Mitochondrial control of immunity: beyond ATP

Key Points

  • Different immune cell subsets use diverse metabolic pathways. In general, inflammatory and suppressive cells each utilize glycolysis and oxidative phosphorylation for distinct purposes.

  • Mitochondrial metabolism produces a variety of signalling molecules (such as mitochondrial reactive oxygen species (mROS) and acetyl-CoA) that can drive changes in immune cell function through the regulation of transcription factors and epigenetics.

  • mROS are produced by the mitochondrial electron transport chain as a signal to increase interleukin-2 (IL-2) production in T cells and IL-1β production in macrophages.

  • Acetyl-CoA produced by fatty acid oxidation or pyruvate oxidation in mitochondria can be transported by the citrate shuttle into the cytoplasm, where it can be used for fatty acid synthesis or acetylation reactions. These pathways have crucial roles in immune cell function.

  • M1 macrophages use an altered tricarboxylic acid (TCA) cycle and reverse electron transport to drive inflammation through increased succinate and mROS levels. M2 macrophages have an intact TCA cycle and require the function of the hexosamine branch of glycolysis.

  • Cellular metabolism can be altered by drugs that target mitochondria, such as metformin and mitochondria-targeted antioxidants.

Abstract

Mitochondria are important signalling organelles, and they dictate immunological fate. From T cells to macrophages, mitochondria form the nexus of the various metabolic pathways that define each immune cell subset. In this central position, mitochondria help to control the various metabolic decision points that determine immune cell function. In this Review, we discuss how mitochondrial metabolism varies across different immune cell subsets, how metabolic signalling dictates cell fate and how this signalling could potentially be targeted therapeutically.

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Figure 1: Important mitochondrial functions and decision points.
Figure 2: T cell metabolism controls immune phenotype.
Figure 3: M1 macrophage metabolism utilizes a 'broken' tricarboxylic acid cycle to drive inflammation.
Figure 4: M2 macrophages require mitochondrial metabolism and glycolysis.
Figure 5: Targeting mitochondrial metabolism as a therapeutic strategy.

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Acknowledgements

This work was supported by the US National Institutes of Health (R35 CA197532, PO1 AG04966502 and PO1 HL071643 to N.S.C.; T32 CA9560 to M.M.M.; and T32 T32HL076139 to S.E.W.).

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Correspondence to Navdeep S. Chandel.

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Glossary

Mitochondrial permeability transition pores

High-conductance inner mitochondrial membrane channels. Persistent opening of these pores irreversibly commits cells to death by causing mitochondrial depolarization (which blocks oxidative phosphorylation and reactive oxygen species production), matrix swelling and cristae unfolding, and results in the release of stored calcium+ and of apoptogenic proteins.

Mitophagy

A special form of autophagy, in which mitochondria (in a damaged or depolarized state) are engulfed by autophagosomes and degraded.

Autophagy

A cellular process, by which cytoplasmic organelles and macromolecular complexes are engulfed by double membrane-bound vesicles for delivery to lysosomes and subsequent degradation. This process is involved in the constitutive turnover of proteins and organelles, and is central to cellular activities that maintain a balance between the synthesis and breakdown of various proteins.

Pentose phosphate pathway

(PPP). A pathway that uses glucose to generate NADPH and pentose sugars (such as ribose). The first (oxidative) phase converts glucose-6-phosphate to ribulose-5-phosphate and generates NADPH. The second (non-oxidative) phase synthesizes other sugars from ribulose-5-phosphate.

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Mehta, M., Weinberg, S. & Chandel, N. Mitochondrial control of immunity: beyond ATP. Nat Rev Immunol 17, 608–620 (2017). https://doi.org/10.1038/nri.2017.66

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