Effect of reactive oxygen species on iron regulatory protein activity.
Iron may be important in catalyzing excessive production of reactive oxygen species (ROS). Cellular iron homeostasis is regulated by iron regulatory proteins (IRPs), which bind to iron-responsive elements (IRE) of mRNAs for ferritin and transferrin receptor (TfR) modulating iron uptake and sequestration, respectively. Although iron is the main regulator of IRP activity, IRP is also influenced by other factors, including the redox state. Therefore, IRP might be sensitive to pathophysiological alterations of redox state caused by ROS. However, previous studies have produced diverging evidence on the effect of oxidative injury on IRP. Results obtained in an animal model close to a pathophysiological condition, such as ischemia reperfusion of the liver as well as in a cell-free system involving an enzymatic source of O2 and H2O2, indicate that IRP is downregulated by oxidative stress. In fact, IRP activity is inhibited at early times of post-ischemic reperfusion. Moreover, the concerted action of O2 and H2O2 produced by xanthine oxidase in a cell-free system caused a remarkable inhibition of IRP activity. IRP seems a direct target of ROS; in fact, in vivo inhibition can be prevented by the antioxidant N-acetylcysteine and by interleukin-1 receptor antagonist. In addition, modulation of iron levels of the cell-free assay did not affect the downregulation imposed by xanthine oxidase. Conceivably, downregulation of IRP activity by O2 and H2O2 may facilitate iron sequestration into ferritin, thus limiting the pro-oxidant challenge of iron.
Cairo
G
G
Centro di Studio sulla Patologia Cellulare CNR, Milano, Italy. gcairo@imiucca.csi.unimi.it
Tacchini
L
L
Recalcati
S
S
Azzimonti
B
B
Minotti
G
G
Bernelli-Zazzera
A
A
D000111:Acetylcysteine / Q000494:pharmacology; D000818:Animals; D015536:Down-Regulation / Q000502:physiology; D005293:Ferritins / Q000378:metabolism; D007501:Iron / Q000378:metabolism*; D035925:Iron-Regulatory Proteins; D007506:Iron-Sulfur Proteins / Q000378:metabolism*; D007511:Ischemia / Q000503:physiopathology; D008099:Liver / Q000503:physiopathology; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000502:physiology; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D016601:RNA-Binding Proteins / Q000378:metabolism* / Q000502:physiology; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism*; D051154:Wnt2 Protein; D019820:Xanthine / Q000378:metabolism; D014969:Xanthine Oxidase / Q000378:metabolism
D035925:Iron-Regulatory Proteins; D007506:Iron-Sulfur Proteins; D011518:Proto-Oncogene Proteins; D016601:RNA-Binding Proteins; D017382:Reactive Oxygen Species; D051154:Wnt2 Protein; D019820:Xanthine; D005293:Ferritins; D007501:Iron; D014969:Xanthine Oxidase; D000111:Acetylcysteine