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  • The EMBO Journal (2006) 25, 3618 - 3626
  • doi:10.1038/sj.emboj.7601249

Published online: 27 July 2006

A novel mitochondrial ubiquitin ligase plays a critical role in mitochondrial dynamics

Ryo Yonashiro1,2, Satoshi Ishido3, Shinkou Kyo2, Toshifumi Fukuda1, Eiji Goto2,3, Yohei Matsuki2,3, Mari Ohmura-Hoshino3, Kiyonao Sada2, Hak Hotta2, Hirohei Yamamura2, Ryoko Inatome1,2 and Shigeru Yanagi1,4

  1. Laboratory of Molecular Biochemistry, School of Life Science, Tokyo University of Pharmacy and Life Science, Hachioji, Tokyo, Japan
  2. Department of Genome Science, Kobe University Graduate School of Medicine, Chuo-Ku, Kobe, Japan
  3. Laboratory for Infectious Immunity, RIKEN Research Center for Allergy and Immunology, Tsurumi-ku, Yokohama, Kanagawa, Japan
  4. PRESTO, Japan Science and Technology Agency (JST), Kawaguchi, Saitama, Japan

Correspondence to:

Shigeru Yanagi, Laboratory of Molecular Biochemistry, School of Life Science, Tokyo University of Pharmacy and Life Science, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan. Tel.: +81 42 676 7146; Fax: +81 42 676 4149; E-mail: syanagi@ls.toyaku.ac.jp

Satoshi Ishido, Laboratory of Molecular Biochemistry, School of Life Science, Tokyo University of Pharmacy and Life Science, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan. Tel.: +81 45 503 7022; Fax: +81 45 503 7021; E-mail: ishido@rcai.riken.jp

Received 24 February 2006; Accepted 29 June 2006

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.

  • Keywords:

    • E3 ubiquitin ligase,
    • mitochondria,
    • mitochondrial dynamics,
    • mitochondrial fission