title: Overexpression of mitochondrial oxodicarboxylate carrier (ODC1) preserves oxidative phosphorylation in a yeast model of Barth syndrome.
abstract: Cardiolipin (CL) is a diglycerol phospholipid mostly found in mitochondria where it optimizes numerous processes, including oxidative phosphorylation (OXPHOS). To function properly, CL needs to be unsaturated, which requires the acyltransferase tafazzin. Loss-of-function mutations in this protein are responsible for Barth syndrome (BTHS), presumably because of a diminished OXPHOS capacity. Here, we show that overexpressing Odc1p, a conserved oxodicarboxylic acid carrier located in the mitochondrial inner membrane, fully restores oxidative phosphorylation in a yeast model (taz1Δ) of BTHS. The rescuing activity involves the recovery of normal expression of key components that sustain oxidative phosphorylation, including cytochromecand electron transport chain complexes IV and III, which are strongly downregulated intaz1Δyeast. Interestingly, overexpression of Odc1p was also shown previously to rescue yeast models of mitochondrial diseases caused by defects in the assembly of ATP synthase and by mutations in the MPV17 protein that result in hepatocerebral mitochondrial DNA depletion syndrome. These findings define the transport of oxodicarboxylic acids across the inner membrane as a potential therapeutic target for a large spectrum of mitochondrial diseases, including BTHS.
authors.affiliation: Université de Bordeaux, Institut de Biochimie et Génétique Cellulaires, CNRS UMR 5095, 1 rue Camille Saint-Saëns, Bordeaux cedex 33077, France.
authors.forename: Maxence
authors.initials: M
authors.lastname: de Taffin de Tilques
authors.affiliation: Université de Bordeaux, Institut de Biochimie et Génétique Cellulaires, CNRS UMR 5095, 1 rue Camille Saint-Saëns, Bordeaux cedex 33077, France tribouillard@ibgc.cnrs.fr lasserre@ibgc.cnrs.fr.
authors.forename: Déborah
authors.identifier: 0000-0002-2290-5375
authors.initials: D
authors.lastname: Tribouillard-Tanvier
authors.affiliation: Université de Bordeaux, Institut de Biochimie et Génétique Cellulaires, CNRS UMR 5095, 1 rue Camille Saint-Saëns, Bordeaux cedex 33077, France.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Tétaud
authors.affiliation: Université de Bordeaux, Laboratoire de biogenèse membranaire, CNRS UMR 5200, INRA Bordeaux Aquitaine BP81, 33883 Villenave d'Ornon Cédex, France.
authors.forename: Eric
authors.initials: E
authors.lastname: Testet
authors.affiliation: Université de Bordeaux, Institut de Biochimie et Génétique Cellulaires, CNRS UMR 5095, 1 rue Camille Saint-Saëns, Bordeaux cedex 33077, France.
authors.forename: Jean-Paul
authors.initials: JP
authors.lastname: di Rago
authors.affiliation: Université de Bordeaux, Institut de Biochimie et Génétique Cellulaires, CNRS UMR 5095, 1 rue Camille Saint-Saëns, Bordeaux cedex 33077, France tribouillard@ibgc.cnrs.fr lasserre@ibgc.cnrs.fr.
authors.forename: Jean-Paul
authors.identifier: 0000-0003-4388-1904
authors.initials: JP
authors.lastname: Lasserre
mesh_terms: D000255:Adenosine Triphosphate / Q000096:biosynthesis; D000332:Aerobiosis; D056889:Barth Syndrome / Q000378:metabolism* / Q000473:pathology*; D029382:Dicarboxylic Acid Transporters / Q000378:metabolism*; D004591:Electrophoresis, Polyacrylamide Gel; D004734:Energy Metabolism / Q000187:drug effects; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008928:Mitochondria / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000378:metabolism; D019301:Oleic Acid / Q000494:pharmacology; D010085:Oxidative Phosphorylation / Q000187:drug effects; D010743:Phospholipids / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000235:genetics / Q000254:growth & development / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins / Q000378:metabolism*
chemical_list: D029382:Dicarboxylic Acid Transporters; D024101:Mitochondrial Proteins; C504820:ODC1 protein, S cerevisiae; D010743:Phospholipids; D029701:Saccharomyces cerevisiae Proteins; D019301:Oleic Acid; D000255:Adenosine Triphosphate
keywords: Barth syndrome; Cardiolipin remodeling; Human mitochondrial disease; Oxidative phosphorylation; Oxodicarboxylic acid transport; Tafazzin