Abstract
Mitochondrial electron transport drives ATP synthesis but also generates reactive oxygen species, which are both cellular signals and damaging oxidants. Superoxide production by respiratory complex III is implicated in diverse signaling events and pathologies, but its role remains controversial. Using high-throughput screening, we identified compounds that selectively eliminate superoxide production by complex III without altering oxidative phosphorylation; they modulate retrograde signaling including cellular responses to hypoxic and oxidative stress.
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Acknowledgements
This work was supported by US National Institutes of Health grants R01 AG033542 (M.D.B.) and TL1 AG032116 (A.L.O.) and the Ellison Medical Foundation grant AG-SS-2288-09 (M.D.B.).
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A.L.O., E.K.A. and M.D.B. devised the project, designed and interpreted the screen and wrote the paper. A.L.O., L.V., C.N.T., J.E.B., J.T.M., V.J.D., S.J.A., J.L., R.L.S.G., I.V.P. and S.L.M. carried out the experiments. H.M.P. advised on compound selection. All authors edited and approved the manuscript.
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L.V., C.N.T., J.E.B., J.T.M., V.J.D., S.J.A. J.L., D.C.Q., 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.
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Orr, A., Vargas, L., Turk, C. et al. Suppressors of superoxide production from mitochondrial complex III. Nat Chem Biol 11, 834â836 (2015). https://doi.org/10.1038/nchembio.1910
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DOI: https://doi.org/10.1038/nchembio.1910
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