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Vol. 19, Issue 6, 2457-2464, June 2008

This Article Full Text Full Text (PDF) Supplemental Materials All Versions of this Article: E08-02-0227v1 19/6/2457    most recent Alert me when this article is cited Alert me if a correction is posted Services Related articles in Mol. Biol. Cell Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Google Scholar Articles by Cohen, M. M.J. Articles by Weissman, A. M. PubMed PubMed Citation Articles by Cohen, M. M.J. Articles by Weissman, A. M.

Ubiquitin–Proteasome-dependent Degradation of a Mitofusin, a Critical Regulator of Mitochondrial Fusion

Mickael M.J. Cohen^*, Guillaume P. Leboucher^*,, Nurit Livnat-Levanon, Michael H. Glickman, and Allan M. Weissman^*

*Laboratory of Protein Dynamics and Signaling, National Cancer Institute, Frederick, MD 21702; and Department of Biology, Technion-Israel Institute of Technology, Haifa 32000, Israel

Submitted February 29, 2008; Accepted March 7, 2008
Monitoring Editor: Janet Shaw

InCytes from MBC

The mitochondrion is a dynamic membranous network whose morphology is conditioned by the equilibrium between ongoing fusion and fission of mitochondrial membranes. In the budding yeast, Saccharomyces cerevisiae, the transmembrane GTPase Fzo1p controls fusion of mitochondrial outer membranes. Deletion or overexpression of Fzo1p have both been shown to alter the mitochondrial fusion process indicating that maintenance of steady-state levels of Fzo1p are required for efficient mitochondrial fusion. Cellular levels of Fzo1p are regulated through degradation of Fzo1p by the F-box protein Mdm30p. How Mdm30p promotes degradation of Fzo1p is currently unknown. We have now determined that during vegetative growth Mdm30p mediates ubiquitylation of Fzo1p and that degradation of Fzo1p is an ubiquitin-proteasome–dependent process. In vivo, Mdm30p associates through its F-box motif with other core components of Skp1-Cullin-F-box (SCF) ubiquitin ligases. We show that the resulting SCF^Mdm30p ligase promotes ubiquitylation of Fzo1p at mitochondria and its subsequent degradation by the 26S proteasome. These results provide the first demonstration that a cytosolic ubiquitin ligase targets a critical regulatory molecule at the mitochondrial outer membrane. This study provides a framework for developing an understanding of the function of Mdm30p-mediated Fzo1p degradation in the multistep process of mitochondrial fusion.

Address correspondence to: Michael H. Glickman (glickman{at}technion.ac.il) or Allan M. Weissman (amw{at}nih.gov)

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InCytes from MBC, June 2008

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