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

TitleSuppressors of Superoxide-HO Production at Site I of Mitochondrial Complex I Protect against Stem Cell Hyperplasia and Ischemia-Reperfusion Injury.
Publication TypeJournal Article
Year of Publication2016
AuthorsBrand MD, Goncalves RLS, Orr AL, Vargas L, Gerencser AA, Jensen MBorch, Wang YT, Melov S, Turk CN, Matzen JT, Dardov VJ, H Petrassi M, Meeusen SL, Perevoshchikova IV, Jasper H, Brookes PS, Ainscow EK
JournalCell Metab
Volume24
Issue4
Pagination582-592
Date Published2016 10 11
ISSN1932-7420
KeywordsAnimals, Astrocytes, Caspase 3, Caspase 7, Cell Proliferation, Cells, Cultured, Cytoprotection, Drosophila, Electron Transport Complex I, Heart, Hydrogen Peroxide, Hyperplasia, Intestines, Mice, Mitochondria, Muscle, Oxidative Phosphorylation, Oxidative Stress, Perfusion, Rats, Reperfusion Injury, Stem Cells, Superoxides, Tunicamycin
Abstract

Using high-throughput screening we identified small molecules that suppress superoxide and/or HO production during reverse electron transport through mitochondrial respiratory complex I (site I) without affecting oxidative phosphorylation (suppressors of site I electron leak, "S1QELs"). S1QELs diminished endogenous oxidative damage in primary astrocytes cultured at ambient or low oxygen tension, showing that site I is a normal contributor to mitochondrial superoxide-HO 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-HO production by site I is involved in cellular stress signaling. They protected against ischemia-reperfusion injury in perfused mouse heart, showing directly that superoxide-HO production by site I is a major contributor to this pathology. S1QELs are tools for assessing the contribution of site I to cell physiology and pathology and have great potential as therapeutic leads.

DOI10.1016/j.cmet.2016.08.012
Alternate JournalCell Metab.
PubMed ID27667666
PubMed Central IDPMC5061631
Grant ListR01 AG033542 / AG / NIA NIH HHS / United States
R01 GM100196 / GM / NIGMS NIH HHS / United States
R01 HL127891 / HL / NHLBI NIH HHS / United States
TL1 AG032116 / AG / NIA NIH HHS / United States