Metformin rescues Parkinson’s disease phenotypes caused by hyperactive mitochondria
Danielle E. Mor, Salman Sohrabi, Rachel Kaletsky, William Keyes, Alp Tartici, Vrinda Kalia, Gary W. Miller, Coleen T. Murphy
Abstract
Significance Uncovering the role of defective metabolism in Parkinson’s disease (PD) may lead to the discovery of disease-modifying therapies. We recently linked branched-chain amino acid (BCAA) metabolism with PD, yet the underlying mechanisms were unknown. We now report the unexpected finding that BCAA metabolic dysfunction causes Parkinson’s-like motor deficits and neurodegeneration by inducing a state of hyperactive mitochondria. We found that the type 2 diabetes medication metformin is able to rescue neuronal viability by reducing mitochondrial respiration. These results offer mitochondrial hyperactivity as a new potential mechanism of mitochondrial dysfunction in Parkinson’s disease, and suggest that efforts to reduce mitochondrial respiration early in the disease—potentially by metformin treatment—may be efficacious.