Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) is a mitochondrial disease caused by mutations in the mitochondrial genome. This study investigated the efficacy of B-lapachone (beta-lap), a natural quinone compound, in rescuing mitochondrial dysfunction in MELAS cybrid cells. beta-Lap significantly restored energy production and mitochondrial membrane potential as well as normalized the elevated ROS level in MELAS cybrid cells. Additionally, beta-lap reduced lactic acidosis and restored glucose uptake in the MELAS cybrid cells. Finally, beta-lap activated Sirt1 by increasing the intracellular NAD(+)/NADH ratio, which was accompanied by increased mtDNA content. Two other quinone compounds (idebenone and CoQ10) that have rescued mitochondrial dysfunction in previous studies of MELAS cybrid cells had a minimal effect in the current study. Taken together, these results demonstrated that beta-lap may provide a novel therapeutic modality for the treatment of MELAS. (C) 2014 Elsevier Inc. All rights reserved.