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

Abstract

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.

How to get rid of mitochondria: crosstalk and regulation of multiple mitophagy pathways

“…These proteins were shown to inhibit the mitochondrial translocation of Parkin and ubiquitylation of mitochondrial substrate proteins, while depolarization and Pink1 accumulation at the MOM still occurred. In line with this observation, BH3-only proteins such as Bad, Bim, Noxa and Puma enhanced Parkin translocation (Hollville et al, 2014).…”

SESN2/sestrin2 suppresses sepsis by inducing mitophagy and inhibiting NLRP3 activation in macrophages

“…7,14,15 Activated PARK2 promotes ubiquitination of outer membrane proteins on the mitochondria, which in turn triggers translocation of the ubiquitin-binding receptor SQSTM1 or NBR1 (neighbor of Brca1 gene 1) to mitochondria, thus completing mitochondrial priming. 6,[16][17][18][19] Among the components of the autophagy machinery required for mitophagy, ULK1 and BNIP3L (BCL2/adenovirus E1B 19kDa interacting protein 3-like), are critical for clearance of mitochondria during erythroid cell maturation. 2,20,21 However, it remains unclear how these 2 steps are connected so that the mitophagy process can be completed under inflammatory conditions.…”

Methylene Blue Reduces Acute Cerebral Ischemic Injury via the Induction of Mitophagy

“…We confirmed this effect of MB using an oxygen-glucose deprivation (OGD) model in vitro and identified that the protection conferred by MB during OGD was abolished due to the inhibition of mitophagy. As mitophagy is directly induced by the loss of mitochondrial membrane potential (MMP) (27,(31)(32)(33), we further explored whether the effect of MB on mitophagy was mediated by the regulation of MMP. We found that the MMP dramatically declined after cells were exposed to OGD, whereas MB attenuated this decline.…”