title: Iron insufficiency compromises motor neurons and their mitochondrial function in Irp2-null mice.
abstract: Genetic ablation of Iron Regulatory Protein 2 (Irp2, Ireb2), which post-transcriptionally regulates iron metabolism genes, causes a gait disorder in mice that progresses to hind-limb paralysis. Here we have demonstrated that misregulation of iron metabolism from loss of Irp2 causes lower motor neuronal degeneration with significant spinal cord axonopathy. Mitochondria in the lumbar spinal cord showed significantly decreased Complex I and II activities, and abnormal morphology. Lower motor neurons appeared to be the most adversely affected neurons, and we show that functional iron starvation due to misregulation of iron import and storage proteins, including transferrin receptor 1 and ferritin, may have a causal role in disease. We demonstrated that two therapeutic approaches were beneficial for motor neuron survival. First, we activated a homologous protein, IRP1, by oral Tempol treatment and found that axons were partially spared from degeneration. Secondly, we genetically decreased expression of the iron storage protein, ferritin, to diminish functional iron starvation. These data suggest that functional iron deficiency may constitute a previously unrecognized molecular basis for degeneration of motor neurons in mice.
authors: Eunice Kennedy Shriver National Institute of Child Health and Development, National Institutes of Health, Bethesda, Maryland, United States of America.
authors: Suh Young
authors: SY
authors: Jeong
authors: Daniel R
authors: DR
authors: Crooks
authors: Hayden
authors: H
authors: Wilson-Ollivierre
authors: Manik C
authors: MC
authors: Ghosh
authors: Rachid
authors: R
authors: Sougrat
authors: Jaekwon
authors: J
authors: Lee
authors: Sharon
authors: S
authors: Cooperman
authors: James B
authors: JB
authors: Mitchell
authors: Carole
authors: C
authors: Beaumont
authors: Tracey A
authors: TA
authors: Rouault
mesh_terms: D000818:Animals; D001052:Apoferritins / Q000096:biosynthesis; D001284:Atrophy / Q000378:metabolism; D001369:Axons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D015415:Biomarkers / Q000378:metabolism; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D003497:Cyclic N-Oxides / Q000494:pharmacology; D017353:Gene Deletion; D006706:Homeostasis / Q000187:drug effects / Q000235:genetics; D007501:Iron / Q000378:metabolism; D000090463:Iron Deficiencies; D035941:Iron Regulatory Protein 1 / Q000172:deficiency / Q000378:metabolism; D035942:Iron Regulatory Protein 2 / Q000172:deficiency* / Q000235:genetics*; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D009046:Motor Neurons / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D018384:Oxidative Stress / Q000187:drug effects / Q000235:genetics; D013113:Spin Labels; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism / Q000473:pathology
chemical_list: D015415:Biomarkers; D003497:Cyclic N-Oxides; D013113:Spin Labels; D001052:Apoferritins; D007501:Iron; D035941:Iron Regulatory Protein 1; D035942:Iron Regulatory Protein 2; C001803:tempol