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 mito chondrial pathway for detoxification of O-2(-), 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 h ematopoietic 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-t erm survival of lethally irradiated host animals. Peripheral blood analysis of leukocyte populations revealed no differences in reconstitution kinetic s 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 p rocess. Loss of SOD2 in erythroid progenitor cells results in enhanced prot ein 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 oxidat ive stress-induced condition. Such therapy may prove useful in treatment of human disorders such as sideroblastic anemia, which SOD2 deficiency most c losely resembles.