Fig. 8: Model: MTMR5/2 and Rubicon suppress neuronal autophagy under basal conditions, while acute mitochondrial stress induces the selective degradation of these negative regulators via MitoSR.
From: Mitochondrial damage triggers the concerted degradation of negative regulators of neuronal autophagy
The upper panel depicts the roles of MTMR5/2 and Rubicon in repressing neuronal autophagy under basal conditions. MTMR5/2 activity hydrolyzes PI3P into PI, inhibiting early steps of autophagosome biogenesis48. Rubicon blocks lysosomal acidification and autophagosome-lysosome fusion, thereby impacting the latter steps of autophagy. The lower panel depicts induction of MitoSR, which acts in parallel to the Pink1/Parkin pathway for mitophagy initiation in response to mitochondrial damage in neurons. Activation of MitoSR induces the ubiquitination of MTMR5, MTMR2 and Rubicon and the targeting of these negative regulators to the proteasome for degradation. MTMR5 and MTMR2 are also subject to proteolytic degradation. This concerted degradation facilitates increased autophagic flux, promoting mitochondrial turnover.
