S3QEL-2, a suppressor of superoxide production from mitochondrial complex III, potently and selectively suppresses site IIIQo superoxide production (IC50=1.7 μM). S3QEL-2 does not affect oxidative phosphorylation, and normal electron flux. S3QEL-2 inhibits HIF-1α accumulation.In Vitro: S3QELs-2 protects against ROS-induced, JNK-mediated cell stress in pancreatic β-cells and S3QEL-2 strongly mitigates the oxidative stress-induced apoptosis that limits the yield of functional β-cells from intact islets.