Renalase activates mitochondrial leak metabolism in response to cellular stress and to repair damage after injury

A variety of mechanisms enhance cell stress response and repair; however, the role of mitochondria in this activity is unclear. Here we show that exogenous renalase (RNLS), an intracellular flavin-dependent NADH oxidase, activates intramitochondrial RNLS activity to promote cell survival. RNLS interacts with the ATP synthase alpha and beta subunits (ATP5α and ATP5β) and opens the ATP synthase c-subunit leak channel to increase complex I and II activities and protein synthesis rate. RNLS causes a selective, sustained, time-dependent increase in cellular protein synthesis without affecting cell proliferation, whereas RNLS deletion or direct inhibition of the mitochondrial leak blocks RNLS-mediated protein synthesis. Functional analysis of newly and differentially synthesized proteins over 24 hours reveals rapid changes in one-carbon metabolism and ribosomal biogenesis pathways as early as one hour after RNLS exposure. Mitochondrial injury is more severe in the RNLS KO kidney after acute stress, related to decreased protein synthesis rate and increased mitophagy. RNLS KO mice exposed to the stress of chronic cardiac pressure overload fail to develop cardiac hypertrophy, the physiological response, and die of heart failure and cardiac rupture. These data highlight the critical role RNLS has in activating mitochondrial leak metabolism to induce selective protein synthesis and protect against acute and chronic stress.