TableEdit

Friedman, JS, Lopez, MF, Fleming, MD, Rivera, A, Martin, FM, Welsh, ML, Boyd, A, Doctrow, SR and Burakoff, SJ (2004) SOD2-deficiency anemia: protein oxidation and altered protein expression reveal targets of damage, stress response, and antioxidant responsiveness. Blood 104:2565-73

SOD2 is an antioxidant protein that protects cells against mitochondrial superoxide. Hematopoietic stem cells (HSCs) lacking SOD2 are capable of rescuing lethally irradiated hosts, but reconstituted animals display a persistent hemolytic anemia characterized by increased oxidative damage to red cells, with morphologic similarity to human "sideroblastic" anemia. We report further characterization of this novel SOD2-deficiency anemia. Electron micrographs of SOD2-deficient reticulocytes reveal striking mitochondrial proliferation and mitochondrial membrane thickening. Peripheral blood smears show abundant iron-stainable granules in mature red cells (siderocytes). Fluorescence-activated cell sorting (FACS) analysis of cells labeled with oxidation-sensitive dyes demonstrates enhanced production of superoxide and hydrogen peroxide by SOD2-deficient cells. Oxidative damage to proteins is increased in SOD2-deficient cells, with much of the damage affecting membrane/insoluble proteins. Red cell proteome analysis demonstrates that several proteins involved in folding/chaperone function, redox regulation, adenosine triphosphate (ATP) synthesis, and red cell metabolism show altered expression in SOD2-deficient cells. This data, combined with information on how protein expression levels change upon antioxidant therapy, will aid in identification of proteins that are sensitive to oxidative damage in this model, and by extension, may have a role in the regulation of red cell lifespan in other hemolytic disorders.

PubMed Online version:10.1182/blood-2003-11-3858

Adenosine Triphosphate/metabolism; Anemia/enzymology; Anemia/genetics; Anemia/metabolism; Anemia/pathology; Animals; Antioxidants/metabolism; Antioxidants/pharmacology; Apoptosis/drug effects; Bone Marrow/metabolism; Bone Marrow/pathology; Catalysis; Chlorides/metabolism; Erythrocytes/drug effects; Erythrocytes/metabolism; Erythrocytes/pathology; Erythropoiesis; Gene Expression Regulation; Hydrogen Peroxide/metabolism; Ion Transport; Iron/metabolism; Mice; Mice, Knockout; Mitochondria/metabolism; Mitochondria/pathology; Oxidation-Reduction; Oxidative Stress; Potassium/metabolism; Proteomics; Protoporphyrins/metabolism; Spleen/metabolism; Spleen/pathology; Superoxide Dismutase/deficiency; Superoxide Dismutase/genetics; Superoxide Dismutase/metabolism; Superoxides/metabolism