Iron insufficiency compromises motor neurons and their mitochondrial function in Irp2-null mice

Suh Young Jeong, Daniel R. Crooks, Hayden Wilson-Ollivierre, Manik C. Ghosh, Rachid Sougrat, Jaekwon Lee, Sharon Cooperman, James B. Mitchell, Carole Beaumont, Tracey A. Rouault

Research output: Contribution to journalArticle

40 Scopus citations

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.

Original languageEnglish (US)
Article numbere25404
JournalPloS one
Volume6
Issue number10
DOIs
StatePublished - Oct 7 2011

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

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    Jeong, S. Y., Crooks, D. R., Wilson-Ollivierre, H., Ghosh, M. C., Sougrat, R., Lee, J., Cooperman, S., Mitchell, J. B., Beaumont, C., & Rouault, T. A. (2011). Iron insufficiency compromises motor neurons and their mitochondrial function in Irp2-null mice. PloS one, 6(10), [e25404]. https://doi.org/10.1371/journal.pone.0025404