title: 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 (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.
mesh_terms: D000255:Adenosine Triphosphate / Q000096:biosynthesis; D000375:Aging / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D002478:Cells, Cultured; D003676:Deferoxamine / Q000494:pharmacology; D015536:Down-Regulation; D042963:Electron Transport Complex II / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000502:physiology*; D006801:Humans; D007425:Intracellular Membranes; D007502:Iron Chelating Agents / Q000494:pharmacology*; D007506:Iron-Sulfur Proteins / Q000037:antagonists & inhibitors; D008564:Membrane Potentials; D008928:Mitochondria / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D024101:Mitochondrial Proteins / Q000172:deficiency / Q000502:physiology; D021122:Protein Subunits / Q000037:antagonists & inhibitors*
chemical_list: D007502:Iron Chelating Agents; D007506:Iron-Sulfur Proteins; D024101:Mitochondrial Proteins; D021122:Protein Subunits; D000255:Adenosine Triphosphate; D042963:Electron Transport Complex II; D003676:Deferoxamine