title: The TOMM machinery is a molecular switch in PINK1 and PARK2/PARKIN-dependent mitochondrial clearance.
abstract: Loss-of-function mutations in PARK2/PARKIN and PINK1 cause early-onset autosomal recessive Parkinson disease (PD). The cytosolic E3 ubiquitin-protein ligase PARK2 cooperates with the mitochondrial kinase PINK1 to maintain mitochondrial quality. A loss of mitochondrial transmembrane potential (ΔΨ) leads to the PINK1-dependent recruitment of PARK2 to the outer mitochondrial membrane (OMM), followed by the ubiquitination and proteasome-dependent degradation of OMM proteins, and by the autophagy-dependent clearance of mitochondrial remnants. We showed here that blockade of mitochondrial protein import triggers the recruitment of PARK2, by PINK1, to the TOMM machinery. PD-causing PARK2 mutations weakened or disrupted the molecular interaction between PARK2 and specific TOMM subunits: the surface receptor, TOMM70A, and the channel protein, TOMM40. The downregulation of TOMM40 or its associated core subunit, TOMM22, was sufficient to trigger OMM protein clearance in the absence of PINK1 or PARK2. However, PARK2 was required to promote the degradation of whole organelles by autophagy. Furthermore, the overproduction of TOMM22 or TOMM40 reversed mitochondrial clearance promoted by PINK1 and PARK2 after ΔΨ loss. These results indicated that the TOMM machinery is a key molecular switch in the mitochondrial clearance program controlled by the PINK1-PARK2 pathway. Loss of functional coupling between mitochondrial protein import and the neuroprotective degradation of dysfunctional mitochondria may therefore be a primary pathogenic mechanism in autosomal recessive PD.
authors.affiliation: Inserm; U 975; CRICM; Hôpital de la Pitié-Salpêtrière; Paris, France; UPMC; Université Paris 06; UMR_S975; Paris, France; CNRS; UMR 7225; Paris, France.
authors.forename: Giulia
authors.initials: G
authors.lastname: Bertolin
authors.forename: Rosa
authors.initials: R
authors.lastname: Ferrando-Miguel
authors.forename: Maxime
authors.initials: M
authors.lastname: Jacoupy
authors.forename: Sabine
authors.initials: S
authors.lastname: Traver
authors.forename: Karl
authors.initials: K
authors.lastname: Grenier
authors.forename: Andrew W
authors.initials: AW
authors.lastname: Greene
authors.forename: Aurélien
authors.initials: A
authors.lastname: Dauphin
authors.forename: François
authors.initials: F
authors.lastname: Waharte
authors.forename: Aurélien
authors.initials: A
authors.lastname: Bayot
authors.forename: Jean
authors.initials: J
authors.lastname: Salamero
authors.forename: Anne
authors.initials: A
authors.lastname: Lombès
authors.forename: Anne-Laure
authors.initials: AL
authors.lastname: Bulteau
authors.forename: Edward A
authors.initials: EA
authors.lastname: Fon
authors.forename: Alexis
authors.initials: A
authors.lastname: Brice
authors.forename: Olga
authors.initials: O
authors.lastname: Corti
mesh_terms: D015536:Down-Regulation; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D026901:Membrane Transport Proteins / Q000378:metabolism*; D008928:Mitochondria / Q000378:metabolism*; D033681:Mitochondrial Membrane Transport Proteins / Q000378:metabolism*; D051336:Mitochondrial Membranes / Q000378:metabolism; D000090622:Mitochondrial Precursor Protein Import Complex Proteins; D063306:Mitophagy; D008954:Models, Biological; D009154:Mutation / Q000235:genetics; D010300:Parkinson Disease / Q000235:genetics; D011485:Protein Binding; D011494:Protein Kinases / Q000378:metabolism*; D021381:Protein Transport; D015398:Signal Transduction; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*; D000099202:PTEN-Induced Putative Kinase
chemical_list: D026901:Membrane Transport Proteins; D033681:Mitochondrial Membrane Transport Proteins; D000090622:Mitochondrial Precursor Protein Import Complex Proteins; D011494:Protein Kinases; D044767:Ubiquitin-Protein Ligases; D000099202:PTEN-Induced Putative Kinase; C489971:TOMM22 protein, human; C400783:TOMM40 protein, human; C402118:TOMM70 protein, human; C111567:parkin protein
keywords: PARK2; PINK1; Parkinson disease; TOMM machinery; mitochondria; mitophagy; outer mitochondrial membrane