Bcl-2 Family Proteins Participate in Mitochondrial Quality Control by Regulating Parkin/PINK1-Dependent Mitophagy

Summary Mitophagy facilitates the selective elimination of impaired or depolarized mitochondria through targeting the latter to autophagosomes. Parkin becomes localized to depolarized mitochondria in a PINK1-dependent manner and polyubiquitinates multiple mitochondrial outer membrane proteins. This permits ubiquitin-binding proteins (e.g., p62 and NBR1) to target impaired mitochondria to autophagosomes via Atg8/LC3II. Bcl-2 family proteins regulate mitochondrial outer membrane permeabilization during apoptosis and can also influence macroautophagy via interactions with Beclin-1. Here, we show that Parkin-dependent mitophagy is antagonized by prosurvival members of the Bcl-2 family (e.g., Bcl-xL and Mcl-1) in a Beclin-1-independent manner. Bcl-2 proteins suppressed mitophagy through inhibition of Parkin translocation to depolarized mitochondria. Consistent with this, Parkin translocation to mitochondria was enhanced by BH3-only proteins or a BH3-only mimetic. Taken together with their role as regulators of apoptosis-associated mitochondrial permeabilization, as well as mitochondrial fission/fusion dynamics, this suggests that Bcl-2 family proteins act as global regulators of mitochondrial homeostasis.