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PMID: 17606867 Published · ppublish English Journal Article Research Support, N.I.H., Intramural Research Support, Non-U.S. Gov't

The mitochondrial E3 ubiquitin ligase MARCH5 is required for Drp1 dependent mitochondrial division.

The Journal of cell biology ·Vol. 178 ·No. 1 ·2007-07-02 ·Pages 71-84

Karbowski M, Neutzner A, Youle RJ

Abstract

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.

MeSH Terms
Dynamins GTP Phosphohydrolases/genetics,metabolism Green Fluorescent Proteins/metabolism HeLa Cells Humans Membrane Proteins/chemistry,genetics,physiology Microscopy, Confocal Microtubule-Associated Proteins/genetics,metabolism Mitochondria/metabolism Mitochondrial Proteins/genetics,metabolism Mutation Protein Structure, Tertiary/genetics RNA Interference Ubiquitin-Protein Ligases/chemistry,genetics,physiology
Chemicals
Membrane Proteins Microtubule-Associated Proteins Mitochondrial Proteins Green Fluorescent Proteins MARCHF5 protein, human Ubiquitin-Protein Ligases GTP Phosphohydrolases DNM1L protein, human Dynamins
Authors & Affiliations
3 authors, click to expand affiliations / ORCID
Karbowski Mariusz
Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20852, USA.
Neutzner Albert
Youle Richard J
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Article Info
Journal
The Journal of cell biology
Abbr.
J Cell Biol
ISSN
0021-9525
DOI
10.1083/jcb.200611064
Published
2007-07-02
Pages
71-84
Language
English
Region
United States
NLM ID
0375356
PMCID
PMC2064424
Subset
IM
Grants
Intramural NIH HHS · United States
External Links
PubMed source DOI: 10.1083/jcb.200611064 PMC Full Text View journal details
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