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Suppressors of superoxide production from mitochondrial complex III

Nature Chemical Biology volume 11, pages 834–836 (2015)Cite this article

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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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Figure 1: Chemical screening using isolated mitochondria identifies suppressors of site IIIQo superoxide production.
Figure 2: S3QELs modulate ROS-mediated signaling in cells.

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References

  1. Sena, L.A. & Chandel, N.S. Mol. Cell 48, 158–167 (2012).

    Article  CAS  Google Scholar 

  2. Quinlan, C.L., Perevoschikova, I.V., Goncalves, R.L.S., Hey-Mogensen, M. & Brand, M.D. Meth. Enzymol. 526, 189–217 (2013).

    Article  CAS  Google Scholar 

  3. Quinlan, C.L., Perevoshchikova, I.V., Hey-Mogensen, M., Orr, A.L. & Brand, M.D. Redox Biol. 1, 304–312 (2013).

    Article  CAS  Google Scholar 

  4. Sherer, T.B. et al. J. Neurosci. 23, 10756–10764 (2003).

    Article  CAS  Google Scholar 

  5. Lambert, A.J., Buckingham, J.A., Boysen, H.M. & Brand, M.D. Aging Cell 9, 78–91 (2010).

    Article  CAS  Google Scholar 

  6. Lin, M.T. & Beal, M.F. Nature 443, 787–795 (2006).

    Article  CAS  Google Scholar 

  7. Ishii, T. et al. Cancer Res. 65, 203–209 (2005).

    CAS  PubMed  Google Scholar 

  8. Quinlan, C.L. et al. J. Biol. Chem. 287, 27255–27264 (2012).

    Article  CAS  Google Scholar 

  9. Heather, L.C. et al. Cardiovasc. Res. 85, 127–136 (2010).

    Article  CAS  Google Scholar 

  10. Adam-Vizi, V. & Tretter, L. Neurochem. Int. 62, 757–763 (2013).

    Article  CAS  Google Scholar 

  11. Chouchani, E.T. et al. Nat. Med. 19, 753–759 (2013).

    Article  CAS  Google Scholar 

  12. Dröse, S. Biochim. Biophys. Acta 1827, 578–587 (2013).

    Article  Google Scholar 

  13. Bleier, L. & Dröse, S. Biochim. Biophys. Acta 1827, 1320–1331 (2013).

    Article  CAS  Google Scholar 

  14. Sena, L.A. et al. Immunity 38, 225–236 (2013).

    Article  CAS  Google Scholar 

  15. Jain, M. et al. J. Biol. Chem. 288, 770–777 (2013).

    Article  CAS  Google Scholar 

  16. Weinberg, F. et al. Proc. Natl. Acad. Sci. USA 107, 8788–8793 (2010).

    Article  CAS  Google Scholar 

  17. Viola, H.M. & Hool, L.C. J. Mol. Cell. Cardiol. 49, 875–885 (2010).

    Article  CAS  Google Scholar 

  18. Kaminski, M.M. et al. Cell Rep. 2, 1300–1315 (2012).

    Article  CAS  Google Scholar 

  19. Srinivas, V. et al. J. Biol. Chem. 276, 21995–21998 (2001).

    Article  CAS  Google Scholar 

  20. Chua, Y.L. et al. J. Biol. Chem. 285, 31277–31284 (2010).

    Article  CAS  Google Scholar 

  21. Lee, S.-J., Hwang, A.B. & Kenyon, C. Curr. Biol. 20, 2131–2136 (2010).

    Article  CAS  Google Scholar 

  22. Jung, H.J. et al. J. Biol. Chem. 285, 11584–11595 (2010).

    Article  CAS  Google Scholar 

  23. Orr, A.L. et al. Free Rad. Biol. Med. 65, 1047–1059 (2013).

    Article  CAS  Google Scholar 

  24. Win, S., Than, T.A., Fernandez-Checa, J.C. & Kaplowitz, N. Cell Death Dis. 5, e989 (2014).

    Article  CAS  Google Scholar 

  25. Quinlan, C.L., Gerencser, A.A., Treberg, J.R. & Brand, M.D. J. Biol. Chem. 286, 31361–31372 (2011).

    Article  CAS  Google Scholar 

  26. Swiss, R., Niles, A., Cali, J.J., Nadanaciva, S. & Will, Y. Toxicol. in Vitro 27, 1789–1797 (2013).

    Article  CAS  Google Scholar 

  27. Orr, A.L. et al. PLoS ONE. 9, e89938 (2014).

    Article  Google Scholar 

  28. Rogers, G.W. et al. PLoS ONE 6, e21746 (2011).

    Article  CAS  Google Scholar 

  29. Kaluz, S., Kaluzová, M. & Stanbridge, E.J. Biochem. Biophys. Res. Commun. 370, 613–618 (2008).

    Article  CAS  Google Scholar 

  30. Soberanes, S. et al. J. Biol. Chem. 284, 2176–2186 (2009).

    Article  CAS  Google Scholar 

  31. Chambers, J.W. & LoGrasso, P.V. J. Biol. Chem. 286, 16052–16062 (2011).

    Article  CAS  Google Scholar 

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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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Author notes

  1. Adam L Orr

    Present address: Present address: Gladstone Institutes, San Francisco, California, USA.,

Authors and Affiliations

  1. Buck Institute for Research on Aging, Novato, California, USA

    Adam L Orr, Renata L S Goncalves, Irina V Perevoshchikova & Martin D Brand

  2. Genomics Institute of the Novartis Research Foundation, San Diego, California, USA

    Leonardo Vargas, Carolina N Turk, Janine E Baaten, Jason T Matzen, Victoria J Dardov, Stephen J Attle, Jing Li, Douglas C Quackenbush, H Michael Petrassi, Shelly L Meeusen & Edward K Ainscow

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  1. Adam L Orr
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Contributions

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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Correspondence to Martin D Brand.

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Competing interests

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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Supplementary Results, Supplementary Tables 1 and 2, Supplementary Figures 1–8 and Supplementary Note. (PDF 1587 kb)

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Orr, A., Vargas, L., Turk, C. et al. Suppressors of superoxide production from mitochondrial complex III. Nat Chem Biol 11, 834–836 (2015). https://doi.org/10.1038/nchembio.1910

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