Protons are transported from the mitochondrial matrix to the intermembrane space of mitochondria during the transfer of electrons to oxygen and shuttled back to the matrix by the a subunit and a ring of identical c subunits across the membrane domain (F_O) of ATP synthase, which is coupled to ATP synthesis. A mutation (m.9176 T > G) of the mitochondrial ATP6 gene that replaces an universally conserved leucine residue into arginine at amino acid position 217 of human subunit a (aL₂₁₇R) has been associated to NARP (Neuropathy, Ataxia and Retinitis Pigmentosa) and MILS (Maternally Inherited Leigh's Syndrome) diseases. We previously showed that an equivalent thereof in Saccharomyces cerevisiae (aL₂₃₇R) severely impairs subunit a assembly/stability and decreases by >90% the rate of mitochondrial ATP synthesis. Herein we identified three spontaneous first-site intragenic suppressors (aR₂₃₇M, aR₂₃₇T and aR₂₃₇S) that fully restore ATP synthase assembly. However, mitochondrial ATP synthesis rate was only partially recovered (40-50% vs wild type yeast). In light of recently described high-resolution yeast ATP synthase structures, the detrimental consequences of the aL₂₃₇R change can be explained by steric and electrostatic hindrance with the universally conserved subunit a arginine residue (aR₁₇₆) that is essential to F_O activity. aL₂₃₇ together with three other nearby hydrophobic residues have been proposed to prevent ion shortage between two physically separated hydrophilic pockets within the F_O. Our results suggest that aL₂₃₇ favors subunit c-ring rotation by optimizing electrostatic interaction between aR₁₇₆ and an acidic residue in subunit c (cE₅₉) known to be essential also to the activity of F_O.

• PMID: 30414414
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Journal Article | Research Support, Non-U.S. Gov't

Authors

Kucharczyk R, Dautant A, Godard F, Tribouillard-Tanvier D, di Rago JP

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