The pathogenic MT-ATP6 m.8851T>C mutation prevents proton movements within the n-side hydrophilic cleft of the membrane domain of ATP synthase

Alain Dautant (1) , Roza Kucharczyk , Kewin Gombeau , François Godard , Déborah Tribouillard-Tanvier , Jean-Paul Di Rago

1 IBGC - Institut de biochimie et génétique cellulaires

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 (aW 109 R). We previously showed that an equivalent thereof in Saccharomyces cerevisiae (aW 126 R) 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 me-thionine, lysine or glycine or by replacing with methionine an arginine residue present at position 169 of subunit a (aR 169). In recently described atomic structures of yeast ATP synthase, aR 169 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 (aR 176 and cE 59). We provide evidence that the aW 126 R change is responsible for electrostatic and steric hindrance that enables aR 169 to engage in a salt bridge with cE 59. As a result, aR 176 cannot interact properly with cE 5 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.

Domaines: Sciences du Vivant [q-bio]; Sciences du Vivant [q-bio]

Alain Dautant, Roza Kucharczyk, Kewin Gombeau, François Godard, Déborah Tribouillard-Tanvier, et al.. The pathogenic MT-ATP6 m.8851T>C mutation prevents proton movements within the n-side hydrophilic cleft of the membrane domain of ATP synthase. Biochimica biophysica acta (BBA) - Bioenergetics, 2019, 1860 (7), pp.562-572. ⟨10.1016/j.bbabio.2019.06.002⟩. ⟨hal-02988559⟩