Mitochondrial damage triggers concerted degradation of negative regulators of neuronal autophagy

ABSTRACT Mutations in genes that regulate mitophagy, a key mitochondrial quality control pathway, are causative for neurological disorders including Parkinson’s. Here, we identify a novel stress response pathway activated by mitochondrial damage that regulates mitophagy in neurons. We find that increasing levels of mitochondrial stress triggers a graded, concerted response that induces proteasomal degradation of negative regulators of autophagy. These include Myotubularin-related phosphatase 5 (MTMR5), MTMR2 and Rubicon. This ‘ Mito phagic S tress R esponse’ (MitoSR) pathway is neuron-specific and acts in parallel to the classical Pink1/Parkin-mediated mitophagy pathway. While MTMR5/MTMR2 inhibits autophagosome biogenesis, we find that Rubicon inhibits lysosomal function and thus blocks autophagosome maturation. Targeted depletion of these negative regulators is sufficient to enhance mitophagy, promoting autophagosome biogenesis and facilitating the fusion of mitophagosomes with lysosomes. Our work suggests that therapeutic activation of the MitoSR pathway to induce degradation of negative regulators of autophagy may enhance mitochondrial quality control in stressed neurons.