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Loss of MARCH5 mitochondrial E3 ubiquitin ligase induces cellular senescence through dynamin-related protein 1 and mitofusin 1.

Authors
Park, YY; Lee, S; Karbowski, M; Neutzner, A; Youle, RJ; Cho, H
Citation
Journal of cell science, 123(Pt.4):619-626, 2010
Journal Title
Journal of cell science
ISSN
0021-95331477-9137
Abstract
Mitochondria constantly divide and combine through fission and fusion activities. MARCH5, a mitochondrial E3 ubiquitin ligase, has been identified as a molecule that binds mitochondrial fission 1 protein (hFis1), dynamin-related protein 1 (Drp1) and mitofusin 2 (Mfn2), key proteins in the control of mitochondrial fission and fusion. However, how these interactions control mitochondrial dynamics, and cellular function has remained obscure. Here, we show that shRNA-mediated MARCH5 knockdown promoted the accumulation of highly interconnected and elongated mitochondria. Cells transfected with MARCH5 shRNA or a MARCH5 RING domain mutant displayed cellular enlargement and flattening accompanied by increased senescence-associated beta-galactosidase (SA-beta-Gal) activity, indicating that these cells had undergone cellular senescence. Notably, a significant increase in Mfn1 level, but not Mfn2, Drp1 or hFis1 levels, was observed in MARCH5-depleted cells, indicating that Mfn1 is a major ubiquitylation substrate. Introduction of Mfn1(T109A), a GTPase-deficient mutant form of Mfn1, into MARCH5-RNAi cells not only disrupted mitochondrial elongation, but also abolished the increase in SA-beta-Gal activity. Moreover, the aberrant mitochondrial phenotypes in MARCH5-RNAi cells were reversed by ectopic expression of Drp1, but not by hFis1, and reversion of the mitochondria morphology in MARCH5-depleted cells was accompanied by a reduction in SA-beta-Gal activity. Collectively, our data indicate that the lack of MARCH5 results in mitochondrial elongation, which promotes cellular senescence by blocking Drp1 activity and/or promoting accumulation of Mfn1 at the mitochondria.
MeSH terms
Amino Acid SubstitutionBase SequenceCell Aging/physiology*Cell LineDNA Primers/geneticsGTP Phosphohydrolases/metabolism*Hela CellsHumansMembrane Proteins/antagonists & inhibitors*Membrane Proteins/chemistryMembrane Proteins/geneticsMembrane Proteins/metabolismMembrane Transport Proteins/metabolism*Microtubule-Associated Proteins/metabolism*Mitochondria/metabolismMitochondria/ultrastructureMitochondrial Proteins/antagonists & inhibitors*Mitochondrial Proteins/geneticsMitochondrial Proteins/metabolismMutagenesis, Site-DirectedProtein Structure, TertiaryRNA InterferenceRNA, Small Interfering/geneticsRecombinant Proteins/chemistryRecombinant Proteins/geneticsRecombinant Proteins/metabolismSubstrate SpecificityTransfectionUbiquitin-Protein Ligases/antagonists & inhibitors*Ubiquitin-Protein Ligases/chemistryUbiquitin-Protein Ligases/geneticsUbiquitin-Protein Ligases/metabolism
DOI
10.1242/jcs.061481
PMID
20103533
Appears in Collections:
Journal Papers > School of Medicine / Graduate School of Medicine > Biochemistry & Molecular Biology
AJOU Authors
조, 혜성
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