Haack TB, Prokisch H, Ghezzi D, Lamperti C, Zeviani M. Common and novel TMEM70 mutations in a cohort of italian patients with mitochondrial encephalocardiomyopathy. JIMD Rep. 2015;15:71–78. doi: 10.1007/8904_2014_300. PubMed DOI PMC

Sarajlija A, Magner M, Djordjevic M, Kecman B, Grujic B, Tesarova M, Minic P. Late-presenting congenital diaphragmatic hernia in a child with TMEM70 deficiency. Congenit Anom (Kyoto) 2017;57:64–65. doi: 10.1111/cga.12194. PubMed DOI

aban A, Adorisio R, Corica B, Rizzo C, Cali F, Semeraro M, Taurisano R, Magliozzi M, Carrozzo R, Parisi F, Dallapiccola B, Vaz FM, Drago F, Dionisi-Vici C. Delayed appearance of 3-methylglutaconic aciduria in neonates with early onset metabolic cardiomyopathies: A potential pitfall for the diagnosis. Am J Med Genet A. 2020;182:64–70. doi: 10.1002/ajmg.a.61383. PubMed DOI

Spiegel R, Khayat M, Shalev SA, Horovitz Y, Mandel H, Hershkovitz E, Barghuti F, Shaag A, Saada A, Korman SH, Elpeleg O, Yatsiv I. TMEM70 mutations are a common cause of nuclear encoded ATP synthase assembly defect: further delineation of a new syndrome. J Med Genet. 2011;48:177–182. doi: 10.1136/jmg.2010.084608. PubMed DOI

Jonckheere AI, Huigsloot M, Lammens M, Jansen J, van den Heuvel LP, Spiekerkoetter U, von Kleist-Retzow JC, Forkink M, Koopman WJ, Szklarczyk R, Huynen MA, Fransen JA, Smeitink JA, Rodenburg RJ. Restoration of complex V deficiency caused by a novel deletion in the human TMEM70 gene normalizes mitochondrial morphology. Mitochondrion. 2011;11:954–963. doi: 10.1016/j.mito.2011.08.012. PubMed DOI

Staretz-Chacham O, Wormser O, Manor E, Birk OS, Ferreira CR. TMEM70 deficiency: Novel mutation and hypercitrullinemia during metabolic decompensation. Am J Med Genet A. 2019;179:1293–1298. doi: 10.1002/ajmg.a.61138. PubMed DOI PMC

Atay Z, Bereket A, Turan S, Haliloglu B, Memisoglu A, Khayat M, Shalev SA, Spiegel R. A novel homozygous TMEM70 mutation results in congenital cataract and neonatal mitochondrial encephalo-cardiomyopathy. Gene. 2013;515:197–199. doi: 10.1016/j.gene.2012.11.044. PubMed DOI

Mackay L, Gijavanekar C, Streff H, Price JF, Elsea SH, Scaglia F. Novel phenotype of aortic root dilatation and late-onset metabolic decompensation in a patient with TMEM70 deficiency. Am J Med Genet A. 2023;191:1366–1372. doi: 10.1002/ajmg.a.63131. PubMed DOI

Cameron JM, Levandovskiy V, Mackay N, Ackerley C, Chitayat D, Raiman J, Halliday WH, Schulze A, Robinson BH. Complex V TMEM70 deficiency results in mitochondrial nucleoid disorganization. Mitochondrion. 2011;11:191–199. doi: 10.1016/j.mito.2010.09.008. PubMed DOI

Shchelochkov OA, Li FY, Wang J, Zhan H, Towbin JA, Jefferies JL, Wong LJ, Scaglia F. Milder clinical course of Type IV 3-methylglutaconic aciduria due to a novel mutation in TMEM70. Mol Genet Metab. 2010;101:282–285. doi: 10.1016/j.ymgme.2010.07.012. PubMed DOI

