Mitochondrial protein MPV17 promotes beta-cell apoptosis in diabetogenesis.

Abstract

MPV17 is a mitochondrial inner membrane protein, and its deficiency can cause mitochondrial DNA (mtDNA) depletion, increase reactive oxygen species (ROS), and promote apoptosis in several cell types, suggesting that MPV17 plays a protective role in cells although the underlying mechanism remains unknown. To test whether MPV17 is also protective in diabetic kidney disease, we treated MPV17-deficient mice with streptozotocin (STZ) and surprisingly found that they were resistant to diabetes. MPV17 deficiency was also found to confer resistance to the diabetes induced by an insulin mutation (Ins2Akita), which represents a mouse model of monogenic diabetes characterized by proinsulin misfolding and beta-cell failure. In both STZ and Ins2Akita models, Mpv17 mutants had significantly less severe beta-cell loss and apoptosis compared with the wild-type mice. We next showed that Mpv17 is expressed in beta-cells of mice normally, suggesting that MPV17 acts beta-cells autonomously to facilitate apoptosis. Consistently, Mpv17 knockdown improved the viability and ameliorated the apoptosis of cultured MIN6 cells treated with STZ and palmitic acid (PA), respectively, accompanied by prevention of caspase 3 activation. The proapoptotic effect of MPV17 in beta-cells is in contrast with its known anti-apoptotic effect in other cell types. Thus, we have identified a novel regulator of beta-cell death in diabetes development.