title: A novel mitochondrial ubiquitin ligase plays a critical role in mitochondrial dynamics.
abstract: In this study, we have identified a novel mitochondrial ubiquitin ligase, designated MITOL, which is localized in the mitochondrial outer membrane. MITOL possesses a Plant Homeo-Domain (PHD) motif responsible for E3 ubiquitin ligase activity and predicted four-transmembrane domains. MITOL displayed a rapid degradation by autoubiquitination activity in a PHD-dependent manner. HeLa cells stably expressing a MITOL mutant lacking ubiquitin ligase activity or MITOL-deficient cells by small interfering RNA showed an aberrant mitochondrial morphology such as fragmentation, suggesting the enhancement of mitochondrial fission by MITOL dysfunction. Indeed, a dominant-negative expression of Drp1 mutant blocked mitochondrial fragmentation induced by MITOL depletion. We found that MITOL associated with and ubiquitinated mitochondrial fission protein hFis1 and Drp1. Pulse-chase experiment showed that MITOL overexpression increased turnover of these fission proteins. In addition, overexpression phenotype of hFis1 could be reverted by MITOL co-overexpression. Our finding indicates that MITOL plays a critical role in mitochondrial dynamics through the control of mitochondrial fission proteins.
authors.affiliation: Laboratory of Molecular Biochemistry, School of Life Science, Tokyo University of Pharmacy and Life Science, Hachioji, Tokyo, Japan.
authors.forename: Ryo
authors.initials: R
authors.lastname: Yonashiro
authors.forename: Satoshi
authors.initials: S
authors.lastname: Ishido
authors.forename: Shinkou
authors.initials: S
authors.lastname: Kyo
authors.forename: Toshifumi
authors.initials: T
authors.lastname: Fukuda
authors.forename: Eiji
authors.initials: E
authors.lastname: Goto
authors.forename: Yohei
authors.initials: Y
authors.lastname: Matsuki
authors.forename: Mari
authors.initials: M
authors.lastname: Ohmura-Hoshino
authors.forename: Kiyonao
authors.initials: K
authors.lastname: Sada
authors.forename: Hak
authors.initials: H
authors.lastname: Hotta
authors.forename: Hirohei
authors.initials: H
authors.lastname: Yamamura
authors.forename: Ryoko
authors.initials: R
authors.lastname: Inatome
authors.forename: Shigeru
authors.initials: S
authors.lastname: Yanagi
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D015536:Down-Regulation; D006367:HeLa Cells; D006801:Humans; D007425:Intracellular Membranes / Q000378:metabolism; D008565:Membrane Proteins; D008856:Microscopy, Fluorescence; D008928:Mitochondria / Q000201:enzymology*; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism*; D008969:Molecular Sequence Data; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*
chemical_list: D008565:Membrane Proteins; D024101:Mitochondrial Proteins; C515578:MARCHF5 protein, human; D044767:Ubiquitin-Protein Ligases