Coupling Krebs cycle metabolites to signalling in immunity and cancer

Abstract

Metabolic reprogramming has become a key focus for both immunologists and cancer biologists, with exciting advances providing new insights into the mechanisms underlying disease. There is now extensive evidence that intermediates and derivatives of the mitochondrial Krebs cycle—metabolites traditionally associated with bioenergetics or biosynthesis—also possess ‘non-metabolic’ signalling functions. In this review, we summarize the non-metabolic signalling mechanisms of succinate, fumarate, itaconate, 2-hydroxyglutarate isomers (d-2-hydroxyglutarate and l-2-hydroxyglutarate) and acetyl-CoA, with a specific focus on how such signalling pathways alter immune cell and transformed cell function. We believe that the insights gained from immune and cancer cells that are summarized here will also be useful for understanding and treating a range of other diseases.

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Fig. 1: The Krebs cycle.
Fig. 2: The diverse signalling roles of succinate.
Fig. 3: Itaconate is a thiol-reactive anti-inflammatory metabolite.
Fig. 4: Fumarate is an oncometabolite and epigenetic modifier.
Fig. 5: 2-HG is an oncometabolite and epigenetic modifier.
Fig. 6: Acetyl-CoA as an epigenetic modifier in immunity and cancer.
Fig. 7: Therapeutic opportunities targeting metabolic signalling pathways.

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Acknowledgements

This work was supported by a grant to M.P.M. from the Medical Research Council UK (MC_U105663142) and a Wellcome Trust Investigator award to MPM (110159/Z/15/Z). The O’Neill laboratory acknowledges the following grant support: European Research Council (ECFP7-ERC-MICROINNATE), Science Foundation Ireland Investigator Award (SFI 12/IA/1531), GlaxoSmithKline Visiting Scientist Programme and The Wellcome Trust (oneill-wellcometrust-metabolic, grant number 205455).

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Ryan, D.G., Murphy, M.P., Frezza, C. et al. Coupling Krebs cycle metabolites to signalling in immunity and cancer. Nat Metab 1, 16–33 (2019). https://doi.org/10.1038/s42255-018-0014-7

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