0448192 - FGÚ 2016 RIV GB eng J - Journal Article
Hejzlarová, Kateřina - Kaplanová, Vilma - Nůsková, Hana - Kovářová, Nikola - Ješina, Pavel - Drahota, Zdeněk - Mráček, Tomáš - Seneca, S. - Houštěk, Josef
Alteration of structure and function of ATP synthase and cytochrome c oxidase by lack of F-o-a and Cox3 subunits caused by mitochondrial DNA 9205delTA mutation.
Biochemical Journal. Roč. 466, č. 3 (2015), s. 601-611. ISSN 0264-6021. E-ISSN 1470-8728
R&D Projects: GA ČR(CZ) GAP303/11/0970; GA ČR(CZ) GB14-36804G; GA MŠMT(CZ) LL1204; GA ČR(CZ) GAP303/12/1363
Institutional support: RVO:67985823
Keywords : ATP synthase * cytochrome c oxidase * mitochondrial diseases * mtDNA MT-ATP6 mutation * oxidative phosphorylation * threshold effect
Subject RIV: EB - Genetics ; Molecular Biology
Impact factor: 3.562, year: 2015
DOI: https://doi.org/10.1042/BJ20141462

Mutations in the MT-ATP6 gene are frequent causes of severe mitochondrial disorders. To gain more insight into the pathogenic mechanism of mtDNA 9205delTA mutation in MT-ATP6 gene, we prepared cybrids with mutation load ranging between 52 and 99% and investigated changes in the structure and function of ATP synthase and the COX. We found that 9205delTA mutation strongly reduced the levels of both Fo-a and Cox3 proteins. Lack of Fo-a alters the structure but not the content of ATP synthase, which assembles into a labile, similar to 60 kDa smaller, complex retaining ATP hydrolytic activity but which is unable to synthesize ATP. In contrast, lack of Cox3 limits the biosynthesis of COX but does not alter the structure of the enzyme. Consequently, the diminished mitochondrial content of COX and non-functional ATP synthase prevent most mitochondrial ATP production. The biochemical effects caused by the 9205delTA microdeletion displayed a pronounced threshold effect above sililar to 90%mutation heteroplasmy, originating from a gene–protein level

Permanent Link: http://hdl.handle.net/11104/0249952