title: 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.
authors.affiliation: Molecular Cell Biology Laboratory, Department of Genetics, The Smurfit Institute, Trinity College Dublin, College Green, 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, College Green, 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, College Green, Dublin 2, Ireland.
authors.forename: Sean P
authors.initials: SP
authors.lastname: Cullen
authors.affiliation: Molecular Cell Biology Laboratory, Department of Genetics, The Smurfit Institute, Trinity College Dublin, College Green, Dublin 2, Ireland. Electronic address: martinsj@tcd.ie.
authors.forename: Seamus J
authors.initials: SJ
authors.lastname: Martin
mesh_terms: D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D000071186:Beclin-1; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism; D008928:Mitochondria / Q000502:physiology*; D063154:Mitochondrial Dynamics; D063306:Mitophagy; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000378:metabolism*; D010446:Peptide Fragments / Q000494:pharmacology; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism; D021381:Protein Transport / Q000187:drug effects; D011518:Proto-Oncogene Proteins / Q000494:pharmacology; D015398:Signal Transduction; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism; D051020:bcl-X Protein / Q000378:metabolism*; D000099202:PTEN-Induced Putative Kinase
chemical_list: D051017:Apoptosis Regulatory Proteins; D000071186:Beclin-1; D008565:Membrane Proteins; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D010446:Peptide Fragments; D011494:Protein Kinases; D011518:Proto-Oncogene Proteins; D044767:Ubiquitin-Protein Ligases; D051020:bcl-X Protein; D000099202:PTEN-Induced Putative Kinase; C494811:BCL2L1 protein, human; C491997:BECN1 protein, human; C474007:Bax protein (53-86); C579095:MCL1 protein, human; C111567:parkin protein