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Metabolites as signalling molecules

Nature Reviews Molecular Cell Biology volume 24, pages 355–374 (2023)Cite this article

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Abstract

Traditional views of cellular metabolism imply that it is passively adapted to meet the demands of the cell. It is becoming increasingly clear, however, that metabolites do more than simply supply the substrates for biological processes; they also provide critical signals, either through effects on metabolic pathways or via modulation of other regulatory proteins. Recent investigation has also uncovered novel roles for several metabolites that expand their signalling influence to processes outside metabolism, including nutrient sensing and storage, embryonic development, cell survival and differentiation, and immune activation and cytokine secretion. Together, these studies suggest that, in contrast to the prevailing notion, the biochemistry of a cell is frequently governed by its underlying metabolism rather than vice versa. This important shift in perspective places common metabolites as key regulators of cell phenotype and behaviour. Yet the signalling metabolites, and the cognate targets and transducers through which they signal, are only beginning to be uncovered. In this Review, we discuss the emerging links between metabolism and cellular behaviour. We hope this will inspire further dissection of the mechanisms through which metabolic pathways and intermediates modulate cell function and will suggest possible drug targets for diseases linked to metabolic deregulation.

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Fig. 1: Principles of metabolite signals drawn from classical experiments.
Fig. 2: Metabolite signals in the regulation of glycolysis, lactic acid fermentation and the TCA cycle.
Fig. 3: Control of mTORC1 activity by AMP and amino acids.
Fig. 4: Extracellular succinate signalling.
Fig. 5: βOHB signalling in ISCs and PEP signalling in TILs.

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Acknowledgements

The authors thank several members of the Rutter laboratory for their careful reading and helpful comments on the manuscript, specifically A. Cluntun, C. Cunningham, A. Leifer, K. Hicks, J. Morgan and S. Johnson. They also thank E. Taylor and T. Ryan for insightful discussion of particular topics.

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Authors and Affiliations

  1. Department of Pathology, University of Utah, Salt Lake City, UT, USA

    Steven Andrew Baker

  2. Department of Biochemistry, University of Utah, Salt Lake City, UT, USA

    Jared Rutter

  3. Howard Hughes Medical Institute, University of Utah School of Medicine, Salt Lake City, UT, USA

    Jared Rutter

  4. Diabetes & Metabolism Research Center, University of Utah, Salt Lake City, UT, USA

    Jared Rutter

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The authors contributed equally to all aspects of the article.

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Correspondence to Steven Andrew Baker or Jared Rutter.

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Supplementary information

Glossary

Carnitine

This common metabolite, named for its abundance in meat, is a critical shuttling molecule when conjugated to long-chain fatty acids. Acyl-carnitines are transported by a dedicated channel (SLC25A20) into the mitochondrial matrix for catabolism. Structurally, carnitine resembles a quaternary ammonium attached to the γ-carbon of β-hydroxybutyrate (βOHB), but in mammals this metabolite is synthesized from lysine via methylation.

Fermentation

The extraction of energy from carbohydrates without the requirement for oxygen. An example in vertebrates would be the generation of ATP from glycolysis where the final product pyruvate is reduced to lactate, thereby recycling NADH to NAD+.

Gluconeogenesis

Literally the synthesis of new glucose. During times of fasting in multicellular organisms, some tissues supply glucose to others by converting smaller carbon-containing metabolites into the six-carbon molecule d-glucose. In vertebrates there are several tissues that contribute to this process including the liver, kidney, small intestine and pancreas. Sources of carbon include lactate, pyruvate, glycerol and several amino acids.

Ketone bodies

Small, water-soluble energy carrrying metabolites derived from fat. These are generally synthesized in the liver and consist of acetone, acetoacetate and β-hydroxybutyrate (βOHB). They are characterized by a ketone functional group. 

Mass action

In chemistry, reactions typically settle on an equilibrium determined by the steady-state level of substrates and products that are achieved under a particular set of conditions. In this state, the forward and reverse reactions still occur but are equivalent in their rate. This steady state can be perturbed to drive the reaction in either the forward or reverse direction by increasing the concentration of one or more reactants such that equilibrium is re-established. Driving the reaction by the addition of reactants to restore equilibrium is an example of mass action.

One-carbon metabolism

The central metabolic pathways generating one-carbon groups for synthesis of nucleotides, amines, phospholipids and creatine. Folate serves as a central cofactor for these pathways and functions as a methyl carrier transferring one-carbon groups directly needed for nucleotide synthesis or transferring that methyl group to the methionine cycle to generate S-adenosyl methionine (SAM).

Pattern recognition receptors

The innate immune system uses certain molecular patterns that are uncommon in healthy host physiology to detect pathogens and cellular damage. These pattern antigens include lipopolysaccharide (LPS), mannose, double-stranded RNA, cytoplasmic DNA, certain bacterial proteins such as flagellin, peptidoglycan and fungal glucans. These molecules are recognized by this class of receptors and help stimulate the immune system.

Peroxisome proliferator-activated receptor-δ

(PPARδ). This nuclear hormone receptor binds to certain fatty acids, such as arachidonic acid, and mediates transcriptional regulation in the nucleus. Expression of its encoding gene (PPARD) is upregulated during adipose catabolism and regulates lipid metabolism.

Phosphoinositide 3-kinase

(PI3K). This family of kinases phosphorylates phosphatidylinositol (PI) at the 3-hydroxy position of the inositol ring. PI is a common constituent of the inner leaflet of the plasma membrane. Although this family consists of numerous kinases with diverse functions, a major class (class I) of this family converts phosphatidylinositol (4,5)-bisphosphate (PI(4,5)P2) into phosphatidylinositol (3,4,5)-trisphosphate (PI(3,4,5)P3), activating downstream Akt protein kinases to regulate cell growth and metabolism.

RNA riboswitches

Structural RNA motifs that interact with a small molecule to alter the function of the containing mRNA. These RNA segments have regulatory function that changes the stability, modification or translation of the mRNA.

S-Adenosyl methionine

(SAM). A metabolite that serves as a universal methyl donor and is synthesized from ATP and methionine by the enzyme S-adenosyl methionine synthetase.

Warburg effect

The observation made by Otto Warburg that tumour cells often consume high levels of glucose and generate lactate even in the presence of available oxygen. Also referred to as aerobic glycolysis.

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Baker, S.A., Rutter, J. Metabolites as signalling molecules. Nat Rev Mol Cell Biol 24, 355–374 (2023). https://doi.org/10.1038/s41580-022-00572-w

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