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The Journal of Clinical Investigation Jan 2022Macrophages exposed to inflammatory stimuli including LPS undergo metabolic reprogramming to facilitate macrophage effector function. This metabolic reprogramming... (Review)
Review
Macrophages exposed to inflammatory stimuli including LPS undergo metabolic reprogramming to facilitate macrophage effector function. This metabolic reprogramming supports phagocytic function, cytokine release, and ROS production that are critical to protective inflammatory responses. The Krebs cycle is a central metabolic pathway within all mammalian cell types. In activated macrophages, distinct breaks in the Krebs cycle regulate macrophage effector function through the accumulation of several metabolites that were recently shown to have signaling roles in immunity. One metabolite that accumulates in macrophages because of the disturbance in the Krebs cycle is itaconate, which is derived from cis-aconitate by the enzyme cis-aconitate decarboxylase (ACOD1), encoded by immunoresponsive gene 1 (Irg1). This Review focuses on itaconate's emergence as a key immunometabolite with diverse roles in immunity and inflammation. These roles include inhibition of succinate dehydrogenase (which controls levels of succinate, a metabolite with multiple roles in inflammation), inhibition of glycolysis at multiple levels (which will limit inflammation), activation of the antiinflammatory transcription factors Nrf2 and ATF3, and inhibition of the NLRP3 inflammasome. Itaconate and its derivatives have antiinflammatory effects in preclinical models of sepsis, viral infections, psoriasis, gout, ischemia/reperfusion injury, and pulmonary fibrosis, pointing to possible itaconate-based therapeutics for a range of inflammatory diseases. This intriguing metabolite continues to yield fascinating insights into the role of metabolic reprogramming in host defense and inflammation.
Topics: Animals; Citric Acid Cycle; Humans; Inflammation; Macrophage Activation; Macrophages; Succinates
PubMed: 35040439
DOI: 10.1172/JCI148548 -
Nature Metabolism Jan 2019Metabolic reprogramming has become a key focus for both immunologists and cancer biologists, with exciting advances providing new insights into underlying mechanisms of... (Review)
Review
Metabolic reprogramming has become a key focus for both immunologists and cancer biologists, with exciting advances providing new insights into underlying mechanisms of disease. Metabolites traditionally associated with bioenergetics or biosynthesis have been implicated in immunity and malignancy in transformed cells, with a particular focus on intermediates of the mitochondrial pathway known as the Krebs cycle. Among these, the intermediates succinate, fumarate, itaconate, 2-hydroxyglutarate isomers (D-2-hydroxyglutarate and L-2-hydroxyglutarate) and acetyl-CoA now have extensive evidence for "non-metabolic" signalling functions in both physiological immune contexts and in disease contexts, such as the initiation of carcinogenesis. This review will describe how metabolic reprogramming, with emphasis placed on these metabolites, leads to altered immune cell and transformed cell function. The latest findings are informative for new therapeutic approaches which could be transformative for a range of diseases.
Topics: Citric Acid Cycle; Humans; Immunity, Innate; Macrophages; Neoplasms; Signal Transduction; Succinate Dehydrogenase; Succinates; Succinic Acid
PubMed: 31032474
DOI: 10.1038/s42255-018-0014-7 -
Immunity Jan 2021Immunometabolism has emerged as a key focus for immunologists, with metabolic change in immune cells becoming as important a determinant for specific immune effector... (Review)
Review
Immunometabolism has emerged as a key focus for immunologists, with metabolic change in immune cells becoming as important a determinant for specific immune effector responses as discrete signaling pathways. A key output for these changes involves post-translational modification (PTM) of proteins by metabolites. Products of glycolysis and Krebs cycle pathways can mediate these events, as can lipids, amino acids, and polyamines. A rich and diverse set of PTMs in macrophages and TĀ cells has been uncovered, altering phenotype and modulating immunity and inflammation in different contexts. We review the recent findings in this area and speculate whether they could be of use in the effort to develop therapeutics for immune-related diseases.
Topics: Animals; Citric Acid Cycle; Glycolysis; Humans; Immune System Diseases; Immunity; Immunotherapy; Inflammation; Macrophages; Protein Processing, Post-Translational; Signal Transduction; T-Lymphocytes
PubMed: 33220233
DOI: 10.1016/j.immuni.2020.09.014 -
Cell Aug 2018Krebs cycle intermediates traditionally link to oxidative phosphorylation whilst also making key cell components. It is now clear that some of these metabolites also act... (Review)
Review
Krebs cycle intermediates traditionally link to oxidative phosphorylation whilst also making key cell components. It is now clear that some of these metabolites also act as signals. Succinate plays an important role in inflammatory, hypoxic, and metabolic signaling, while itaconate (from another Krebs cycle intermediate, cis-aconitate) has an anti-inflammatory role.
