Abstract
Most cells have the inherent capacity to shift their reliance on glycolysis relative to oxidative metabolism, and studies in model systems have shown that targeting such shifts may be useful in treating or preventing a variety of diseases ranging from cancer to ischemic injury. However, we currently have a limited number of mechanistically distinct classes of drugs that alter the relative activities of these two pathways. We screen for such compounds by scoring the ability of >3,500 small molecules to selectively impair growth and viability of human fibroblasts in media containing either galactose or glucose as the sole sugar source. We identify several clinically used drugs never linked to energy metabolism, including the antiemetic meclizine, which attenuates mitochondrial respiration through a mechanism distinct from that of canonical inhibitors. We further show that meclizine pretreatment confers cardioprotection and neuroprotection against ischemia-reperfusion injury in murine models. Nutrient-sensitized screening may provide a useful framework for understanding gene function and drug action within the context of energy metabolism.
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Acknowledgements
We thank E. Shoubridge for the MCH58 cell line; M. MacDonald for immortalized striatal cells; R. Xavier for the HRE luciferase construct; S. Norton, B. Wagner and the Broad Chemical Screening Platform for assistance in compound arraying; J. Evans of the Whitehead Institute/MIT BioImaging Center for assistance with high-throughput microscopy; C. Belcher-Timme for technical assistance; T. Kitami for assistance with mitochondrial imaging; M. Mehta for assistance reviewing drug toxicity data; S. Calvo, A. Chess, R. Gould, E. Lander, A. Ting, S. Vafai and members of Mootha lab for valuable discussions and comments. This work was supported by fellowships or grants from the United Mitochondrial Disease Foundation (V.M.G.); Howard Hughes Medical Institute (S.A.S. and V.K.M.); National Institutes of Health (RO1 HL-071158 to P.S.B.); Deane Institute for Integrative Research in Stroke and Atrial Fibrillation (C.A.); American Heart Association (#0815770D to A.P.W.); the Burroughs Wellcome Fund (V.K.M.); the Center for Integration of Medical and Innovative Technology (V.K.M.); and the American Diabetes Association/Smith Family Foundation (V.K.M.).
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V.M.G. and V.K.M. conceived the project; V.M.G., S.A.S., J.H.L., W.C., F.P., C.B.C. and A.P.W. performed experiments; V.M.G., S.A.S., J.H.L., R.N., F.P., C.A., P.S.B. and V.K.M. performed statistical and data analysis; V.M.G., S.A.S. and V.K.M. wrote the paper.
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V.K.M., V.M.G. and S.A.S. are listed as inventors on a patent application filed by the Massachusetts General Hospital.
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Sglu/gal score of all compounds tested (XLS 280 kb)
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Gohil, V., Sheth, S., Nilsson, R. et al. Nutrient-sensitized screening for drugs that shift energy metabolism from mitochondrial respiration to glycolysis. Nat Biotechnol 28, 249–255 (2010). https://doi.org/10.1038/nbt.1606
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DOI: https://doi.org/10.1038/nbt.1606
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