PINK1 and BECN1 relocalize at mitochondria-associated membranes during mitophagy and promote ER-mitochondria tethering and autophagosome formation
Open Access
- 17 February 2017
- journal article
- research article
- Published by Informa UK Limited in Autophagy
- Vol. 13 (4), 654-669
- https://doi.org/10.1080/15548627.2016.1277309
Abstract
Mitophagy is a highly specialized process to remove dysfunctional or superfluous mitochondria through the macroautophagy/autophagy pathway, aimed at protecting cells from the damage of disordered mitochondrial metabolism and apoptosis induction. PINK1, a neuroprotective protein mutated in autosomal recessive Parkinson disease, has been implicated in the activation of mitophagy by selectively accumulating on depolarized mitochondria, and promoting PARK2/Parkin translocation to them. While these steps have been characterized in depth, less is known about the process and site of autophagosome formation upon mitophagic stimuli. A previous study reported that, in starvation-induced autophagy, the proautophagic protein BECN1/Beclin1 (which we previously showed to interact with PINK1) relocalizes at specific regions of contact between the endoplasmic reticulum (ER) and mitochondria called mitochondria-associated membranes (MAM), from which the autophagosome originates. Here we show that, following mitophagic stimuli, autophagosomes also form at MAM; moreover, endogenous PINK1 and BECN1 were both found to relocalize at MAM, where they promoted the enhancement of ER-mitochondria contact sites and the formation of omegasomes, that represent autophagosome precursors. PARK2 was also enhanced at MAM following mitophagy induction. However, PINK1 silencing impaired BECN1 enrichment at MAM independently of PARK2, suggesting a novel role for PINK1 in regulating mitophagy. MAM have been recently implicated in many key cellular events. In this light, the observed prevalent localization of PINK1 at MAM may well explain other neuroprotective activities of this protein, such as modulation of mitochondrial calcium levels, mitochondrial dynamics, and apoptosis.Keywords
This publication has 67 references indexed in Scilit:
- Autophagosomes form at ER–mitochondria contact sitesNature, 2013
- PINK1-mediated phosphorylation of the Parkin ubiquitin-like domain primes mitochondrial translocation of Parkin and regulates mitophagyScientific Reports, 2012
- PINK1 and Parkin Target Miro for Phosphorylation and Degradation to Arrest Mitochondrial MotilityCell, 2011
- Mitochondrial BCL-2 inhibits AMBRA1-induced autophagyThe EMBO Journal, 2011
- PINK1-dependent recruitment of Parkin to mitochondria in mitophagyProceedings of the National Academy of Sciences of the United States of America, 2009
- Isolation of mitochondria-associated membranes and mitochondria from animal tissues and cellsNature Protocols, 2009
- PINK1 function in health and diseaseEMBO Molecular Medicine, 2009
- Loss of PINK1 Function Promotes Mitophagy through Effects on Oxidative Stress and Mitochondrial FissionPublished by Elsevier BV ,2009
- PINK1-Associated Parkinson's Disease Is Caused by Neuronal Vulnerability to Calcium-Induced Cell DeathMolecular Cell, 2009
- Structural and functional features and significance of the physical linkage between ER and mitochondriaThe Journal of cell biology, 2006