Hirono K, Ichida F, Nishio N, Ogawa-Tominaga M, Fushimi T, Feichtinger RG, Mayr JA, Kohda M, Kishita Y, Okazaki Y, Ohtake A, Murayama K. Mitochondrial complex deficiency by novel compound heterozygous TMEM70 variants and correlation with developmental delay, undescended testicle, and left ventricular noncompaction in a Japanese patient: A case report. Clin Case Rep. 2019;7:553–557. doi: 10.1002/ccr3.2050. PubMed DOI PMC

Brambilla A, Olivotto I, Favilli S, Spaziani G, Passantino S, Procopio E, Morrone A, Donati MA. Impact of cardiovascular involvement on the clinical course of paediatric mitochondrial disorders. Orphanet J Rare Dis. 2020;15:196. doi: 10.1186/s13023-020-01466-w. PubMed DOI PMC

Rabier D, Diry C, Rotig A, Rustin P, Heron B, Bardet J, Parvy P, Ponsot G, Marsac C, Saudubray JM, Munnich A, Kamoun P. Persistent hypocitrullinaemia as a marker for mtDNA NARP T 8993 G mutation? J Inherit Metab Dis. 1998;21:216–219. doi: 10.1023/A:1005391300203. PubMed DOI

Ribas GS, Lopes FF, Deon M, Vargas CR. Hyperammonemia in Inherited Metabolic Diseases. Cell Mol Neurobiol. 2022;42:2593–2610. doi: 10.1007/s10571-021-01156-6. PubMed DOI PMC

Scaglia F, Scheuerle AE, Towbin JA, Armstrong DL, Sweetman L, Wong LJ. Neonatal presentation of ventricular tachycardia and a Reye-like syndrome episode associated with disturbed mitochondrial energy metabolism. BMC Pediatr. 2002;2:12. doi: 10.1186/1471-2431-2-12. PubMed DOI PMC

Jones DE, Klacking E, Ryan RO. Inborn errors of metabolism associated with 3-methylglutaconic aciduria. Clin Chim Acta. 2021;522:96–104. doi: 10.1016/j.cca.2021.08.016. PubMed DOI PMC

Wortmann SB, Duran M, Anikster Y, Barth PG, Sperl W, Zschocke J, Morava E, Wevers RA. Inborn errors of metabolism with 3-methylglutaconic aciduria as discriminative feature: proper classification and nomenclature. J Inherit Metab Dis. 2013;36:923–928. doi: 10.1007/s10545-012-9580-0. PubMed DOI

Taylor RW, Pyle A, Griffin H, Blakely EL, Duff J, He L, Smertenko T, Alston CL, Neeve VC, Best A, Yarham JW, Kirschner J, Schara U, Talim B, Topaloglu H, Baric I, Holinski-Feder E, Abicht A, Czermin B, Kleinle S, Morris AA, Vassallo G, Gorman GS, Ramesh V, Turnbull DM, Santibanez-Koref M, McFarland R, Horvath R, Chinnery PF. Use of whole-exome sequencing to determine the genetic basis of multiple mitochondrial respiratory chain complex deficiencies. JAMA. 2014;312:68–77. doi: 10.1001/jama.2014.7184. PubMed DOI PMC

Wortmann SB, Koolen DA, Smeitink JA, van den Heuvel L, Rodenburg RJ. Whole exome sequencing of suspected mitochondrial patients in clinical practice. J Inherit Metab Dis. 2015;38:437–443. doi: 10.1007/s10545-015-9823-y. PubMed DOI PMC

Calvo SE, Compton AG, Hershman SG, Lim SC, Lieber DS, Tucker EJ, Laskowski A, Garone C, Liu S, Jaffe DB, Christodoulou J, Fletcher JM, Bruno DL, Goldblatt J, Dimauro S, Thorburn DR, Mootha VK. Molecular diagnosis of infantile mitochondrial disease with targeted next-generation sequencing. Sci Transl Med. 2012;4:118ra110. doi: 10.1126/scitranslmed.3003310. PubMed DOI PMC

Carroll CJ, Brilhante V, Suomalainen A. Next-generation sequencing for mitochondrial disorders. Br J Pharmacol. 2014;171:1837–1853. doi: 10.1111/bph.12469. PubMed DOI PMC

