Decoding the role of SOD2 in sickle cell disease

Atinuke M. Dosunmu-Ogunbi, Katherine C. Wood, Enrico M. Novelli and Adam C. Straub

Article Figures & Data


  • Figure 1.

    Schematic of SCD-associated oxidative stress pathways and antioxidant systems. In the intravascular space, sickled RBCs undergo hemolysis, releasing hemoglobin (Hb) and heme. Hemoglobin reacts with (1) NO·, forming nitrate (NO3), and (2) hydrogen peroxide (H2O2), producing hydroxyl radical (OH). Endothelial-bound xanthine oxidase (XO) generates superoxide (O2·) and H2O2. Free heme binds to Toll-like receptor 4 (TLR4) producing reactive species through the activation of the NFκB pathway. SOD3 is found in the extracellular compartment and converts O2· to H2O2. In the endothelial cell (EC) cytoplasm, endothelial NO synthase (eNOS) uncoupling and NADPH oxidase 2 (Nox2), Nox4, and Nox5 produce O2·, which is dismutated by SOD1. eNOS normally generates NO·, which is capable of reacting with O2· to form peroxynitrite (ONOO). In the mitochondrial matrix, electrons leaked from complexes I and III of the respiratory chain react with oxygen (O2), forming O2·. SOD2 dismutates O2· to H2O2, which is further broken down to water by catalase (CAT). SOD2 expression and activity is maintained at a precise balance. Overexpression of SOD2 decreases O2· levels and increases H2O2 levels, which are then free to oxidize protein thiols. SOD2 underexpression or dysfunction increases O2· levels, increasing nitration and oxidation of iron sulfur clusters and decreasing metabolism and adenosine triphosphate (ATP) production.