SOD2 catalyzes the dismutation of superoxide to hydrogen peroxide in mitochondria, therefore reducing mitochondrial damage. A prevalent genetic mutation among sickle cell disease patients is the SOD2 amino acid valine-to-alanine substitution at position 16 (V16A) in the mitochondrial leader sequence (SCD). However, little was known regarding the cardiovascular effects of SOD2V16A in V with SCD, as well as its impact on endothelial cell function. 

SOD2V16A is associated with higher tricuspid regurgitant velocity (TRV), systolic blood pressure, right ventricular area at systole, and decreased 6-minute walk distance in 410 patients with SCD, according to the findings. Plasma lactate dehydrogenase, an indicator of oxidative stress and hemolysis, was found to be substantially related to greater TRV. Researchers introduced the SOD2V16A variation into endothelial cells to determine the impact of SOD2V16A on the endothelium. 

When compared to controls, SOD2V16A increased the generation of hydrogen peroxide and mitochondrial reactive oxygen species (ROS). Surprisingly, the increased ROS was not caused by SOD2V16A mislocalization, but by mitochondrial complex IV and a concurrent reduction in basal respiration and complex IV activity. 

In conclusion, SOD2V16A is a unique clinical biomarker of cardiovascular dysfunction in SCD patients due to its capacity to reduce mitochondrial complex IV activity while increasing ROS generation in the endothelium.