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
| Autor: | Edward K. Ainscow, Carolina N. Turk, Leonardo Vargas, Simon Melov, Heinrich Jasper, Yves T. Wang, Renata L.S. Goncalves, Adam L. Orr, Akos A. Gerencser, H. Michael Petrassi, Irina V. Perevoshchikova, Martin D. Brand, Martin Borch Jensen, Jason T. Matzen, Paul S. Brookes, Shelly Meeusen, Victoria J. Dardov |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Cell physiology Pathology medicine.medical_specialty Physiology Superoxide Endoplasmic reticulum Cell Biology Oxidative phosphorylation Mitochondrion Biology medicine.disease 3. Good health Cell biology Reverse electron flow 03 medical and health sciences chemistry.chemical_compound 030104 developmental biology chemistry medicine Stem cell Molecular Biology Reperfusion injury |
| Zdroj: | Cell Metabolism. 24:582-592 |
| ISSN: | 1550-4131 |
| DOI: | 10.1016/j.cmet.2016.08.012 |
| Popis: | Summary Using high-throughput screening we identified small molecules that suppress superoxide and/or H 2 O 2 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-H 2 O 2 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-H 2 O 2 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-H 2 O 2 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. |
| Databáze: | OpenAIRE |
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