Stimulating the sir2-pgc-1α axis rescues exercise capacity and mitochondrial respiration in Drosophila tafazzin mutants.

Cardiolipin (CL) is a phospholipid required for proper mitochondrial function. Tafazzin remodels CL to create highly unsaturated fatty acid chains. However, when tafazzin is mutated, CL remodeling is impeded, leading to mitochondrial dysfunction and the disease Barth syndrome. Patients with Barth syndrome often have severe exercise intolerance, which negatively impacts their overall quality of life. Boosting NAD+ levels can improve symptoms of other mitochondrial diseases, but its effect in the context of Barth syndrome has not been examined. We demonstrate for the first time that nicotinamide riboside (NR) can rescue exercise tolerance and mitochondrial respiration in a Drosophila tafazzin mutant and that the beneficial effects are dependent on sir2 and pgc-1. Overexpressing pgc-1 increased the total abundance of cardiolipin in mutants. In addition, muscles and neurons were identified as key targets for future therapies because sir2 or pgc-1 overexpression in either of these tissues is sufficient to restore the exercise capacity of Drosophila tafazzin mutants. Summary StatementNicotinamide riboside rescues the exercise capacity and mitochondrial function of a Drosophila model of Barth syndrome in a Sir2/Pgc-1[a] dependent manner.