Parkin Sensitizes toward Apoptosis Induced by Mitochondrial Depolarization through Promoting Degradation of Mcl-1

Richard G. Carroll, Emilie Hollville, Seamus J. Martin*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

119 Citations (Scopus)

Abstract

Mitochondrial depolarization promotes Parkin- and PTEN-induced kinase 1 (PINK1)-dependent polyubiquitination of multiple proteins on mitochondrial outer membranes, resulting in the removal of defective mitochondria via mitophagy. Because Parkin mutations occur in Parkinson's disease, a condition associated with the death of dopaminergic neurons in the midbrain, wild-type Parkin is thought to promote neuronal survival. However, here we show that wild-type Parkin greatly sensitized toward apoptosis induced by mitochondrial depolarization but not by proapoptotic stimuli that failed to activate Parkin. Parkin-dependent apoptosis required PINK1 and was efficiently blocked by prosurvival members of the Bcl-2 family or knockdown of Bax and Bak. Upon mitochondrial depolarization, the Bcl-2 family member Mcl-1 underwent rapid Parkin- and PINK1-dependent polyubiquitination and degradation, which sensitized toward apoptosis via opening of the Bax/Bak channel. These data suggest that similar to other sensors of cell stress, such as p53, Parkin has cytoprotective (mitophagy) or cytotoxic modes (apoptosis), depending on the degree of mitochondrial damage.

Original languageEnglish
Pages (from-to)1538-1553
Number of pages16
JournalCell Reports
Volume9
Issue number4
DOIs
Publication statusPublished - 20 Nov 2014

Bibliographical note

Funding Information:
We thank Dr. Stephen Tait for provision of GFP-Parkin-expressing HeLa cells, Dr. Richard Youle for provision of mCherry-Parkin and YFP-Parkin plasmids, 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 PI (08/IN.1/B2031) and SRC (07/SRC/B1144) grants from Science Foundation Ireland. S.J.M. is a Science Foundation Ireland Principal Investigator.

Publisher Copyright:
© 2014 The Authors.

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