title: PINK1 protects against cell death induced by mitochondrial depolarization, by phosphorylating Bcl-xL and impairing its pro-apoptotic cleavage.
abstract: Mutations in the PINK1 gene are a frequent cause of autosomal recessive Parkinson's disease (PD). PINK1 encodes a mitochondrial kinase with neuroprotective activity, implicated in maintaining mitochondrial homeostasis and function. In concurrence with Parkin, PINK1 regulates mitochondrial trafficking and degradation of damaged mitochondria through mitophagy. Moreover, PINK1 can activate autophagy by interacting with the pro-autophagic protein Beclin-1. Here, we report that, upon mitochondrial depolarization, PINK1 interacts with and phosphorylates Bcl-xL, an anti-apoptotic protein also known to inhibit autophagy through its binding to Beclin-1. PINK1-Bcl-xL interaction does not interfere either with Beclin-1 release from Bcl-xL or the mitophagy pathway; rather it protects against cell death by hindering the pro-apoptotic cleavage of Bcl-xL. Our data provide a functional link between PINK1, Bcl-xL and apoptosis, suggesting a novel mechanism through which PINK1 regulates cell survival. This pathway could be relevant for the pathogenesis of PD as well as other diseases including cancer.
authors.affiliation: Neurogenetics Unit, Mendel Laboratory, IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, FG, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Arena
authors.forename: V
authors.initials: V
authors.lastname: Gelmetti
authors.forename: L
authors.initials: L
authors.lastname: Torosantucci
authors.forename: D
authors.initials: D
authors.lastname: Vignone
authors.forename: G
authors.initials: G
authors.lastname: Lamorte
authors.forename: P
authors.initials: P
authors.lastname: De Rosa
authors.forename: E
authors.initials: E
authors.lastname: Cilia
authors.forename: E A
authors.initials: EA
authors.lastname: Jonas
authors.forename: E M
authors.initials: EM
authors.lastname: Valente
mesh_terms: D017209:Apoptosis / Q000502:physiology*; D051017:Apoptosis Regulatory Proteins / Q000502:physiology; D001343:Autophagy / Q000502:physiology; D000071186:Beclin-1; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000502:physiology; D057809:HEK293 Cells; D006801:Humans; D008565:Membrane Proteins / Q000502:physiology; D008928:Mitochondria / Q000502:physiology*; D010766:Phosphorylation / Q000502:physiology; D011494:Protein Kinases / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology; D051020:bcl-X Protein / Q000378:metabolism*; D000099202:PTEN-Induced Putative Kinase
chemical_list: D051017:Apoptosis Regulatory Proteins; D000071186:Beclin-1; D008565:Membrane Proteins; D011494:Protein Kinases; D051020:bcl-X Protein; D000099202:PTEN-Induced Putative Kinase; C494811:BCL2L1 protein, human; C491997:BECN1 protein, human