Tempol-mediated activation of latent iron regulatory protein activity prevents symptoms of neurodegenerative disease in IRP2 knockout mice.
In mammals, two homologous cytosolic regulatory proteins, iron regulatory protein 1 (also known as IRP1 and Aco1) and iron regulatory protein 2 (also known as IRP2 and Ireb2), sense cytosolic iron levels and posttranscriptionally regulate iron metabolism genes, including transferrin receptor 1 (TfR1) and ferritin H and L subunits, by binding to iron-responsive elements (IREs) within target transcripts. Mice that lack IRP2 develop microcytic anemia and neurodegeneration associated with functional cellular iron depletion caused by low TfR1 and high ferritin expression. IRP1 knockout (IRP1(-/-)) animals do not significantly misregulate iron metabolism, partly because IRP1 is an iron-sulfur protein that functions mainly as a cytosolic aconitase in mammalian tissues and IRP2 activity increases to compensate for loss of the IRE binding form of IRP1. The neurodegenerative disease of IRP2(-/-) animals progresses slowly as the animals age. In this study, we fed IRP2(-/-) mice a diet supplemented with a stable nitroxide, Tempol, and showed that the progression of neuromuscular impairment was markedly attenuated. In cell lines derived from IRP2(-/-) animals, and in the cerebellum, brainstem, and forebrain of animals maintained on the Tempol diet, IRP1 was converted from a cytosolic aconitase to an IRE binding protein that stabilized the TfR1 transcript and repressed ferritin synthesis. We suggest that Tempol protected IRP2(-/-) mice by disassembling the cytosolic iron-sulfur cluster of IRP1 and activating IRE binding activity, which stabilized the TfR1 transcript, repressed ferritin synthesis, and partially restored normal cellular iron homeostasis in the brain.
Ghosh
Manik C
MC
National Institute of Child Health and Human Development and Radiation Biology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Tong
Wing-Hang
WH
Zhang
Deliang
D
Ollivierre-Wilson
Hayden
H
Singh
Anamika
A
Krishna
Murali C
MC
Mitchell
James B
JB
Rouault
Tracey A
TA
D000818:Animals; D002460:Cell Line; D003497:Cyclic N-Oxides / Q000737:chemistry / Q000494:pharmacology; D018450:Disease Progression; D004789:Enzyme Activation; D006801:Humans; D035941:Iron Regulatory Protein 1 / Q000378:metabolism; D035942:Iron Regulatory Protein 2 / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D015394:Molecular Structure; D019636:Neurodegenerative Diseases / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control*; D011485:Protein Binding; D011990:Receptors, Transferrin / Q000378:metabolism; D013113:Spin Labels
D003497:Cyclic N-Oxides; D011990:Receptors, Transferrin; D013113:Spin Labels; C480029:Tfrc protein, mouse; D035941:Iron Regulatory Protein 1; D035942:Iron Regulatory Protein 2; C001803:tempol