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Why succinate? Physiological regulation by a mitochondrial coenzyme Q sentinel

Nature Chemical Biology volume 18, pages 461–469 (2022)Cite this article

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Abstract

Metabolites once considered solely in catabolism or anabolism turn out to have key regulatory functions. Among these, the citric acid cycle intermediate succinate stands out owing to its multiple roles in disparate pathways, its dramatic concentration changes and its selective cell release. Here we propose that succinate has evolved as a signaling modality because its concentration reflects the coenzyme Q (CoQ) pool redox state, a central redox couple confined to the mitochondrial inner membrane. This connection is of general importance because CoQ redox state integrates three bioenergetic parameters: mitochondrial electron supply, oxygen tension and ATP demand. Succinate, by equilibrating with the CoQ pool, enables the status of this central bioenergetic parameter to be communicated from mitochondria to the rest of the cell, into the circulation and to other cells. The logic of this form of regulation explains many emerging roles of succinate in biology, and suggests future research questions.

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Fig. 1: Mitochondrial bioenergetics and the coenzyme Q (CoQ) pool.
Fig. 2: Succinate controls mitochondrial superoxide production through mitochondrial complex I.
Fig. 3: Accumulated mitochondrial succinate regulates cellular αKG-dependent dioxygenases.
Fig. 4: pH-gated succinate secretion regulates systemic physiology.
Fig. 5: Logic of succinate as a local and systemic bioenergetic sensor.

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Acknowledgements

This work was supported by the Claudia Adams Barr Program (E.T.C.), the Lavine Family Fund (E.T.C.), the Pew Charitable Trust (E.T.C.), NIH DK123095 (E.T.C.), The Smith Family Foundation (E.T.C.), Medical Research Council UK (MC_UU_00015/3) (M.P.M.) and by a Wellcome Trust Investigator award (220257/Z/20/Z) (M.P.M.).

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Authors and Affiliations

  1. Medical Research Council Mitochondrial Biology Unit, University of Cambridge, Cambridge, UK

    Michael P. Murphy

  2. Department of Medicine, University of Cambridge, Cambridge, UK

    Michael P. Murphy

  3. Department of Cancer Biology, Dana–Farber Cancer Institute, Boston, MA, USA

    Edward T. Chouchani

  4. Department of Cell Biology, Harvard Medical School, Boston, MA, USA

    Edward T. Chouchani

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Correspondence to Michael P. Murphy or Edward T. Chouchani.

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E.T.C. is a founder, board member and equity holder in Matchpoint Therapeutics. M.P.M. holds shares in Antipodean Pharmaceuticals Inc. E.T.C. and M.P.M. hold patents in the field of therapeutic modulation of succinate metabolism.

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Murphy, M.P., Chouchani, E.T. Why succinate? Physiological regulation by a mitochondrial coenzyme Q sentinel. Nat Chem Biol 18, 461–469 (2022). https://doi.org/10.1038/s41589-022-01004-8

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