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

Publication date: Available online 18 May 2018 Source:Biochimica et Biophysica Acta (BBA) - Bioenergetics Author(s): Natalia Skoczeń, Alain Dautant, Krystyna Binko, François Godard, Marine Bouhier, Xin Su, Jean-Paul Lasserre, Marie-France Giraud, Déborah Tribouillard-Tanvier, Huimei Chen, Jean-Paul di Rago, Roza Kucharczyk 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, indicating 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...
Source: Biochimica et Biophysica Acta (BBA) Bioenergetics - Category: Biochemistry Source Type: research