Fatty acid-mediated intracellular iron translocation: a synergistic mechanism of oxidative injury.
Fatty acid has been reported to be associated with cardiovascular diseases and cancer, but the possible mechanism remains unclear. Here, we reported a novel mechanism for the permissive role of fatty acid on iron intracellular translocation and subsequent oxidative injury. In vitro study from endothelial cells showed that iron alone had little effect, whereas in combination with PA (palmitic acid), iron-mediated toxicity was markedly potentiated, as reflected in mitochondrial dysfunction, cell death, apoptosis, and DNA mutation. We also showed that PA not only facilitated iron translocation into cells through a transferrin-receptor (TfR)-independent mechanism, but also translocated iron into mitochondria; the subsequent intracellular iron overload resulted in reactive oxygen species (ROS) overgeneration and lipid oxidation. Further investigation revealed that PA-facilitated iron translocation is due to Fe/PA-mediated extracellular oxidative stress and the subsequent membrane damage with increased membrane permeability. Fe/PA-mediated toxic effects were reduced in rho0 cells lacking mitochondrial DNA or by antioxidant enzyme SOD, especially mitochondrially localized MnSOD, suggesting a permissive role of PA for iron deposition on the vascular wall and its subsequent toxicity via mitochondrial oxidative stress. This observation was confirmed in vivo in mice, wherein higher vascular iron deposition and accompanying superoxide release were observed in the presence of a high-fat diet with iron administration.
Yao
Dachun
D
Internal Medicine of Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, People's Republic of China.
Shi
Weibin
W
Gou
Yulan
Y
Zhou
Xinrong
X
Yee Aw
Tak
T
Zhou
Yikai
Y
Liu
Zhengxiang
Z
D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D017209:Apoptosis; D001692:Biological Transport; D002318:Cardiovascular Diseases / Q000473:pathology; D016923:Cell Death; D002470:Cell Survival; D002478:Cells, Cultured; D003600:Cytosol / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism; D005227:Fatty Acids / Q000378:metabolism*; D005609:Free Radicals; D006801:Humans; D020287:In Situ Nick-End Labeling; D007501:Iron / Q000378:metabolism*; D008055:Lipids / Q000737:chemistry; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D008928:Mitochondria / Q000378:metabolism / Q000473:pathology; D008954:Models, Biological; D009154:Mutation; D009369:Neoplasms / Q000378:metabolism; D018384:Oxidative Stress; D010100:Oxygen / Q000737:chemistry; D019308:Palmitic Acid / Q000378:metabolism / Q000494:pharmacology; D017382:Reactive Oxygen Species; D013482:Superoxide Dismutase / Q000378:metabolism; D013997:Time Factors; D014162:Transfection
D000975:Antioxidants; D005227:Fatty Acids; D005609:Free Radicals; D008055:Lipids; D017382:Reactive Oxygen Species; D019308:Palmitic Acid; D004247:DNA; D007501:Iron; D013482:Superoxide Dismutase; D010100:Oxygen