SOD2 V16A amplifies vascular dysfunction in sickle cell patients by curtailing mitochondria complex IV activity.

Abstract

Superoxide dismutase 2 (SOD2) catalyzes the dismutation of superoxide to hydrogen peroxide in mitochondria, limiting mitochondrial damage. The SOD2 amino acid valine-to-alanine substitution at position 16 (V16A) in the mitochondrial leader sequence is a common genetic variant among patients with sickle cell disease (SCD). However, little is known about the cardiovascular consequences of SOD2V16A in SCD patients or its impact on endothelial cell function. Here, we show SOD2V16A associates with increased tricuspid regurgitant velocity (TRV), systolic blood pressure, right ventricle area at systole, and declined 6-minute walk distance in 410 SCD patients. Plasma lactate dehydrogenase, a marker of oxidative stress and hemolysis, significantly associated with higher TRV. To define the impact of SOD2V16A in the endothelium, we introduced the SOD2V16A variant into endothelial cells. SOD2V16A increases hydrogen peroxide and mitochondrial reactive oxygen species (ROS) production compared with controls. Unexpectedly, the increased ROS was not due to SOD2V16A mislocalization but was associated with mitochondrial complex IV and a concomitant decrease in basal respiration and complex IV activity. In sum, SOD2V16A is a novel clinical biomarker of cardiovascular dysfunction in SCD patients through its ability to decrease mitochondrial complex IV activity and amplify ROS production in the endothelium.

• Authors: Atinuke Dosunmu-Ogunbi, Shuai Yuan, Michael Reynolds, Luca Giordano, Subramaniam Sanker, Mara Sullivan, Donna Beer Stolz, Brett A Kaufman, Katherine C Wood, Yingze Zhang, Sruti Shiva, Seyed Mehdi Nouraie, Adam C Straub
• Journal: Blood (Blood) Vol. 139 Issue 11 Pg. 1760-1765 (03 17 2022) ISSN: 1528-0020 [Electronic] United States
• PMID: 34958669 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2022 by The American Society of Hematology.

Chemical References

• Reactive Oxygen Species
• Superoxide Dismutase
• superoxide dismutase 2

Topics

• Anemia, Sickle Cell (complications, genetics, metabolism)
• Endothelial Cells (metabolism)
• Humans
• Mitochondria (metabolism)
• Reactive Oxygen Species (metabolism)
• Superoxide Dismutase (genetics, metabolism)