title: Parkin sensitizes toward apoptosis induced by mitochondrial depolarization through promoting degradation of Mcl-1.
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.
authors.affiliation: Molecular Cell Biology Laboratory, Department of Genetics, The Smurfit Institute, Trinity College, Dublin 2, Ireland.
authors.forename: Richard G
authors.initials: RG
authors.lastname: Carroll
authors.affiliation: Molecular Cell Biology Laboratory, Department of Genetics, The Smurfit Institute, Trinity College, Dublin 2, Ireland.
authors.forename: Emilie
authors.initials: E
authors.lastname: Hollville
authors.affiliation: Molecular Cell Biology Laboratory, Department of Genetics, The Smurfit Institute, Trinity College, Dublin 2, Ireland. Electronic address: martinsj@tcd.ie.
authors.forename: Seamus J
authors.initials: SJ
authors.lastname: Martin
mesh_terms: D017209:Apoptosis; D045744:Cell Line, Tumor; D055785:Gene Knockdown Techniques; D020868:Gene Silencing; D006801:Humans; D053078:Membrane Potential, Mitochondrial; D008928:Mitochondria / Q000378:metabolism*; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000378:metabolism*; D025821:Polyubiquitin / Q000378:metabolism; D011494:Protein Kinases / Q000378:metabolism; D021381:Protein Transport; D059748:Proteolysis; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*; D054875:Ubiquitination; D051028:bcl-2-Associated X Protein / Q000378:metabolism; D000099202:PTEN-Induced Putative Kinase
chemical_list: D064549:Myeloid Cell Leukemia Sequence 1 Protein; D025821:Polyubiquitin; D011494:Protein Kinases; D044767:Ubiquitin-Protein Ligases; D051028:bcl-2-Associated X Protein; D000099202:PTEN-Induced Putative Kinase; C579095:MCL1 protein, human; C111567:parkin protein