title: The PINK1, synphilin-1 and SIAH-1 complex constitutes a novel mitophagy pathway.
abstract: PTEN-induced putative kinase 1 (PINK1) and parkin are mutated in familial forms of Parkinson's disease and are important in promoting the mitophagy of damaged mitochondria. In this study, we showed that synphilin-1 interacted with PINK1 and was recruited to the mitochondria. Once in the mitochondria, it promoted PINK1-dependent mitophagy, as revealed by Atg5 knockdown experiments and the recruitment of LC3 and Lamp1 to the mitochondria. PINK1-synphilin-1 mitophagy did not depend on PINK1-mediated phosphorylation of synphilin-1 and occurred in the absence of parkin. Synphilin-1 itself caused depolarization of the mitochondria and increased the amount of uncleaved PINK1 at the organelle. Furthermore, synphilin-1 recruited seven in absentia homolog (SIAH)-1 to the mitochondria where it promoted mitochondrial protein ubiquitination and subsequent mitophagy. Mitophagy via this pathway was impaired by synphilin-1 knockdown or by the use of a synphilin-1 mutant that is unable to recruit SIAH-1 to the mitochondria. Likewise, knockdown of SIAH-1 or the use of a catalytically inactive SIAH-1 mutant abrogated mitophagy. PINK1 disease mutants failed to recruit synphilin-1 and did not activate mitophagy, indicating that PINK1-synphilin-1-SIAH-1 represents a new parkin-independent mitophagy pathway. Drugs that activate this pathway will provide a novel strategy to promote the clearance of damaged mitochondria in Parkinson's disease.
authors.affiliation: Department of Biochemistry, The B. Rappaport Faculty of Medicine and Institute of Medical Research, Technion-Israel Institute of Technology, Haifa 31096, Israel.
authors.forename: Raymonde
authors.initials: R
authors.lastname: Szargel
authors.affiliation: Department of Biochemistry, The B. Rappaport Faculty of Medicine and Institute of Medical Research, Technion-Israel Institute of Technology, Haifa 31096, Israel.
authors.forename: Vered
authors.initials: V
authors.lastname: Shani
authors.affiliation: Department of Biochemistry, The B. Rappaport Faculty of Medicine and Institute of Medical Research, Technion-Israel Institute of Technology, Haifa 31096, Israel.
authors.forename: Fatimah
authors.initials: F
authors.lastname: Abd Elghani
authors.affiliation: Department of Biochemistry, The B. Rappaport Faculty of Medicine and Institute of Medical Research, Technion-Israel Institute of Technology, Haifa 31096, Israel.
authors.forename: Lucy N
authors.initials: LN
authors.lastname: Mekies
authors.affiliation: Department of Biochemistry, The B. Rappaport Faculty of Medicine and Institute of Medical Research, Technion-Israel Institute of Technology, Haifa 31096, Israel.
authors.forename: Esti
authors.initials: E
authors.lastname: Liani
authors.affiliation: Department of Biochemistry, The B. Rappaport Faculty of Medicine and Institute of Medical Research, Technion-Israel Institute of Technology, Haifa 31096, Israel.
authors.forename: Ruth
authors.initials: R
authors.lastname: Rott
authors.affiliation: Department of Biochemistry, The B. Rappaport Faculty of Medicine and Institute of Medical Research, Technion-Israel Institute of Technology, Haifa 31096, Israel simone@tx.technion.ac.il.
authors.forename: Simone
authors.initials: S
authors.lastname: Engelender
mesh_terms: D000071187:Autophagy-Related Protein 5 / Q000235:genetics; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008928:Mitochondria / Q000235:genetics / Q000473:pathology; D063306:Mitophagy / Q000235:genetics*; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D010300:Parkinson Disease / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation; D011485:Protein Binding; D011494:Protein Kinases / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D025801:Ubiquitin; D044767:Ubiquitin-Protein Ligases / Q000235:genetics* / Q000378:metabolism; D054875:Ubiquitination; D000098563:Seven in Absentia Proteins; D000099202:PTEN-Induced Putative Kinase
chemical_list: D000071187:Autophagy-Related Protein 5; D002352:Carrier Proteins; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D011494:Protein Kinases; D025801:Ubiquitin; D044767:Ubiquitin-Protein Ligases; D000098563:Seven in Absentia Proteins; D000099202:PTEN-Induced Putative Kinase; C118958:SNCAIP protein, human