Mitochondrial dysfunction via disruption of complex II activity during iron chelation-induced senescence-like growth arrest of Chang cells.
When cells are deprived of iron, their growth is invariably inhibited. However, the mechanism involved remains largely unclear. Recently, we have reported that subcytotoxic concentration of deferoxamine mesylate (DFO), an iron chelator, specifically inhibited transition of Chang cell, a normal hepatocyte cell line, from G1 to S phase, which was accompanied by irreversible appearance of senescent biomarkers. To investigate factors responsible for the irreversible arrest, we examined mitochondrial activities because they require several irons for their proper structure and function. After exposure to 1 M DFO, total cellular ATP level was irreversibly decreased with concurrent disruption of mitochondrial membrane potential (DeltaPsim), implying that it might be one of the crucial factors involved in the arrest. DFO did not directly inhibit the mitochondrial respiratory activities in vitro. Among the respiratory activities, complex II activity was specifically inhibited through a down-regulation of the expression of its iron-sulfur subunit. We also observed that mitochondrial morphology was drastically changed to highly elongated form. Our results suggest that mitochondrial function is sensitive to cellular iron level and iron deprivation might be involved in inducing the senescent arrest. In addition, complex II, which is a part of both oxidative phosphorylation and the Krebs cycle, could be one of the critical factors that regulate mitochondrial function by responding to iron levels.
Yoon
Young-Sil
YS
Department of Biochemistry and Molecular Biology, Ajou University School of Medicine, Suwon 442-721, South Korea.
Cho
Hyeseong
H
Lee
Jae-Ho
JH
Yoon
Gyesoon
G
D015415:Biomarkers; D002453:Cell Cycle / Q000187:drug effects; D002460:Cell Line; D016922:Cellular Senescence; D003676:Deferoxamine / Q000494:pharmacology; D015536:Down-Regulation; D042963:Electron Transport Complex II / Q000502:physiology*; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D007501:Iron / Q000378:metabolism*; D007502:Iron Chelating Agents / Q000494:pharmacology; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D021122:Protein Subunits / Q000235:genetics / Q000378:metabolism
D015415:Biomarkers; D007502:Iron Chelating Agents; D021122:Protein Subunits; D007501:Iron; D042963:Electron Transport Complex II; D003676:Deferoxamine