Molecular basis of diseases induced by the mitochondrial DNA mutation m.9032T>C.

Autor: Baranowska E; Institute of Biochemistry and Biophysics, Polish Academy of Sciences, 02-206 Warsaw, Poland., Niedzwiecka K; Institute of Biochemistry and Biophysics, Polish Academy of Sciences, 02-206 Warsaw, Poland., Panja C; Institute of Biochemistry and Biophysics, Polish Academy of Sciences, 02-206 Warsaw, Poland., Charles C; Univ. Bordeaux, CNRS, IBGC, UMR 5095, F-33000 Bordeaux, France., Dautant A; Univ. Bordeaux, CNRS, IBGC, UMR 5095, F-33000 Bordeaux, France., di Rago JP; Univ. Bordeaux, CNRS, IBGC, UMR 5095, F-33000 Bordeaux, France., Tribouillard-Tanvier D; Univ. Bordeaux, CNRS, IBGC, UMR 5095, F-33000 Bordeaux, France., Kucharczyk R; Institute of Biochemistry and Biophysics, Polish Academy of Sciences, 02-206 Warsaw, Poland.
Jazyk: angličtina
Zdroj: Human molecular genetics [Hum Mol Genet] 2023 Apr 06; Vol. 32 (8), pp. 1313-1323.
DOI: 10.1093/hmg/ddac292
Abstrakt: The mitochondrial DNA mutation m.9032T>C was previously identified in patients presenting with NARP (Neuropathy Ataxia Retinitis Pigmentosa). Their clinical features had a maternal transmission and patient's cells showed a reduced oxidative phosphorylation capacity, elevated reactive oxygen species (ROS) production and hyperpolarization of the mitochondrial inner membrane, providing evidence that m.9032T>C is truly pathogenic. This mutation leads to replacement of a highly conserved leucine residue with proline at position 169 of ATP synthase subunit a (L169P). This protein and a ring of identical c-subunits (c-ring) move protons through the mitochondrial inner membrane coupled to ATP synthesis. We herein investigated the consequences of m.9032T>C on ATP synthase in a strain of Saccharomyces cerevisiae with an equivalent mutation (L186P). The mutant enzyme assembled correctly but was mostly inactive as evidenced by a  > 95% drop in the rate of mitochondrial ATP synthesis and absence of significant ATP-driven proton pumping across the mitochondrial membrane. Intragenic suppressors selected from L186P yeast restoring ATP synthase function to varying degrees (30-70%) were identified at the original mutation site (L186S) or in another position of the subunit a (H114Q, I118T). In light of atomic structures of yeast ATP synthase recently described, we conclude from these results that m.9032T>C disrupts proton conduction between the external side of the membrane and the c-ring, and that H114Q and I118T enable protons to access the c-ring through a modified pathway.
(© The Author(s) 2022. Published by Oxford University Press.)
Databáze: MEDLINE