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

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

  • Cell Metab. 2016 Oct 11;24(4):582-592. doi: 10.1016/j.cmet.2016.08.012.
Martin D Brand 1,  Renata L S Goncalves 2,  Adam L Orr 2,  Leonardo Vargas 3,  Akos A Gerencser 2,  Martin Borch Jensen 2,  Yves T Wang 4,  Simon Melov 2,  Carolina N Turk 3,  Jason T Matzen 3,  Victoria J Dardov 3,  H Michael Petrassi 3,  Shelly L Meeusen 3,  Irina V Perevoshchikova 2,  Heinrich Jasper 2,  Paul S Brookes 4,  Edward K Ainscow 3
Affiliations

Affiliations

  • 1 Buck Institute for Research on Aging, Novato, CA 94945, USA. Electronic address: mbrand@buckinstitute.org.
  • 2 Buck Institute for Research on Aging, Novato, CA 94945, USA.
  • 3 Genomics Institute of the Novartis Research Foundation, San Diego, CA 92121, USA.
  • 4 Department of Anesthesiology, University of Rochester Medical Center, Rochester, NY 14642, USA.
PMID: 27667666 DOI: 10.1016/j.cmet.2016.08.012
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 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.

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