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

Publication date: Available online 8 June 2019Source: Biochimica et Biophysica Acta (BBA) - BioenergeticsAuthor(s): Roza Kucharczyk, Alain Dautant, Kewin Gombeau, François Godard, Déborah Tribouillard-Tanvier, Jean-Paul di RagoAbstractDozens 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 in 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 mitochondri...

Source: Biochimica et Biophysica Acta (BBA) Bioenergetics - June 8, 2019 Category: Biochemistry Source Type: research