Molecular basis of diseases caused by the mtDNA mutation m.8969G>A in the subunit a of ATP synthase

• Published in: Biochimica et biophysica acta. Bioenergetics 2018-08, Vol.1859 (8), p.602-611
• Main Authors: Skoczeń, Natalia, Dautant, Alain, Binko, Krystyna, Godard, François, Bouhier, Marine, Su, Xin, Lasserre, Jean-Paul, Giraud, Marie-France, Tribouillard-Tanvier, Déborah, Chen, Huimei, di Rago, Jean-Paul, Kucharczyk, Roza
• Format: Article
• Language: English
• Subjects: Adenosine Triphosphate - metabolism; Amino Acid Sequence; ATP synthase; Catalytic Domain; DNA, Mitochondrial - genetics; Life Sciences; Metabolic disease; Mitochondria - metabolism; Mitochondria - pathology; Mitochondrial Diseases - enzymology; Mitochondrial Diseases - genetics; Mitochondrial Diseases - pathology; Mitochondrial Proton-Translocating ATPases - chemistry; Mitochondrial Proton-Translocating ATPases - genetics; Mitochondrial Proton-Translocating ATPases - metabolism; MT-ATP6; mtDNA; Mutation; Oxidative phosphorylation; Protein Conformation; Protein Subunits; Protons; Saccharomyces cerevisiae - growth & development; Saccharomyces cerevisiae - metabolism; Sequence Homology; Subunit a
• ISSN: 0005-2728; 1879-2650
• DOI: 10.1016/j.bbabio.2018.05.009

The ATP synthase which provides aerobic eukaryotes with ATP, organizes into a membrane-extrinsic catalytic domain, where ATP is generated, and a membrane-embedded FO domain that shuttles protons across the membrane. We previously identified a mutation in the mitochondrial MT-ATP6 gene (m.8969G>A) in a 14-year-old Chinese female who developed an isolated nephropathy followed by brain and muscle problems. This mutation replaces a highly conserved serine residue into asparagine at amino acid position 148 of the membrane-embedded subunit a of ATP synthase. We showed that an equivalent of this mutation in yeast (aS175N) prevents FO-mediated proton translocation. Herein we identified four first-site intragenic suppressors (aN175D, aN175K, aN175I, and aN175T), which, in light of a recently published atomic structure of yeast FO indicates that the detrimental consequences of the original mutation result from the establishment of hydrogen bonds between aN175 and a nearby glutamate residue (aE172) that was proposed to be critical for the exit of protons from the ATP synthase towards the mitochondrial matrix. Interestingly also, we found that the aS175N mutation can be suppressed by second-site suppressors (aP12S, aI171F, aI171N, aI239F, and aI200M), of which some are very distantly located (by 20–30 Å) from the original mutation. The possibility to compensate through long-range effects the aS175N mutation is an interesting observation that holds promise for the development of therapeutic molecules. •The pathogenic m.8969G>A mutation block the proton translocation in FO domain of ATP synthase.•This results from the establishment of a hydrogen bond between aN175 and aE172 critical for protons exit.•The conserved aS175 (aS148 in human) in subunit a of ATP synthase is not involved in proton transport.•The long-distance suppressors of aN175 hold promise for the development of therapeutic molecules.