Rab5 and Alsin regulate stress-activated cytoprotective signaling on mitochondria

Abstract

Mitochondrial stress response is essential for cell survival, and damaged mitochondria are a hallmark of neurodegenerative diseases. It is thus fundamental to understand how mitochondria relay information within the cell. Here, by investigating mitochondrial-endosome contact sites we made the surprising observation that the small GTPase Rab5 translocates from early endosomes to the outer mitochondrial membrane upon oxidative stress. This is accompanied by an increase in Rab5-positive endosomes in contact with mitochondria. Interestingly, activation of Rab5 on mitochondria depend on the Rab5-GEF ALS2/Alsin, which is encoded by a gene mutated in amyotrophic lateral sclerosis (ALS). Alsin-/- human induced pluripotent stem cell-derived spinal motor neurons cannot relocate Rab5 to mitochondria and display increased susceptibility to oxidative stress. These findings define a novel pathway whereby Alsin catalyzes assembly of the Rab5 endocytic machinery on mitochondria. Defects in stress-sensing by endosomes could be crucial for mitochondrial quality control during the onset of ALS.