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

Abstract

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 (⌬⌿m), but the ATP loss itself did not seem to be essential in progression to the senescent arrest. The ⌬⌿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.

Reduction of exportin 6 activity leads to actin accumulation via failure of RanGTP restoration and NTF2 sequestration in the nuclei of senescent cells

“…The findings are in good agreement with our previous study that ATP level is decreased and the cell growth is arrested after deferoxamine treatment due to the limited complex II activity and mitochondria elongation [9,50]. To examine whether the lower energy charge regulated Ran distribution in cellular senescence or not, young HDF cells were treated with antimycin A, and the result showed significant inhibition of ATP generation and subsequent loss of RanGTP in the nuclei of the cells in 30 min to 2 h of the treatment (Fig.…”

“…3). The data are in good support of our earlier studies that cell cycle delay in the senescence-associated growth arrest is due to the limited complex II activity and mitochondrial dysfunction [9,50].…”

Manganese Superoxide Dismutase Induces p53-Dependent Senescence in Colorectal Cancer Cells

“…Kim and coworkers (17) have reported that MnSOD can give rise to depolarization across the mitochondrial membrane, a phenomenon that has also been implicated in the development of senescence (49). Therefore, we measured the MMP in our cells.…”

Chloramphenicol-induced Mitochondrial Stress Increases p21 Expression and Prevents Cell Apoptosis through a p21-dependent Pathway

“…Senescent cells often show a decline in death signaling that would lead to accumulation of damaged cells, possibly representing a significant factor in the development of cancer (49). Mitochondria have been demonstrated that will operate the senescence biogenesis, especially in cellular redox regulation.…”