Absence of mitochondrial superoxide dismutase results in a murine hemolytic anemia responsive to therapy with a catalytic antioxidant

Jeff S. Friedman, Vivienne I. Rebel, Ryan Derby, Kirsten Bell, Ting Ting Huang, Frans A. Kuypers, Charles J. Epstein, Steven J. Burakoff

Research output: Contribution to journalArticlepeer-review

63 Scopus citations

Abstract

Manganese superoxide dismutase 2 (SOD2) is a critical component of the mitochondrial pathway for detoxification of O2-, and targeted disruption of this locus leads to embryonic or neonatal lethality in mice. To follow the effects of SOD2 deficiency in cells over a longer time course, we created hematopoietic chimeras in which all blood cells are derived from fetal liver stem cells of Sod2 knockout, heterozygous, or wild-type littermates. Stem cells of each genotype efficiently rescued hematopoiesis and allowed long-term survival of lethally irradiated host animals. Peripheral blood analysis of leukocyte populations revealed no differences in reconstitution kinetics of T cells, B cells, or myeloid cells when comparing Sod2+/+, Sod2-/-, and Sod2+/- fetal liver recipients. However, animals receiving Sod2-/- cells were persistently anemic, with findings suggestive of a hemolytic process. Loss of SOD2 in erythroid progenitor cells results in enhanced protein oxidative damage, altered membrane deformation, and reduced survival of red cells. Treatment of anemic animals with Euk-8, a catalytic antioxidant with both SOD and catalase activities, significantly corrected this oxidative stress-induced condition. Such therapy may prove useful in treatment of human disorders such as sideroblastic anemia, which SOD2 deficiency most closely resembles.

Original languageEnglish (US)
Pages (from-to)925-934
Number of pages10
JournalJournal of Experimental Medicine
Volume193
Issue number8
DOIs
StatePublished - Apr 16 2001

Keywords

  • Antioxidant
  • Oxidative stress
  • SOD2
  • Stem cells
  • Transplantation (fetal liver)

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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