Suppressors of Superoxide-H 2 O 2 Production at Site I Q of Mitochondrial Complex I Protect against Stem Cell Hyperplasia and Ischemia-Reperfusion Injury

Abstract

SUMMARY 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.

ROS Control Mitochondrial Motility through p38 and the Motor Adaptor Miro/Trak

“…This process may enable to recruit additional mitochondria at the site of ROS elevation, and serve both ROS scavenging and propagation of ROS production, which may have relevance in pathophysiological conditions. Finally, in line with recent findings on ROS/Ca 2+ communication at mitochondria-ER contact sites (Booth et al, 2016) and on the involvement of mitochondrial respiratory complex I and III-originated ROS in ER-stress-induced caspase activation (Brand et al, 2016), a Ca 2+ -induced rise in mitochondrial ROS could serve as a signal to stop mitochondria in the proximity to ER to establish new contact sites to serve as signaling modulators. Thus, our findings offer some clues relevant for mitochondrial quality control and for both cell survival and death signaling.…”

Hydrogen peroxide as a central redox signaling molecule in physiological oxidative stress: Oxidative eustress

“…Conversely, the assembly of mitochondrial Complex I into supercomplexes determines, for example, the differential production of reactive oxygen species in neurons and astrocytes [109]. Addressing specific sites of mitochondrial H 2 O 2 production may have therapeutic potential [110].…”

The Putative Drp1 Inhibitor mdivi-1 Is a Reversible Mitochondrial Complex I Inhibitor that Modulates Reactive Oxygen Species

“…Succinate accumulates during ischemia and is oxidized rapidly during reperfusion, producing ROS by reverse electron transfer that contribute to injury (Chouchani et al, 2014; Brand et al, 2016). RET ROS is also thought to play a role in Alzheimer’s disease (Zhang et al, 2015) and lifespan (Lambert et al, 2007; Scialo et al, 2016).…”