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Mitochondrial dysfunction by complex II inhibition delays overall cell cycle progression via reactive oxygen species production.

Authors
Byun, HO; Kim, HY; Lim, JJ; Seo, YH; Yoon, G
Citation
Journal of cellular biochemistry, 104(5):1747-1759, 2008
Journal Title
Journal of cellular biochemistry
ISSN
0730-23121097-4644
Abstract
Mitochondrial complex II defect has recently been implicated in cellular senescence and in the ageing process of which a critical phenotype is retardation and arrest of cellular growth. However, the underlying mechanisms of how complex II defect affects cellular growth, remain unclear. In this study, we investigated the effect of complex II inhibition using a subcytotoxic dose (400 microM) of 2-thenoyltrifluoroacetone (TTFA), a conventional complex II inhibitor, on cell cycle progression. TTFA (400 microM) directly decreased KCN-sensitive cellular respiration rate to 67% of control and disrupted the mitochondrial membrane potential. In contrast to other respiratory inhibitors such as rotenone, antimycin A, and oligomycin, TTFA prolonged the duration of each phase of the cell cycle (G1, S, and G2/M) equally, thereby delaying overall cell cycle progression. This delay was accompanied by a biphasic increase of reactive oxygen species (ROS) and concurrent glutathione oxidation, in addition to a slight decrease in the cellular ATP level. Finally, the delay in cell cycle progression caused by TTFA was proved to be mainly due to ROS overproduction and subsequent oxidative stress, as evidenced by its reversal following pretreatment with antioxidants. Taken together, these results suggest that an overall delay in cell cycle progression due to complex II defects may contribute to ageing and degenerative diseases via inhibition of cellular growth and proliferation without arrest at any specific phase of the cell cycle.
MeSH terms
Adenosine Triphosphate/metabolismCell Cycle*/drug effectsCell Death/drug effectsCell LineCell Proliferation/drug effectsCyclin-Dependent Kinase Inhibitor p21/metabolismElectron Transport Complex II/antagonists & inhibitors*Glucose/pharmacologyIntracellular Space/drug effectsIntracellular Space/metabolismMitochondria/drug effectsMitochondria/enzymology*Mitochondria/pathology*Mitochondria/ultrastructureOxidative Stress/drug effectsReactive Oxygen Species/metabolism*Thenoyltrifluoroacetone/pharmacology
DOI
10.1002/jcb.21741
PMID
18395845
Appears in Collections:
Journal Papers > School of Medicine / Graduate School of Medicine > Biochemistry & Molecular Biology
AJOU Authors
윤, 계순
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