Format

Send to

Choose Destination
Cell Metab. 2016 Oct 11;24(4):582-592. doi: 10.1016/j.cmet.2016.08.012. Epub 2016 Sep 22.

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

Author information

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.

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.

PMID:
27667666
PMCID:
PMC5061631
DOI:
10.1016/j.cmet.2016.08.012
[Indexed for MEDLINE]
Free PMC Article

Conflict of interest statement

L.V., C.N.T., J.T.M., V.J.D., H.M.P., S.L.M., and E.K.A. were employed by the Genomics Institute of the Novartis Research Foundation during the period of their contribution to this research. M.D.B. has consulted for Seahorse Bioscience. A.A.G. has a financial interest in Image Analyst Software.

Supplemental Content

Full text links

Icon for Elsevier Science Icon for PubMed Central
Loading ...
Support Center