한빛사 논문
Yong-Yea Park1,2, Seungmin Lee1,2, Mariusz Karbowski3, Albert Neutzner4, Richard J. Youle4
and Hyeseong Cho1,2,*
1Department of Biochemistry, Ajou University School of Medicine, Yeongtong-gu, Suwon 443-721, Korea
2Graduate School of Molecular Science and Technology, Ajou University, Yeongtong-gu, Suwon 443-721, Korea
3University of Maryland Biotechnology Institute, Medical Biotechnology Center, Baltimore, MD 20892, USA
4Biochemistry Section, SNB, NINDS, National Institutes of Health, Bethesda, MD 20892, USA
*Author for correspondence
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 β-galactosidase (SA-β-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 Mfn1T109A, a GTPase-deficient mutant form of Mfn1, into MARCH5-RNAi cells not only disrupted mitochondrial elongation, but also abolished the increase in SA-β-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-β-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.
Key words: MARCH5, Cellular senescence, Mfn1, Drp1
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