Topics: Animals; Citric Acid Cycle; Humans; Signal Transduction; Succinates; Succinic Acid
PubMed: 30096309
DOI: 10.1016/j.cell.2018.07.030 -
The Journal of Biological Chemistry Feb 2023The tricarboxylic acid (TCA) cycle, otherwise known as the Krebs cycle, is a central metabolic pathway that performs the essential function of oxidizing nutrients to... (Review)
Review
The tricarboxylic acid (TCA) cycle, otherwise known as the Krebs cycle, is a central metabolic pathway that performs the essential function of oxidizing nutrients to support cellular bioenergetics. More recently, it has become evident that TCA cycle behavior is dynamic, and products of the TCA cycle can be co-opted in cancer and other pathologic states. In this review, we revisit the TCA cycle, including its potential origins and the history of its discovery. We provide a detailed accounting of the requirements for sustained TCA cycle function and the critical regulatory nodes that can stimulate or constrain TCA cycle activity. We also discuss recent advances in our understanding of the flexibility of TCA cycle wiring and the increasingly appreciated heterogeneity in TCA cycle activity exhibited by mammalian cells. Deeper insight into how the TCA cycle can be differentially regulated and, consequently, configured in different contexts will shed light on how this pathway is primed to meet the requirements of distinct mammalian cell states.
Topics: Animals; Citric Acid Cycle; Energy Metabolism; Mammals
PubMed: 36581208
DOI: 10.1016/j.jbc.2022.102838 -
Protein & Cell Feb 2018The tricarboxylic acid (TCA) cycle is a central route for oxidative phosphorylation in cells, and fulfills their bioenergetic, biosynthetic, and redox balance... (Review)
Review
The tricarboxylic acid (TCA) cycle is a central route for oxidative phosphorylation in cells, and fulfills their bioenergetic, biosynthetic, and redox balance requirements. Despite early dogma that cancer cells bypass the TCA cycle and primarily utilize aerobic glycolysis, emerging evidence demonstrates that certain cancer cells, especially those with deregulated oncogene and tumor suppressor expression, rely heavily on the TCA cycle for energy production and macromolecule synthesis. As the field progresses, the importance of aberrant TCA cycle function in tumorigenesis and the potentials of applying small molecule inhibitors to perturb the enhanced cycle function for cancer treatment start to evolve. In this review, we summarize current knowledge about the fuels feeding the cycle, effects of oncogenes and tumor suppressors on fuel and cycle usage, common genetic alterations and deregulation of cycle enzymes, and potential therapeutic opportunities for targeting the TCA cycle in cancer cells. With the application of advanced technology and in vivo model organism studies, it is our hope that studies of this previously overlooked biochemical hub will provide fresh insights into cancer metabolism and tumorigenesis, subsequently revealing vulnerabilities for therapeutic interventions in various cancer types.
Topics: Animals; Citric Acid Cycle; Humans; Molecular Targeted Therapy; Neoplasms; Oncogenes; Tumor Suppressor Proteins
PubMed: 28748451
DOI: 10.1007/s13238-017-0451-1 -
Nature Reviews. Cancer Oct 2016The resurgence of research into cancer metabolism has recently broadened interests beyond glucose and the Warburg effect to other nutrients, including glutamine. Because... (Review)
Review
The resurgence of research into cancer metabolism has recently broadened interests beyond glucose and the Warburg effect to other nutrients, including glutamine. Because oncogenic alterations of metabolism render cancer cells addicted to nutrients, pathways involved in glycolysis or glutaminolysis could be exploited for therapeutic purposes. In this Review, we provide an updated overview of glutamine metabolism and its involvement in tumorigenesis in vitro and in vivo, and explore the recent potential applications of basic science discoveries in the clinical setting.
