Loss of MARCH5 mitochondrial E3 ubiquitin ligase induces cellular senescence through dynamin-related protein 1 and mitofusin 1
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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.
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Blocking the fission process by depleting FIS1 or blocking DRP1 activity leads to cell senescence in human cells accompanied by the accumulation of damaged mitochondria showing lower mitochondrial potential and higher ROS production.
“Blocking the fission process by depleting FIS1 or blocking DRP1 activity leads to cell senescence in human cells accompanied by the accumulation of damaged mitochondria showing lower mitochondrial potential and higher ROS production (Lee et al., 2007; Park et al., 2010).”
From Mitochondrial Activity and Dynamics Changes Regarding Metabolism in Ageing and Obesity (2017) · cites this paper as Park et al., 2010
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- Authors
- Park, Y.-Y., Lee, S., Karbowski, M., Neutzner, A., Youle, R. J., & Cho, H.
- Affiliations
- Ajou University (KR)
- Department of Biochemistry, Ajou University School of Medicine, Yeongtong-gu, Suwon 443-721, Korea
- University of Maryland, Baltimore (US)
- National Institutes of Health (US)
- Venue
- Journal of Cell Science
- Publisher
- The Company of Biologists
- Published
- 2010-02-15
- Volume
- 123
- Issue
- 4
- Pages
- 619-626
- ISSN
- 0021-9533 (ISSN-L)
- 1477-9137
- PMC
- PMC2818198
- OpenAlex
- W2077001214
- Cited by
- 244
- References
- 45
- Citations by year
- 2026: 9 · 2025: 13 · 2024: 11 · 2023: 14 · 2022: 20 · 2021: 16 · 2020: 13 · 2019: 15 · 2018: 7 · 2017: 11 · 2016: 23 · 2015: 12 · 2014: 25 · 2013: 17 · 2012: 16
- FWCI
- 7.03
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Journal of Cell Science (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- AJOU Open Repository (Ajou University) (submittedVersion)
- Funders
- National Institutes of Health
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Keywords
- MARCH5, cellular senescence, Drp1, mitofusin 1, mitofusin 2, mitochondrial fission, mitochondrial fusion, mitochondrial dynamics, mitochondrial elongation, ubiquitination, senescence-associated β-galactosidase, RING domain
- MeSH terms
- Base Sequence, Cell Line, HeLa Cells, Humans, Membrane Proteins, Microtubule-Associated Proteins, Mitochondria, Recombinant Proteins, Substrate Specificity, Transfection, Mutagenesis, Site-Directed, Cellular Senescence, Protein Structure, Tertiary, DNA Primers, Amino Acid Substitution, GTP Phosphohydrolases, Mitochondrial Proteins, Membrane Transport Proteins, Mitochondrial Membrane Transport Proteins, Dynamins, RNA Interference, RNA, Small Interfering, Ubiquitin-Protein Ligases
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