Absence of mitochondrial superoxide dismutase results in a murine hemolytic anemia responsive to therapy with a catalytic antioxidant.
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.
Friedman
J S
JS
Department of Pediatric Oncology, Dana Farber Cancer Institute, Boston, Massachusetts 02115, USA. jeff_friedman@dfci.harvard.com
Rebel
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Derby
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Bell
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Huang
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Kuypers
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Epstein
C J
CJ
Burakoff
S J
SJ
D000743:Anemia, Hemolytic / Q000097:blood / Q000188:drug therapy* / Q000235:genetics*; D000818:Animals; D000975:Antioxidants / Q000627:therapeutic use*; D001402:B-Lymphocytes / Q000276:immunology; D001854:Bone Marrow Cells / Q000276:immunology; D017690:Cell Transplantation; D005029:Ethylenediamines / Q000627:therapeutic use*; D016332:Fetal Tissue Transplantation / Q000502:physiology; D016166:Free Radical Scavengers / Q000627:therapeutic use; D005838:Genotype; D006579:Heterozygote; D007527:Isoenzymes / Q000172:deficiency / Q000235:genetics; D008099:Liver / Q000166:cytology; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000201:enzymology*; D009942:Organometallic Compounds / Q000627:therapeutic use*; D016133:Polymerase Chain Reaction; D013154:Spleen / Q000276:immunology; D013482:Superoxide Dismutase / Q000172:deficiency* / Q000235:genetics; D013601:T-Lymphocytes / Q000276:immunology; D013950:Thymus Gland / Q000276:immunology; D018183:Transplantation Chimera
D000975:Antioxidants; D005029:Ethylenediamines; D016166:Free Radical Scavengers; D007527:Isoenzymes; D009942:Organometallic Compounds; C090577:N,N'-bis(salicylideneamino)ethane-manganese(II); D013482:Superoxide Dismutase