title: Mutations in Fis1 disrupt orderly disposal of defective mitochondria.
abstract: Mitochondrial fission is mediated by the dynamin-related protein Drp1 in metazoans. Drp1 is recruited from the cytosol to mitochondria by the mitochondrial outer membrane protein Mff. A second mitochondrial outer membrane protein, named Fis1, was previously proposed as recruitment factor, but Fis1(-/-) cells have mild or no mitochondrial fission defects. Here we show that Fis1 is nevertheless part of the mitochondrial fission complex in metazoan cells. During the fission cycle, Drp1 first binds to Mff on the surface of mitochondria, followed by entry into a complex that includes Fis1 and endoplasmic reticulum (ER) proteins at the ER-mitochondrial interface. Mutations in Fis1 do not normally affect fission, but they can disrupt downstream degradation events when specific mitochondrial toxins are used to induce fission. The disruptions caused by mutations in Fis1 lead to an accumulation of large LC3 aggregates. We conclude that Fis1 can act in sequence with Mff at the ER-mitochondrial interface to couple stress-induced mitochondrial fission with downstream degradation processes.
authors.affiliation: Department of Biological Chemistry, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095 Biochemistry Section, Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892 Department of Neurology, Juntendo University School of Medicine, Tokyo 113-8421, Japan.
authors.forename: Qinfang
authors.initials: Q
authors.lastname: Shen
authors.forename: Koji
authors.initials: K
authors.lastname: Yamano
authors.forename: Brian P
authors.initials: BP
authors.lastname: Head
authors.forename: Sumihiro
authors.initials: S
authors.lastname: Kawajiri
authors.forename: Jesmine T M
authors.initials: JT
authors.lastname: Cheung
authors.forename: Chunxin
authors.initials: C
authors.lastname: Wang
authors.forename: Jeong-Hoon
authors.initials: JH
authors.lastname: Cho
authors.forename: Nobutaka
authors.initials: N
authors.lastname: Hattori
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Youle
authors.forename: Alexander M
authors.initials: AM
authors.lastname: van der Bliek
mesh_terms: D000818:Animals; D017173:Caenorhabditis elegans / Q000166:cytology / Q000235:genetics / Q000378:metabolism*; D029742:Caenorhabditis elegans Proteins / Q000235:genetics* / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism; D045325:HCT116 Cells; D006367:HeLa Cells; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D063154:Mitochondrial Dynamics; D024101:Mitochondrial Proteins / Q000235:genetics* / Q000378:metabolism; D009132:Muscles / Q000166:cytology; D020125:Mutation, Missense; D059748:Proteolysis
chemical_list: D029742:Caenorhabditis elegans Proteins; D008565:Membrane Proteins; D008869:Microtubule-Associated Proteins; D024101:Mitochondrial Proteins; C000590681:fis-1 protein, C elegans