Mitophagy Restricts BAX/BAK-independent, Parkin-mediated Apoptosis

Overview

Journal Sci Adv

Specialties Biology
Science

Date 2023 May 24

PMID 37224250

Authors

Giovanni Quarato

Luigi Mari

Nicholas J Barrows

Mao Yang

Sebastian Ruehl

Mark J Chen

Cliff S Guy

Jonathan Low

Taosheng Chen

Douglas R Green

Affiliations

Soon will be listed here.

Abstract

Degradation of defective mitochondria is an essential process to maintain cellular homeostasis and it is strictly regulated by the ubiquitin-proteasome system (UPS) and lysosomal activities. Here, using genome-wide CRISPR and small interference RNA screens, we identified a critical contribution of the lysosomal system in controlling aberrant induction of apoptosis following mitochondrial damage. After treatment with mitochondrial toxins, activation of the PINK1-Parkin axis triggered a BAX- and BAK-independent process of cytochrome c release from mitochondria followed by APAF1 and caspase 9-dependent apoptosis. This phenomenon was mediated by UPS-dependent outer mitochondrial membrane (OMM) degradation and was reversed using proteasome inhibitors. We found that the subsequent recruitment of the autophagy machinery to the OMM protected cells from apoptosis, mediating the lysosomal degradation of dysfunctional mitochondria. Our results underscore a major role of the autophagy machinery in counteracting aberrant noncanonical apoptosis and identified autophagy receptors as key elements in the regulation of this process.

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