Molecular basis of diseases induced by the mitochondrial DNA mutation m.9032T>C. Issue 8 (26th November 2022)

• Record Type: Journal Article
• Authors: Baranowska, Emilia; Niedzwiecka, Katarzyna; Panja, Chiranjit; Charles, Camille; Dautant, Alain; di Rago, Jean-Paul; Tribouillard-Tanvier, Déborah; Kucharczyk, Roza
• Is Part Of: Human molecular genetics. Volume 32:Issue 8(2023)
• Page Start: 1313
• Page End: 1323
• Publication Date: 2022-11-26
• Subjects: Human molecular genetics -- Periodicals; Human chromosome abnormalities -- Periodicals; 572.8
• DOI: 10.1093/hmg/ddac292
• Languages: English
• ISSNs: 0964-6906

Abstract

Abstract: 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 (L169 P). 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 (L186 P). 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 L186 P yeast restoring ATP synthase function to varying degrees (30–70%) were identified at the original mutation site (L186 S) or in another position of the subunit a (H114 Q, I118 T). 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 H114 Q and I118 T enable protons to access the c -ring through a modified pathway.