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 journalArticle

60 Citations (Scopus)

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
Externally publishedYes

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Hemolytic Anemia
Superoxide Dismutase
Antioxidants
Fetal Stem Cells
Sideroblastic Anemia
Erythroid Precursor Cells
Liver
Hematopoiesis
Myeloid Cells
Therapeutics
Catalase
Blood Cells
Cell Survival
Oxidative Stress
Leukocytes
B-Lymphocytes
Stem Cells
Genotype
T-Lymphocytes
Membranes

Keywords

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

ASJC Scopus subject areas

  • Immunology

Cite this

Absence of mitochondrial superoxide dismutase results in a murine hemolytic anemia responsive to therapy with a catalytic antioxidant. / Friedman, Jeff S.; Rebel, Vivienne I.; Derby, Ryan; Bell, Kirsten; Huang, Ting Ting; Kuypers, Frans A.; Epstein, Charles J.; Burakoff, Steven J.

In: Journal of Experimental Medicine, Vol. 193, No. 8, 16.04.2001, p. 925-934.

Research output: Contribution to journalArticle

Friedman, JS, Rebel, VI, Derby, R, Bell, K, Huang, TT, Kuypers, FA, Epstein, CJ & Burakoff, SJ 2001, 'Absence of mitochondrial superoxide dismutase results in a murine hemolytic anemia responsive to therapy with a catalytic antioxidant', Journal of Experimental Medicine, vol. 193, no. 8, pp. 925-934. https://doi.org/10.1084/jem.193.8.925
Friedman, Jeff S. ; Rebel, Vivienne I. ; Derby, Ryan ; Bell, Kirsten ; Huang, Ting Ting ; Kuypers, Frans A. ; Epstein, Charles J. ; Burakoff, Steven J. / Absence of mitochondrial superoxide dismutase results in a murine hemolytic anemia responsive to therapy with a catalytic antioxidant. In: Journal of Experimental Medicine. 2001 ; Vol. 193, No. 8. pp. 925-934.
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