Variability of Clinical Phenotypes Caused by Isolated Defects of Mitochondrial ATP Synthase

Overview

Journal Physiol Res

Specialty Physiology

Date 2024 Jul 17

PMID 39016153

Authors

K Tauchmannova

A Pecinova

J Houstek

T Mracek

Affiliations

Soon will be listed here.

Abstract

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.

References

Ardissone A, Ferrera G, Lamperti C, Tiranti V, Ghezzi D, Moroni I . Phenotyping mitochondrial DNA-related diseases in childhood: A cohort study of 150 patients. Eur J Neurol. 2023; 30(7):2079-2091. DOI: 10.1111/ene.15814. View

Pastores G, Santorelli F, Shanske S, Gelb B, Fyfe B, Wolfe D . Leigh syndrome and hypertrophic cardiomyopathy in an infant with a mitochondrial DNA point mutation (T8993G). Am J Med Genet. 1994; 50(3):265-71. DOI: 10.1002/ajmg.1320500310. View

Carrozzo R, Tessa A, Piemonte F, Patrono C, Malandrini A, Dionisi-Vici C . The T9176G mtDNA mutation severely affects ATP production and results in Leigh syndrome. Neurology. 2001; 56(5):687-90. DOI: 10.1212/wnl.56.5.687. View

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

Wittig I, Meyer B, Heide H, Steger M, Bleier L, Wumaier Z . Assembly and oligomerization of human ATP synthase lacking mitochondrial subunits a and A6L. Biochim Biophys Acta. 2010; 1797(6-7):1004-11. DOI: 10.1016/j.bbabio.2010.02.021. View

Ganetzky R, Markhard A, Yee I, Clever S, Cahill A, Shah H . Congenital Hypermetabolism and Uncoupled Oxidative Phosphorylation. N Engl J Med. 2022; 387(15):1395-1403. PMC: 9754853. DOI: 10.1056/NEJMoa2202949. View

Kytovuori L, Lipponen J, Rusanen H, Komulainen T, Martikainen M, 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(11):2188-2195. DOI: 10.1007/s00415-016-8249-2. View

DiMauro S, Bonilla E, Lee C, SCHOTLAND D, Scarpa A, Conn Jr H . Luft's disease. Further biochemical and ultrastructural studies of skeletal muscle in the second case. J Neurol Sci. 1976; 27(2):217-32. DOI: 10.1016/0022-510x(76)90063-0. View

Scaglia F, Scheuerle A, Towbin J, Armstrong D, Sweetman L, Wong L . Neonatal presentation of ventricular tachycardia and a Reye-like syndrome episode associated with disturbed mitochondrial energy metabolism. BMC Pediatr. 2003; 2:12. PMC: 140035. DOI: 10.1186/1471-2431-2-12. View

10.

Al-Kafaji G, Bakheit H, Alali F, Fattah M, Alhajeri S, Alharbi M . Next-generation sequencing of the whole mitochondrial genome identifies functionally deleterious mutations in patients with multiple sclerosis. PLoS One. 2022; 17(2):e0263606. PMC: 8820615. DOI: 10.1371/journal.pone.0263606. View

11.

Honzik T, Tesarova M, Vinsova K, Hansikova H, Magner M, Kratochvilova H . Different laboratory and muscle biopsy findings in a family with an m.8851T>C mutation in the mitochondrial MTATP6 gene. Mol Genet Metab. 2012; 108(1):102-5. DOI: 10.1016/j.ymgme.2012.11.002. View

12.

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(6):4177-82. DOI: 10.1074/jbc.275.6.4177. View

13.

Galber C, Carissimi S, Baracca A, Giorgio V . The ATP Synthase Deficiency in Human Diseases. Life (Basel). 2021; 11(4). PMC: 8068106. DOI: 10.3390/life11040325. View

14.

Puddu P, Barboni P, Mantovani V, Montagna P, Cerullo A, Bragliani M . Retinitis pigmentosa, ataxia, and mental retardation associated with mitochondrial DNA mutation in an Italian family. Br J Ophthalmol. 1993; 77(2):84-8. PMC: 504435. DOI: 10.1136/bjo.77.2.84. View

15.

Wei Y, Cui L, Peng B . Mitochondrial DNA mutations in late-onset Leigh syndrome. J Neurol. 2018; 265(10):2388-2395. DOI: 10.1007/s00415-018-9014-5. View

16.

Ng Y, Martikainen M, Gorman G, Blain A, Bugiardini E, Bunting A . Pathogenic variants in MT-ATP6: A United Kingdom-based mitochondrial disease cohort study. Ann Neurol. 2019; 86(2):310-315. PMC: 6771528. DOI: 10.1002/ana.25525. View

17.

Catteruccia M, Verrigni D, Martinelli D, Torraco A, Agovino T, Bonafe L . Persistent pulmonary arterial hypertension in the newborn (PPHN): a frequent manifestation of TMEM70 defective patients. Mol Genet Metab. 2014; 111(3):353-359. DOI: 10.1016/j.ymgme.2014.01.001. View

18.

Yu X, Yan C, Ji K, Lin P, Xu X, Dai T . Clinical, Neuroimaging, and Pathological Analyses of 13 Chinese Leigh Syndrome Patients with Mitochondrial DNA Mutations. Chin Med J (Engl). 2018; 131(22):2705-2712. PMC: 6247594. DOI: 10.4103/0366-6999.245265. View

19.

He J, Ford H, Carroll J, Douglas C, Gonzales E, Ding S . Assembly of the membrane domain of ATP synthase in human mitochondria. Proc Natl Acad Sci U S A. 2018; 115(12):2988-2993. PMC: 5866602. DOI: 10.1073/pnas.1722086115. View

20.

Zech M, Kopajtich R, Steinbrucker K, Bris C, Gueguen N, Feichtinger R . Variants in Mitochondrial ATP Synthase Cause Variable Neurologic Phenotypes. Ann Neurol. 2021; 91(2):225-237. PMC: 9939050. DOI: 10.1002/ana.26293. View