Overexpression of mitochondrial oxodicarboxylate carrier (ODC1) preserves oxidative phosphorylation in a yeast model of the Barth syndrome
Disease Models & Mechanisms. 2017-01-01; :
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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 the 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 the Barth syndrome. The rescuing activity involves the recovery of a normal expression of key components that sustain oxidative phosphorylation, including the cytochrome c and complexes IV and III, that are strongly down regulated in taz1Δ yeast. Interestingly, overexpressing Odc1p was shown previously to rescue also yeast models of mitochondrial diseases caused by defects in the assembly of ATP synthase and by mutations in the MPV17 protein that result in the hepatocerebral mitochondrial DNA depletion syndrome. These findings define the transport of oxidicarboxylic acids across the inner membrane as a potential therapeutic target for a large spectrum of mitochondrial disease including BTHS.