Complex II Defect via Down-regulation of Iron-Sulfur Subunit Induces Mitochondrial Dysfunction and Cell Cycle Delay in Iron Chelation-induced Senescence-associated Growth Arrest
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Mitochondria play a pivotal role as an ATP generator in aerobically growing cells, and their defects have long been implicated in the cellular aging process, although its detailed underlying mechanisms remain unclear. Recently, we found that, in the cellular senescent process of Chang cells induced by desferroxamine mesylate, an iron chelator, a significant decrease of intracellular ATP level was accompanied by decline in complex II activity, which preceded acquisition of the senescent phenotype. In the present study, we investigated the mechanism of how the mitochondrial ATP productivity was damaged by iron chelation and how complex II defect was involved in the senescent arrest. The ATP loss was irreversible and accompanied by sustained collapse of mitochondrial membrane potential (Delta psi m), but the ATP loss itself did not seem to be essential in progression to the senescent arrest. The Delta psi m disruption was due to decreased mitochondrial respiration, which was primarily associated with the defective complex II activity. Furthermore, we found that the declined activity of complex II was mainly due to down-regulation of protein expression of the iron-sulfur subunit, which was associated with the irreversibility of the arrest. Finally, we demonstrated that specific inhibition of complex II with 2-thenoyltrifluoroacetone induced overall delay of the cell cycle, suggesting that the delayed arrest by desferroxamine mesylate might be in part due to inhibition of complex II activity. Taken together, our results suggest that complex II might be considered as one of the primary factors to regulate mitochondrial respiratory function by responding to the cellular iron level, thereby influencing cellular growth.
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Early cellular senescence features impaired mitochondrial OXPHOS.
“For example, defects in mitochondrial OXPHOS are observed in the early stages of cellular senescence91–93.”
From Mitochondrial and metabolic dysfunction in ageing and age-related diseases (2022) · cites this paper as [91]
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- Authors
- Yoon, Y.-S., Byun, H.-O., Cho, H., Kim, B.-K., & Yoon, G.
- Affiliations
- Ajou University (KR)
- Corresponding author
- Yoon, Gyesoon
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2003-12
- Volume
- 278
- Issue
- 51
- Pages
- 51577-51586
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2039750130
- Cited by
- 91
- References
- 41
- Citations by year
- 2026: 2 · 2025: 4 · 2024: 2 · 2023: 7 · 2022: 6 · 2021: 8 · 2020: 6 · 2019: 4 · 2018: 6 · 2017: 3 · 2016: 5 · 2015: 3 · 2014: 3 · 2013: 4 · 2012: 3
- FWCI
- 1.03
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- AJOU Open Repository (Ajou University) (submittedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Keywords
- succinate dehydrogenase, cellular senescence, iron chelation, mitochondrial dysfunction, mitochondrial membrane potential, mitochondrial respiration, ATP depletion, cell cycle arrest, thenoyltrifluoroacetone, cellular iron homeostasis, Chang cells
- MeSH terms
- Adenosine Triphosphate, Aging, Cell Cycle, Cells, Cultured, Deferoxamine, Humans, Intracellular Membranes, Iron Chelating Agents, Iron-Sulfur Proteins, Membrane Potentials, Mitochondria, Down-Regulation, Protein Subunits, Mitochondrial Proteins, Electron Transport Complex II
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