title: Dynamin-Related Protein 1 Deficiency Leads to Receptor-Interacting Protein Kinase 3-Mediated Necroptotic Neurodegeneration.
abstract: Mitochondria are dynamic organelles that divide and fuse to modulate their number and shape. We have previously reported that the loss of dynamin-related protein 1 (Drp1), which mediates mitochondrial division, leads to the degeneration of cerebellar Purkinje cells in mice. Because Drp1 has been shown to be important for apoptosis and necroptosis, it is puzzling how Purkinje neurons die in the absence of Drp1. In this study, we tested whether neurodegeneration involves necrotic cell death by generating Purkinje cell-specific Drp1-knockout (KO) mice that lack the receptor-interacting protein kinase 3 (Rip3), which regulates necroptosis. We found that the loss of Rip3 significantly delays the degeneration of Drp1-KO Purkinje neurons. In addition, before neurodegeneration, mitochondrial tubules elongate because of unopposed fusion and subsequently become large spheres as a result of oxidative damage. Surprisingly, Rip3 loss also helps Drp1-KO Purkinje cells maintain the elongated morphology of the mitochondrial tubules. These data suggest that Rip3 plays a role in neurodegeneration and mitochondrial morphology in the absence of mitochondrial division.
authors.affiliation: Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Yamada
authors.affiliation: Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Adachi
authors.affiliation: Department of Anatomy, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Fukaya
authors.affiliation: Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Miho
authors.initials: M
authors.lastname: Iijima
authors.affiliation: Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, Maryland. Electronic address: hsesaki@jhmi.edu.
authors.forename: Hiromi
authors.initials: H
authors.lastname: Sesaki
mesh_terms: D000818:Animals; D017209:Apoptosis; D004195:Disease Models, Animal; D034281:Dynamins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism; D063154:Mitochondrial Dynamics; D009336:Necrosis / Q000378:metabolism; D019636:Neurodegenerative Diseases / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D010084:Oxidation-Reduction; D011689:Purkinje Cells / Q000473:pathology; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism
chemical_list: D053422:Receptor-Interacting Protein Serine-Threonine Kinases; C485615:Ripk3 protein, mouse; C486391:Dnm1l protein, mouse; D034281:Dynamins