Bcl-2 family proteins participate in mitochondrial quality control by regulating parkin/PINK1-dependent mitophagy

Emilie Hollville, Richard G. Carroll, Sean P. Cullen, Seamus J. Martin*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

160 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)451-466
Number of pages16
JournalMolecular Cell
Issue number3
Publication statusPublished - 7 Aug 2014

Bibliographical note

Funding Information:
We gratefully thank Dr. Richard Youle for provision of mCherry-Parkin and YFP-Parkin plasmids; Dr. Stephen Tait for provision of HeLa cells stably expressing YFP-Parkin; Dr. Dennis J. Selkoe for provision of PINK1-FLAG plasmid; and Dr. Maria Soengas for provision of shRNA plasmids targeted against BAX and BAK. The S.J.M. laboratory is supported by Principal Investigator (08/IN.1/B2031) and Strategic Research Cluster (07/SRC/B1144) grants from Science Foundation Ireland. S.J.M. is a Science Foundation Ireland Principal Investigator.


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