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

Handle URI:
http://hdl.handle.net/10754/325294
Title:
Iron insufficiency compromises motor neurons and their mitochondrial function in Irp2-null mice
Authors:
Jeong, Suh Young; Crooks, Daniel R.; Wilson-Ollivierre, Hayden; Ghosh, Manik C.; Sougrat, Rachid; Lee, Jaekwon; Cooperman, Sharon; Mitchell, James B.; Beaumont, Carole; Rouault, Tracey A.
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.
Citation:
Jeong SY, Crooks DR, Wilson-Ollivierre H, Ghosh MC, Sougrat R, et al. (2011) Iron Insufficiency Compromises Motor Neurons and Their Mitochondrial Function in Irp2-Null Mice. PLoS ONE 6: e25404. doi:10.1371/journal.pone.0025404.
Publisher:
Public Library of Science (PLoS)
Journal:
PLoS ONE
Issue Date:
7-Oct-2011
DOI:
10.1371/journal.pone.0025404
PubMed ID:
22003390
PubMed Central ID:
PMC3189198
Type:
Article
ISSN:
19326203
Appears in Collections:
Articles

Full metadata record

DC FieldValue Language
dc.contributor.authorJeong, Suh Youngen
dc.contributor.authorCrooks, Daniel R.en
dc.contributor.authorWilson-Ollivierre, Haydenen
dc.contributor.authorGhosh, Manik C.en
dc.contributor.authorSougrat, Rachiden
dc.contributor.authorLee, Jaekwonen
dc.contributor.authorCooperman, Sharonen
dc.contributor.authorMitchell, James B.en
dc.contributor.authorBeaumont, Caroleen
dc.contributor.authorRouault, Tracey A.en
dc.date.accessioned2014-08-27T09:45:27Z-
dc.date.available2014-08-27T09:45:27Z-
dc.date.issued2011-10-07en
dc.identifier.citationJeong SY, Crooks DR, Wilson-Ollivierre H, Ghosh MC, Sougrat R, et al. (2011) Iron Insufficiency Compromises Motor Neurons and Their Mitochondrial Function in Irp2-Null Mice. PLoS ONE 6: e25404. doi:10.1371/journal.pone.0025404.en
dc.identifier.issn19326203en
dc.identifier.pmid22003390en
dc.identifier.doi10.1371/journal.pone.0025404en
dc.identifier.urihttp://hdl.handle.net/10754/325294en
dc.description.abstractGenetic 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.en
dc.language.isoenen
dc.publisherPublic Library of Science (PLoS)en
dc.rightsThis is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.en
dc.rightsArchived with thanks to PLoS ONEen
dc.subjectCD71 antigenen
dc.subjectferritinen
dc.subjectironen
dc.subjectiron regulatory protein 1en
dc.subjectiron regulatory protein 2en
dc.subjectreduced nicotinamide adenine dinucleotide dehydrogenase (ubiquinone)en
dc.subjectsuccinate dehydrogenase (ubiquinone)en
dc.subjectamine oxideen
dc.subjectapoferritinen
dc.subjectbiological markeren
dc.subjectironen
dc.subjectiron regulatory protein 1en
dc.subjectiron regulatory protein 2en
dc.subjecttempolen
dc.subjectanimal experimenten
dc.subjectanimal tissueen
dc.subjectcell functionen
dc.subjectcell lysateen
dc.subjectcontrolled studyen
dc.subjectDNA modificationen
dc.subjectenzyme activityen
dc.subjectgene expression regulationen
dc.subjecthomeostasisen
dc.subjectimmunohistochemistryen
dc.subjectiron deficiencyen
dc.subjectiron storageen
dc.subjectlumbar spinal corden
dc.subjectmitochondrionen
dc.subjectmotoneuronen
dc.subjectmouseen
dc.subjectnerve cell degenerationen
dc.subjectnerve fiber degenerationen
dc.subjectneuropathyen
dc.subjectprotein synthesisen
dc.subjectatrophyen
dc.subjectbiosynthesisen
dc.subjectbrainen
dc.subjectdrug effecten
dc.subjectgene deletionen
dc.subjectgeneticsen
dc.subjectmetabolismen
dc.subjectmitochondrionen
dc.subjectnerve fiberen
dc.subjectoxidative stressen
dc.subjectpathologyen
dc.subjectspin labelingen
dc.subjectspinal corden
dc.subjectMusen
dc.subjectApoferritinsen
dc.subjectAtrophyen
dc.subjectAxonsen
dc.subjectBiological Markersen
dc.subjectBrainen
dc.subjectCyclic N-Oxidesen
dc.subjectGene Deletionen
dc.subjectHomeostasisen
dc.subjectIronen
dc.subjectIron Regulatory Protein 1en
dc.subjectIron Regulatory Protein 2en
dc.subjectMiceen
dc.subjectMitochondriaen
dc.subjectMotor Neuronsen
dc.subjectOxidative Stressen
dc.subjectSpin Labelsen
dc.subjectSpinal Corden
dc.titleIron insufficiency compromises motor neurons and their mitochondrial function in Irp2-null miceen
dc.typeArticleen
dc.identifier.journalPLoS ONEen
dc.identifier.pmcidPMC3189198en
dc.eprint.versionPublisher's Version/PDFen
dc.contributor.institutionEunice Kennedy Shriver National Institute of Child Health and Development, National Institutes of Health, Bethesda, MD, United Statesen
dc.contributor.institutionDepartment of Biochemistry, University of Nebraska, Lincoln, NE, United Statesen
dc.contributor.institutionNational Cancer Institute, National Institutes of Health, Bethesda, MD, United Statesen
dc.contributor.institutionINSERM U773, Centre de Recherche Biomdicale Bichat-Beaujon, Universit Paris Diderot, Paris, Franceen
dc.contributor.affiliationKing Abdullah University of Science and Technology (KAUST)en
kaust.authorSougrat, Rachiden

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