Topics: Adenosine Triphosphate; Citric Acid Cycle; Glutamine; Glutarates; Humans; Neoplasms
PubMed: 27492215
DOI: 10.1038/nrc.2016.71 -
International Journal of Biological... 2023Mitochondria are intracellular organelles involved in energy production, cell metabolism and cell signaling. They are essential not only in the process of ATP synthesis,... (Review)
Review
Mitochondria are intracellular organelles involved in energy production, cell metabolism and cell signaling. They are essential not only in the process of ATP synthesis, lipid metabolism and nucleic acid metabolism, but also in tumor development and metastasis. Mutations in mtDNA are commonly found in cancer cells to promote the rewiring of bioenergetics and biosynthesis, various metabolites especially oncometabolites in mitochondria regulate tumor metabolism and progression. And mutation of enzymes in the TCA cycle leads to the unusual accumulation of certain metabolites and oncometabolites. Mitochondria have been demonstrated as the target for cancer treatment. Cancer cells rely on two main energy resources: oxidative phosphorylation (OXPHOS) and glycolysis. By manipulating OXPHOS genes or adjusting the metabolites production in mitochondria, tumor growth can be restrained. For example, enhanced complex I activity increases NAD/NADH to prevent metastasis and progression of cancers. In this review, we discussed mitochondrial function in cancer cell metabolism and specially explored the unique role of mitochondria in cancer stem cells and the tumor microenvironment. Targeting the OXPHOS pathway and mitochondria-related metabolism emerging as a potential therapeutic strategy for various cancers.
Topics: Humans; Neoplasms; Mitochondria; Energy Metabolism; Citric Acid Cycle; Oxidative Phosphorylation; Tumor Microenvironment
PubMed: 36778129
DOI: 10.7150/ijbs.81609 -
Seminars in Immunology Aug 2015Macrophages display a spectrum of functional activation phenotypes depending on the composition of the microenvironment they reside in, including type of tissue/organ... (Review)
Review
Macrophages display a spectrum of functional activation phenotypes depending on the composition of the microenvironment they reside in, including type of tissue/organ and character of injurious challenge they are exposed to. Our understanding of how macrophage plasticity is regulated by the local microenvironment is still limited. Here we review and discuss the recent literature regarding the contribution of cellular metabolic pathways to the ability of the macrophage to sense the microenvironment and to alter its function. We propose that distinct alterations in the microenvironment induce a spectrum of inducible and reversible metabolic programs that might form the basis of the inducible and reversible spectrum of functional macrophage activation/polarization phenotypes. We highlight that metabolic pathways in the bidirectional communication between macrophages and stromals cells are an important component of chronic inflammatory conditions. Recent work demonstrates that inflammatory macrophage activation is tightly associated with metabolic reprogramming to aerobic glycolysis, an altered TCA cycle, and reduced mitochondrial respiration. We review cytosolic and mitochondrial mechanisms that promote initiation and maintenance of macrophage activation as they relate to increased aerobic glycolysis and highlight potential pathways through which anti-inflammatory IL-10 could promote macrophage deactivation. Finally, we propose that in addition to their role in energy generation and regulation of apoptosis, mitochondria reprogram their metabolism to also participate in regulating macrophage activation and plasticity.
Topics: Citric Acid Cycle; Glycolysis; Humans; Inflammation; Macrophage Activation; Macrophages
PubMed: 26454572
DOI: 10.1016/j.smim.2015.09.001 -
Cell Metabolism Sep 2018Enhanced glucose uptake and a switch to glycolysis are key traits of M1 macrophages, whereas enhanced fatty acid oxidation and oxidative phosphorylation are the main...
Enhanced glucose uptake and a switch to glycolysis are key traits of M1 macrophages, whereas enhanced fatty acid oxidation and oxidative phosphorylation are the main metabolic characteristics of M2 macrophages. Recent studies challenge this traditional view, indicating that glycolysis may also be critically important for M2 macrophage differentiation, based on experiments with 2-DG. Here we confirm the inhibitory effect of 2-DG on glycolysis, but also demonstrate that 2-DG impairs oxidative phosphorylation and significantly reduces C-labeled Krebs cycle metabolites and intracellular ATP levels. These metabolic derangements were associated with reduced JAK-STAT6 pathway activity and M2 differentiation marker expression. While glucose deprivation and glucose substitution with galactose effectively suppressed glycolytic activity, there was no effective suppression of oxidative phosphorylation, intracellular ATP levels, STAT6 phosphorylation, and M2 differentiation marker expression. These data indicate that glycolytic stimulation is not required for M2 macrophage differentiation as long as oxidative phosphorylation remains active.
Topics: Animals; Cell Differentiation; Cell Line; Citric Acid Cycle; Deoxyglucose; Glucose; Glycolysis; Janus Kinases; Macrophage Activation; Macrophages; Mice; Mice, Inbred C57BL; Oxidative Phosphorylation; STAT6 Transcription Factor; Signal Transduction
PubMed: 30184486
DOI: 10.1016/j.cmet.2018.08.012