Dozens of pathogenic mutations have been localized in the mitochondrial gene (MT-ATP6) that encodes the subunit a of ATP synthase. The subunit a together with a ring of identical subunits c moves protons across the mitochondrial inner membrane coupled to rotation of the subunit c-ring and ATP synthesis. One of these mutations, m.8851T>C, has been associated with bilateral striatal lesions of childhood (BSLC), a group of rare neurological disorders characterized by symmetric degeneration of the corpus striatum. It converts a highly conserved tryptophan residue into arginine at position 109 of subunit a (aW₁₀₉R). We previously showed that an equivalent thereof in Saccharomyces cerevisiae (aW₁₂₆R) severely impairs by an unknown mechanism the functioning of ATP synthase without any visible assembly/stability defect. Herein we show that ATP synthase function was recovered to varying degree by replacing the mutant arginine residue 126 with methionine, lysine or glycine or by replacing with methionine an arginine residue present at position 169 of subunit a (aR₁₆₉). In recently described atomic structures of yeast ATP synthase, aR₁₆₉ is at the center of a hydrophilic cleft along which protons are transported from the subunit c-ring to the mitochondrial matrix, in the proximity of the two residues known from a long time to be essential to the activity of F_O (aR₁₇₆ and cE₅₉). We provide evidence that the aW₁₂₆R change is responsible for electrostatic and steric hindrance that enables aR₁₆₉ to engage in a salt bridge with cE₅₉. As a result, aR₁₇₆ cannot interact properly with cE₅ and ATP synthase fails to effectively move protons across the mitochondrial membrane. In addition to insight into the pathogenic mechanism induced by the m.8851T>C mutation, the present study brings interesting information about the role of specific residues of subunit a in the energy-transducing activity of ATP synthase.

• PMID: 31181185
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Reference Type

Journal Article | Research Support, Non-U.S. Gov't

Authors

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

Primary Lit For

ATP6

Additional Lit For

ATP8

Review For