title: Functional interplay between Parkin and Drp1 in mitochondrial fission and clearance.
abstract: Autosomal recessive early-onset Parkinson's disease is most often caused by mutations in the genes encoding the cytosolic E3 ubiquitin ligase Parkin and the mitochondrial serine/threonine kinase PINK1. Studies in Drosophila models and mammalian cells have demonstrated that these proteins regulate various aspects of mitochondrial physiology, including organelle transport, dynamics and turnover. How PINK1 and Parkin orchestrate these processes, and whether they always do so within a common pathway remain to be clarified. We have revisited the role of PINK1 and Parkin in mitochondrial dynamics, and explored its relation to the mitochondrial clearance program controlled by these proteins. We show that PINK1 and Parkin promote Drp1-dependent mitochondrial fission by mechanisms that are at least in part independent. Parkin-mediated mitochondrial fragmentation was abolished by treatments interfering with the calcium/calmodulin/calcineurin signaling pathway, suggesting that it requires dephosphorylation of serine 637 of Drp1. Parkinson's disease-causing mutations with differential impact on mitochondrial morphology and organelle degradation demonstrated that the pro-fission effect of Parkin is not required for efficient mitochondrial clearance. In contrast, the use of Förster energy transfer imaging microscopy revealed that Drp1 and Parkin are co-recruited to mitochondria in proximity of PINK1 following mitochondrial depolarization, indicating spatial coordination between these events in mitochondrial degradation. Our results also hint at a major role of the outer mitochondrial adaptor MiD51 in Drp1 recruitment and Parkin-dependent mitophagy. Altogether, our observations provide new insight into the mechanisms underlying the regulation of mitochondrial dynamics by Parkin and its relation to the mitochondrial clearance program mediated by the PINK1/Parkin pathway.
authors.affiliation: Inserm, U 1127, F-75013 Paris, France; CNRS, UMR 7225, F-75013 Paris, France; Sorbonne Universités, UPMC Univ Paris 06, UMR S 1127, F-75013 Paris, France; Institut du Cerveau et de la Moelle épinière, ICM, F-75013, Paris, France; Department of Biomedical Sciences, Midwestern University, 19555N 59th Avenue, Glendale, Arizona 85308, United States.
authors.forename: Lori
authors.initials: L
authors.lastname: Buhlman
authors.affiliation: Inserm, U 1127, F-75013 Paris, France; CNRS, UMR 7225, F-75013 Paris, France; Sorbonne Universités, UPMC Univ Paris 06, UMR S 1127, F-75013 Paris, France; Institut du Cerveau et de la Moelle épinière, ICM, F-75013, Paris, France.
authors.forename: Maria
authors.initials: M
authors.lastname: Damiano
authors.affiliation: Inserm, U 1127, F-75013 Paris, France; CNRS, UMR 7225, F-75013 Paris, France; Sorbonne Universités, UPMC Univ Paris 06, UMR S 1127, F-75013 Paris, France; Institut du Cerveau et de la Moelle épinière, ICM, F-75013, Paris, France.
authors.forename: Giulia
authors.initials: G
authors.lastname: Bertolin
authors.affiliation: Inserm, U 1127, F-75013 Paris, France; CNRS, UMR 7225, F-75013 Paris, France; Sorbonne Universités, UPMC Univ Paris 06, UMR S 1127, F-75013 Paris, France; Institut du Cerveau et de la Moelle épinière, ICM, F-75013, Paris, France.
authors.forename: Rosa
authors.initials: R
authors.lastname: Ferrando-Miguel
authors.affiliation: Inserm U 1016, Institut Cochin, F-75014, Paris, France; CNRS UMR 8104, F-75014 Paris, France; Université Paris 05, UMR_S1016 F-75014, Paris, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Lombès
authors.affiliation: Inserm, U 1127, F-75013 Paris, France; CNRS, UMR 7225, F-75013 Paris, France; Sorbonne Universités, UPMC Univ Paris 06, UMR S 1127, F-75013 Paris, France; Institut du Cerveau et de la Moelle épinière, ICM, F-75013, Paris, France.
authors.forename: Alexis
authors.initials: A
authors.lastname: Brice
authors.affiliation: Inserm, U 1127, F-75013 Paris, France; CNRS, UMR 7225, F-75013 Paris, France; Sorbonne Universités, UPMC Univ Paris 06, UMR S 1127, F-75013 Paris, France; Institut du Cerveau et de la Moelle épinière, ICM, F-75013, Paris, France. Electronic address: olga.corti@upmc.fr.
authors.forename: Olga
authors.initials: O
authors.lastname: Corti
mesh_terms: D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D034281:Dynamins / Q000378:metabolism*; D006801:Humans; D008928:Mitochondria / Q000378:metabolism*; D063154:Mitochondrial Dynamics; D024101:Mitochondrial Proteins / Q000378:metabolism; D063306:Mitophagy; D009154:Mutation / Q000235:genetics; D010300:Parkinson Disease / Q000235:genetics; D010766:Phosphorylation; D011485:Protein Binding; D011494:Protein Kinases / Q000378:metabolism; D020836:Protein Structure, Quaternary; D015398:Signal Transduction; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*; D000099202:PTEN-Induced Putative Kinase
chemical_list: D034281:Dynamins; D024101:Mitochondrial Proteins; D011494:Protein Kinases; D044767:Ubiquitin-Protein Ligases; D000099202:PTEN-Induced Putative Kinase; C111567:parkin protein
keywords: Calcium/calmodulin/calcineurin signaling; Drp1; MiD51; Mitochondrial clearance; Mitochondrial dynamics; PINK1/Parkin pathway