Alston CL, Rocha MC, Lax NZ, Turnbull DM, Taylor RW. The genetics and pathology of mitochondrial disease. J Pathol. 2017;241:236–250. doi: 10.1002/path.4809. PubMed DOI PMC

Theunissen TEJ, Nguyen M, Kamps R, Hendrickx AT, Sallevelt S, Gottschalk RWH, Calis CM, Stassen APM, de Koning B, Mulder-Den Hartog ENM, Schoonderwoerd K, Fuchs SA, Hilhorst-Hofstee Y, de Visser M, Vanoevelen J, Szklarczyk R, Gerards M, de Coo IFM, Hellebrekers D, Smeets HJM. Whole exome sequencing is the preferred strategy to identify the genetic defect in patients with a probable or possible mitochondrial cause. Front Genet. 2018;9:400. doi: 10.3389/fgene.2018.00400. PubMed DOI PMC

Thompson K, Collier JJ, Glasgow RIC, Robertson FM, Pyle A, Blakely EL, Alston CL, Olahova M, McFarland R, Taylor RW. Recent advances in understanding the molecular genetic basis of mitochondrial disease. J Inherit Metab Dis. 2020;43:36–50. doi: 10.1002/jimd.12104. PubMed DOI PMC

Abicht A, Scharf F, Kleinle S, Schon U, Holinski-Feder E, Horvath R, Benet-Pages A, Diebold I. Mitochondrial and nuclear disease panel (Mito-aND-Panel): Combined sequencing of mitochondrial and nuclear DNA by a cost-effective and sensitive NGS-based method. Mol Genet Genomic Med. 2018;6:1188–1198. doi: 10.1002/mgg3.500. PubMed DOI PMC

Walsh N, Cooper A, Dockery A, O' Byrne JJ. Variant reclassification and clinical implications. J Med Genet. 2024;61:207–211. doi: 10.1136/jmg-2023-109488. PubMed DOI

Zhang H, Burr SP, Chinnery PF. The mitochondrial DNA genetic bottleneck: inheritance and beyond. Essays Biochem. 2018;62:225–234. doi: 10.1042/EBC20170096. PubMed DOI

Sallevelt SC, de Die-Smulders CE, Hendrickx AT, Hellebrekers DM, de Coo IF, Alston CL, Knowles C, Taylor RW, McFarland R, Smeets HJ. De novo mtDNA point mutations are common and have a low recurrence risk. J Med Genet. 2017;54:73–83. doi: 10.1136/jmedgenet-2016-103876. PubMed DOI PMC

Spikes TE, Montgomery MG, Walker JE. Structure of the dimeric ATP synthase from bovine mitochondria. Proc Natl Acad Sci U S A. 2020;117:23519–23526. doi: 10.1073/pnas.2013998117. PubMed DOI PMC

Jumper J, Evans R, Pritzel A, Green T, Figurnov M, Ronneberger O, Tunyasuvunakool K, Bates R, Zidek A, Potapenko A, Bridgland A, Meyer C, Kohl SAA, Ballard AJ, Cowie A, Romera-Paredes B, Nikolov S, Jain R, Adler J, Back T, Petersen S, Reiman D, Clancy E, Zielinski M, Steinegger M, Pacholska M, Berghammer T, Bodenstein S, Silver D, Vinyals O, Senior AW, Kavukcuoglu K, Kohli P, Hassabis D. Highly accurate protein structure prediction with AlphaFold. Nature. 2021;596:583–589. doi: 10.1038/s41586-021-03819-2. PubMed DOI PMC

Varadi M, Anyango S, Deshpande M, Nair S, Natassia C, Yordanova G, Yuan D, Stroe O, Wood G, Laydon A, Zidek A, Green T, Tunyasuvunakool K, Petersen S, Jumper J, Clancy E, Green R, Vora A, Lutfi M, Figurnov M, Cowie A, Hobbs N, Kohli P, Kleywegt G, Birney E, Hassabis D, Velankar S. AlphaFold Protein Structure Database: massively expanding the structural coverage of protein-sequence space with high-accuracy models. Nucleic Acids Res. 2022;50:D439–D444. doi: 10.1093/nar/gkab1061. PubMed DOI PMC