Krebs cycle Reborn in macrophage immunometabolism
Abstract
A striking change has happened in the field of immunology whereby specific metabolic processes have been shown to be a critical determinant of immune cell activation. Multiple immune receptor types rewire metabolic pathways as a key part of how they promote effector functions. Perhaps surprisingly for immunologists, the Krebs cycle has emerged as the central immunometabolic hub of the macrophage. During proinflammatory macrophage activation, there is an accumulation of the Krebs cycle intermediates succinate and citrate, and the Krebs cycle–derived metabolite itaconate. These metabolites have distinct nonmetabolic signaling roles that influence inflammatory gene expression. A key bioenergetic target for the Krebs cycle, the electron transport chain, also becomes altered, generating reactive oxygen species from Complexes I and III. Similarly, alternatively activated macrophages require α-ketoglutarate-dependent epigenetic reprogramming to elicit anti-inflammatory gene expression. In this review, we discuss these advances and speculate on the possibility of targeting these events therapeutically for inflammatory diseases.
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The TCA cycle is a broadly conserved metabolic pathway that harnesses high-energy electrons from fuel sources.
“At the nexus of both catabolic and anabolic metabolism lies the tricarboxylic acid (TCA) cycle, a broadly conserved metabolic pathway consisting of a cyclic series of chemical reactions that harness high-energy electrons from fuel sources (1, 2, 3).”
From Regulation and function of the mammalian tricarboxylic acid cycle (2023) · cites this paper as [3]
The TCA cycle itself neither consumes molecular oxygen nor produces meaningful amounts of ATP; it removes electrons from inputs and transfers them to electron carriers that deposit electrons onto the ETC.
“The TCA cycle itself neither consumes molecular oxygen nor produces meaningful amounts of ATP; rather, the TCA cycle removes electrons (reducing equivalents) from inputs (e.g., acetyl-CoA) and transfers them to electron carriers that deposit their electrons onto the electron transport chain (ETC).”
From Regulation and function of the mammalian tricarboxylic acid cycle (2023) · cites this paper as [3]
Electron funneling through the ETC is coupled to generation of the mitochondrial membrane potential used to power ATP production via OXPHOS, with oxygen as terminal electron acceptor.
“Electron funneling through the complexes of the ETC is coupled to generation of the mitochondrial membrane potential that is ultimately used to power the production of the cellular currency (ATP) in a process known as oxidative phosphorylation (OXPHOS), as oxygen serves as the terminal acceptor for electrons that transit through the ETC (Fig. 1) (3).”
From Regulation and function of the mammalian tricarboxylic acid cycle (2023) · cites this paper as [3]
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Regulation and function of the mammalian tricarboxylic acid cycle
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Determinants, mechanisms, and functional outcomes of myeloid cell diversity in cancer
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- Authors
- Ryan, D. G., & O'Neill, L. A. J.
- Affiliations
- Trinity College Dublin (IE)
- Corresponding author
- O'Neill, Luke A.J.
- Venue
- Annual Review of Immunology
- Publisher
- Annual Reviews
- Published
- 2020-04-26
- Volume
- 38
- Issue
- 1
- Pages
- 289-313
- ISSN
- 0732-0582 (ISSN-L)
- 1545-3278
- OpenAlex
- W3003556593
- Semantic Scholar
- b35b14866c0ddf4cffcedc7639319cdad881e5bd
- Cited by
- 444
- References
- 110
- Citations by year
- 2026: 73 · 2025: 71 · 2024: 88 · 2023: 74 · 2022: 63 · 2021: 50 · 2020: 25
- FWCI
- 5.18
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Annual Review of Immunology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Wellcome Trust (109443/Z/15/Z)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Keywords
- TCA cycle, macrophage immunometabolism, succinic acid, citrate, itaconate, electron transport chain, reactive oxygen species, alternative activation, M2 macrophages, alpha-ketoglutarate, epigenetic reprogramming, inflammatory gene expression, metabolic reprogramming, inflammatory diseases
- MeSH terms
- Animals, Citric Acid Cycle, Disease Susceptibility, Energy Metabolism, Humans, Immunity, Macrophage Activation, Macrophages, Signal Transduction, Immunomodulation
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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