Suppressors of Superoxide-H2O2 Production at Site IQ of Mitochondrial Complex I Protect against Stem Cell Hyperplasia and Ischemia-Reperfusion Injury

Using high-throughput screening we identified small molecules that suppress superoxide and/or H2O2 production during reverse electron transport through mitochondrial respiratory complex I (site IQ) without affecting oxidative phosphorylation (suppressors of site IQ electron leak, “S1QELs”). S1QELs diminished endogenous oxidative damage in primary astrocytes cultured at ambient or low oxygen tension, showing that site IQ is a normal contributor to mitochondrial superoxide-H2O2 production in cells. They diminished stem cell hyperplasia in Drosophila intestine in vivo and caspase activation in a cardiomyocyte cell model driven by endoplasmic reticulum stress, showing that superoxide-H2O2 production by site IQ is involved in cellular stress signaling. They protected against ischemia-reperfusion injury in perfused mouse heart, showing directly that superoxide-H2O2 production by site IQ is a major contributor to this pathology. S1QELs are tools for assessing the contribution of site IQ to cell physiology and pathology and have great potential as therapeutic leads. [Display omitted] •S1QELs suppress site IQ ROS production without affecting oxidative phosphorylation•Site IQ generates superoxide-H2O2 in resting cells and in stress signaling•Site IQ drives ischemia-reperfusion injury in perfused heart and S1QELs protect•S1QELs are tools to assess the contribution of site IQ and therapeutic leads In this article, Brand et al. identified small molecules (S1QELs) that suppress superoxide-H2O2 production during reverse electron transport through mitochondrial respiratory complex I (site IQ) without affecting oxidative phosphorylation. S1QELs diminished endogenous oxidative damage in primary astrocytes, stress signaling in vivo, and ischemia-reperfusion heart injury.