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

Abstract

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 I_Q) without affecting oxidative phosphorylation (suppressors of site I_Q electron leak, "S1QELs"). S1QELs diminished endogenous oxidative damage in primary astrocytes cultured at ambient or low oxygen tension, showing that site I_Q 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 I_Q is involved in cellular stress signaling. They protected against ischemia-reperfusion injury in perfused mouse heart, showing directly that superoxide-H₂O₂ production by site I_Q is a major contributor to this pathology. S1QELs are tools for assessing the contribution of site I_Q to cell physiology and pathology and have great potential as therapeutic leads.