title: PINK1 and BECN1 relocalize at mitochondria-associated membranes during mitophagy and promote ER-mitochondria tethering and autophagosome formation.
abstract: Mitophagy is a highly specialized process to remove dysfunctional or superfluous mitochondria through the macroautophagy/autophagy pathway, aimed at protecting cells from the damage of disordered mitochondrial metabolism and apoptosis induction. PINK1, a neuroprotective protein mutated in autosomal recessive Parkinson disease, has been implicated in the activation of mitophagy by selectively accumulating on depolarized mitochondria, and promoting PARK2/Parkin translocation to them. While these steps have been characterized in depth, less is known about the process and site of autophagosome formation upon mitophagic stimuli. A previous study reported that, in starvation-induced autophagy, the proautophagic protein BECN1/Beclin1 (which we previously showed to interact with PINK1) relocalizes at specific regions of contact between the endoplasmic reticulum (ER) and mitochondria called mitochondria-associated membranes (MAM), from which the autophagosome originates. Here we show that, following mitophagic stimuli, autophagosomes also form at MAM; moreover, endogenous PINK1 and BECN1 were both found to relocalize at MAM, where they promoted the enhancement of ER-mitochondria contact sites and the formation of omegasomes, that represent autophagosome precursors. PARK2 was also enhanced at MAM following mitophagy induction. However, PINK1 silencing impaired BECN1 enrichment at MAM independently of PARK2, suggesting a novel role for PINK1 in regulating mitophagy. MAM have been recently implicated in many key cellular events. In this light, the observed prevalent localization of PINK1 at MAM may well explain other neuroprotective activities of this protein, such as modulation of mitochondrial calcium levels, mitochondrial dynamics, and apoptosis.
authors.affiliation: a Neurogenetics Unit, IRCCS Santa Lucia Foundation , Rome , Italy.
authors.forename: Vania
authors.initials: V
authors.lastname: Gelmetti
authors.affiliation: b IRCCS Casa Sollievo della Sofferenza, CSS-Mendel Institute , Rome , Italy.
authors.forename: Priscilla
authors.initials: P
authors.lastname: De Rosa
authors.affiliation: b IRCCS Casa Sollievo della Sofferenza, CSS-Mendel Institute , Rome , Italy.
authors.forename: Liliana
authors.initials: L
authors.lastname: Torosantucci
authors.affiliation: c Department of Bioscience , University of Oslo , Oslo , Norway.
authors.forename: Elettra Sara
authors.initials: ES
authors.lastname: Marini
authors.affiliation: d National Institute for Infectious Diseases "LazzaroSpallanzani" IRCCS , Rome , Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Romagnoli
authors.affiliation: d National Institute for Infectious Diseases "LazzaroSpallanzani" IRCCS , Rome , Italy.|e Department of Biology , "Tor Vergata" University , Rome , Italy.
authors.forename: Martina
authors.initials: M
authors.lastname: Di Rienzo
authors.affiliation: f IRCM, Institut de Recherche en Cancérologie de Montpellier, INSERM U1194, Université Montpellier, Institutrégional du Cancer Montpellier , Montpellier , France.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Arena
authors.affiliation: g In vitro Pharmacology Unit, IRBM Science Park , Rome , Italy.
authors.forename: Domenico
authors.initials: D
authors.lastname: Vignone
authors.affiliation: d National Institute for Infectious Diseases "LazzaroSpallanzani" IRCCS , Rome , Italy.|h Department of Biological and Environmental Sciences and Technologies (DiSTeBA) , University of Salento , Lecce , Italy.
authors.forename: Gian Maria
authors.initials: GM
authors.lastname: Fimia
authors.affiliation: a Neurogenetics Unit, IRCCS Santa Lucia Foundation , Rome , Italy.|i Department of Molecular Medicine , University of Pavia , Pavia , Italy.
authors.forename: Enza Maria
authors.initials: EM
authors.lastname: Valente
mesh_terms: D000071182:Autophagosomes / Q000378:metabolism*; D000071186:Beclin-1 / Q000378:metabolism*; D002258:Carbonyl Cyanide m-Chlorophenyl Hydrazone / Q000494:pharmacology; D002451:Cell Compartmentation / Q000187:drug effects; D045744:Cell Line, Tumor; D015536:Down-Regulation; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D006801:Humans; D008928:Mitochondria / Q000378:metabolism*; D051336:Mitochondrial Membranes / Q000378:metabolism*; D063306:Mitophagy; D011494:Protein Kinases / Q000378:metabolism*; D000099202:PTEN-Induced Putative Kinase
chemical_list: D000071186:Beclin-1; D002258:Carbonyl Cyanide m-Chlorophenyl Hydrazone; D011494:Protein Kinases; D000099202:PTEN-Induced Putative Kinase
keywords: BECN1; CCCP; PARK2; PINK1; Parkinson disease; autophagosome formation; endoplasmic reticulum-mitochondria tethering; mitochondria-associated membranes; mitophagy; omegasome