Decoding the role of SOD2 in sickle cell disease

Abstract

Sickle cell disease (SCD) is an inherited hemoglobinopathy caused by a single point mutation in the β-globin gene. As a consequence, deoxygenated hemoglobin polymerizes triggering red blood cell sickling and hemolysis, vaso-occlusion, and ischemia/reperfusion. Allied to these pathologies is the overproduction of reactive oxygen species driven by hemoglobin Fenton chemistry and peroxidase reactions as well as by secondary activation of vascular oxidases, including NAD(P)H oxidase and xanthine oxidase. In addition, hypoxia, produced by sickle red blood cell occlusion, disrupts mitochondrial metabolism and generates excess superoxide through electron leak from the mitochondrial respiratory chain. Superoxide dismutase 2 (SOD2) is a mitochondrial-specific antioxidant enzyme that dismutates superoxide to hydrogen peroxide, which is then converted to water by catalase and glutathione peroxidase. In SCD, the antioxidant defense system is significantly diminished through decreased expression and activity levels of antioxidant enzymes, including superoxide dismutase, catalase, and glutathione peroxidase. From a translational perspective, genetic variants including a missense variant in SOD2 (valine to alanine at position 16) are present in 45% of people with African ancestry and are associated with increased sickle complications. While it is known that there is an imbalance between oxidative species and antioxidant defenses in SCD, much more investigation is warranted. This review summarizes our current understanding of antioxidant defense systems in SCD, particularly focused on SOD2, and provides insight into challenges and opportunities as the field moves forward.

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 H₂O_2, 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.