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Published online July 2, 2007
doi:10.1083/jcb.200611064
The Journal of Cell Biology, Vol. 178, No. 1, 71-84
The Rockefeller University Press, 0021-9525 $30.00
© 2007 Karbowski et al.
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 The mitochondrial E3 ubiquitin ligase MARCH5 is required for Drp1 dependent mitochondrial division

Mariusz Karbowski1,2, Albert Neutzner1, and Richard J. Youle1

1 Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20852
2 Medical Biotechnology Center, University of Maryland Biotechnology Institute, Baltimore, MD 21201

Correspondence to Richard J. Youle: youler{at}ninds.nih.gov

We identify a mitochondrial E3 ubiquitin ligase, MARCH5, as a critical regulator of mitochondrial fission. MARCH5 RING mutants and MARCH5 RNA interference induce an abnormal elongation and interconnection of mitochondria indicative of an inhibition of mitochondrial division. The aberrant mitochondrial phenotypes in MARCH5 RING mutant–expressing cells are reversed by ectopic expression of Drp1, but not another mitochondrial fission protein Fis1. Moreover, as indicated by abnormal clustering and mitochondrial accumulation of Drp1, as well as decreased cellular mobility of YFP-Drp1 in cells expressing MARCH5 RING mutants, MARCH5 activity regulates the subcellular trafficking of Drp1, likely by impacting the correct assembly at scission sites or the disassembly step of fission complexes. Loss of this activity may account for the observed mitochondrial division defects. Finally, MARCH5 RING mutants and endogenous Drp1, but not wild-type MARCH5 or Fis1, co-assemble into abnormally enlarged clusters in a Drp1 GTPase-dependent manner, suggesting molecular interactions among these proteins. Collectively, our data suggest a model in which mitochondrial division is regulated by a MARCH5 ubiquitin-dependent switch.

M. Karbowski and A. Neutzner contributed equally to this paper.

Abbreviations used in this paper: HM, heavy membrane; MEF, mouse embryonic fibroblast; OMM, outer mitochondrial membrane; ROI, region of interest.


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