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Blood, 15 October 2004, Vol. 104, No. 8, pp. 2565-2573.
Prepublished online as a Blood First Edition Paper on June 17, 2004; DOI 10.1182/blood-2003-11-3858.
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Submitted November 12, 2003
Accepted May 28, 2004
SOD2 Deficiency Anemia: Protein Oxidation and Altered Protein Expression Reveal Targets of Damage, Stress Response and Anti-oxidant Responsiveness
Jeffrey S Friedman*, Mary F Lopez, Mark D Fleming, Alicia Rivera, Florent M Martin, Megan L Welsh, Ashleigh S Boyd, Susan R Doctrow, and Steven J Burakoff
The Scripps Research Institute, La Jolla, CA, USA
Perkin-Elmer Life and Analytical Sciences, Boston, MA, USA
The Children's Hospital, Boston, MA, USA
Oxford University, Oxford, United Kingdom
Eukarion Incorporated, Bedford, MA, USA
Skirball Institute and NYU School of Medicine, New York, NY, USA
* Corresponding author; email: friedman{at}scripps.edu.
SOD2 is an antioxidant protein that protects cells against mitochondrial superoxide. Hematopoietic stem cells (HSC) 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). 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, 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 regulation of red cell lifespan in other hemolytic disorders.
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