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The human ATP synthase is an assembly of 29 subunits of 18 different types, of which only two ( a  and  8 ) are encoded in the mitochondrial genome. Subunit  a,  together with an oligomeric ring of  c -subunit ( c -ring), forms the proton pathway responsible for the transport of protons through the mitochondrial inner membrane, coupled to rotation of the  c -ring and ATP synthesis. Neuromuscular diseases have been associated to a number of mutations in the gene encoding subunit  a ,  ATP6 . The most common, m.8993 T &gt; G, leads to replacement of a strictly conserved leucine residue with arginine ( a L 156 R). We previously showed that the equivalent mutation ( a L 173 R) dramatically compromises respiratory growth of  Saccharomyces cerevisiae  and causes a 90% drop in the rate of mitochondrial ATP synthesis. Here, we isolated revertants from the  a L 173 R strain that show improved respiratory growth. Four first-site reversions at codon 173 ( a L 173 M,  a L 173 S,  a L 173 K and  a L 173 W) and five second-site reversions at another codon ( a R 169 M,  a R 169 S,  a A 170 P,  a A 170 G and  a I 216 S) were identified. Based on the atomic structures of yeast ATP synthase and the biochemical properties of the revertant strains, we propose that the  a L 173 R mutation is responsible for unfavorable electrostatic interactions that prevent the release of protons from the  c -ring into a channel from which protons move from the  c -ring to the mitochondrial matrix. The results provide further evidence that yeast  a L 173  (and thus human  a L 156 ) optimizes the exit of protons from ATP synthase, but is not essential despite its strict evolutionary conservation.

The pathogenic m.8993 T > G mutation in mitochondrial ATP6 gene prevents proton release from the subunit c -ring rotor of ATP synthase