Overexpression of mitochondrial ferritin sensitizes cells to oxidative stress via an iron-mediated mechanism.
Mitochondrial ferritin (MtFt) is a newly identified H-ferritin-like protein expressed only in mitochondria. Previous studies have shown that its overexpression markedly affects intracellular iron homeostasis and rescues defects caused by frataxin deficiency. To assess how MtFt exerts its function under oxidative stress conditions, MtFt overexpressing cells were treated with tert-butyl-hydroperoxide (tBHP), and the effects of MtFt expression on cell survival and iron homeostasis were examined. We found that MtFt expression was associated with decreased mitochondrial metabolic activity and reduced glutathione levels as well as a concomitant increase in reactive oxygen species levels and apoptosis. Moreover, mechanistic studies demonstrated that tBHP treatment led to a prolonged decrease in cytosolic ferritins levels in MtFt-expressing cells, while ferritin levels recovered to basal levels in control counterparts. tBHP treatment also resulted in elevated transferrin receptors, followed by more iron acquisition in MtFt expressing cells. The high molecular weight desferrioxamine, targeting to lysosomes, as well as the hydrophobic iron chelator salicylaldehyde isonicotinoyl hydrazone significantly attenuated tBHP-induced cell damage. In conclusion, the current study indicates that both the newly acquired iron from the extracellular environment and internal iron redistribution from ferritin degradation may be responsible for the increased sensitivity to oxidative stress in MtFt-expressing cells.
Lu
Zhongbing
Z
State Key Laboratory of Brain and Recognition Laboratory, Institute of Biophysics, Beijing, China.
Nie
Guangjun
G
Li
Yiye
Y
Soe-Lin
Shan
S
Tao
Yi
Y
Cao
Yuanlin
Y
Zhang
Zhiyong
Z
Liu
Nianqing
N
Ponka
Prem
P
Zhao
Baolu
B
D000447:Aldehydes / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001483:Base Sequence; D015153:Blotting, Western; D045744:Cell Line, Tumor; D017931:DNA Primers; D003676:Deferoxamine / Q000494:pharmacology; D004797:Enzyme-Linked Immunosorbent Assay; D005293:Ferritins / Q000378:metabolism*; D006706:Homeostasis; D006801:Humans; D006835:Hydrazones / Q000494:pharmacology; D007502:Iron Chelating Agents / Q000494:pharmacology; D008247:Lysosomes / Q000187:drug effects / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism*; D018384:Oxidative Stress; D017382:Reactive Oxygen Species / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D020122:tert-Butylhydroperoxide / Q000494:pharmacology
D000447:Aldehydes; D017931:DNA Primers; D006835:Hydrazones; D007502:Iron Chelating Agents; D017382:Reactive Oxygen Species; C413684:salicylaldehyde isonicotinoyl hydrazone; D005293:Ferritins; D020122:tert-Butylhydroperoxide; D003676:Deferoxamine