Mitochondrial dysfunction by complex II inhibition delays overall cell cycle progression via reactive oxygen species production.
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.
Byun
Hae-Ok
HO
Department of Biochemistry and Molecular Biology, Ajou University School of Medicine, Suwon 443-721, South Korea.
Kim
Hee Young
HY
Lim
Jin J
JJ
Seo
Yong-Hak
YH
Yoon
Gyesoon
G
D000255:Adenosine Triphosphate / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D042963:Electron Transport Complex II / Q000037:antagonists & inhibitors*; D005947:Glucose / Q000494:pharmacology; D042541:Intracellular Space / Q000187:drug effects / Q000378:metabolism; D008928:Mitochondria / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology* / Q000648:ultrastructure; D018384:Oxidative Stress / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism*; D013804:Thenoyltrifluoroacetone / Q000494:pharmacology
D050759:Cyclin-Dependent Kinase Inhibitor p21; D017382:Reactive Oxygen Species; D013804:Thenoyltrifluoroacetone; D000255:Adenosine Triphosphate; D042963:Electron Transport Complex II; D005947:Glucose