MAPK15 Induces Mitophagy and Protects from Oxidative Stress-Dependent Cellular Senescence

Mitochondria are the major source of reactive oxygen species (ROS), whose aberrant production by dysfunctional mitochondria leads to oxidative stress, thus contributing to aging as well as to the pathogenesis of various diseases, such as neurodegenerative disorders and cancer. Cells efficiently eliminate damaged mitochondria through a selective type of autophagy, named mitophagy. Here, we unveil the involvement of the atypical MAP kinase family member MAPK15 in mechanisms preserving mitochondrial quality, ultimately affecting DNA damage and senescence. We demonstrate that reduced MAPK15 expression strongly decreases mitochondrial respiration and ATP production, while increasing mitochondrial ROS levels. We show that MAPK15 controls the mitophagic process by recruiting damaged mitochondria to autophagosomal and lysosomal compartments, thus leading to a reduction in the mass of these dysfunctional organelles, but also by participating in the reorganization of the mitochondrial network that usually anticipates their disposal. Ultimately, we demonstrate that mitophagy induction by MAPK15 protects cells from accumulation of nuclear DNA damage due to mitochondrial ROS and, consequently, from senescence deriving from this chronic DNA insult. Altogether, our results indicate a new specific role for MAPK15 in controlling mitochondrial fitness by efficient disposal of old and damaged organelles and suggest this kinase as a potential therapeutic target in diverse human diseases where these processes are deregulated.