Leigh syndrome is the most common form of mitochondrial disease in children. The mechanisms underlying its pathogenesis are not fully understood and no therapies are approved for the treatment of patients with Leigh syndrome. In a new study, Yoon and colleagues shed light on the pathophysiological mechanisms of cardio-encephalomyopathy in Leigh syndrome and demonstrates that nicotinamide riboside (NR) provides significant amelioration in disease models of Leigh syndrome