S3QEL-2 is a cell-permeable, selective suppressor of electron leak from mitochondrial respiratory complex III, inhibiting site IIIQo superoxide production (IC50 = 1.7 μM) without altering normal bioenergetics function. It reduces production of H2O2 during oxidation of glutamate plus malate to 25% of the control level. S3QEL-2 also protects against ROS-induced cell stress in pancreatic β-cells and decreases HIF-1α induction in response to hypoxia.