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International Journal of Molecular... Jul 2023When tissues are under physiological stresses, such as vigorous exercise and cold exposure, skeletal muscle cells secrete succinate into the extracellular space for... (Review)
Review
When tissues are under physiological stresses, such as vigorous exercise and cold exposure, skeletal muscle cells secrete succinate into the extracellular space for adaptation and survival. By contrast, environmental toxins and injurious agents induce cellular secretion of succinate to damage tissues, trigger inflammation, and induce tissue fibrosis. Extracellular succinate induces cellular changes and tissue adaptation or damage by ligating cell surface succinate receptor-1 (SUCNR-1) and activating downstream signaling pathways and transcriptional programs. Since SUCNR-1 mediates not only pathological processes but also physiological functions, targeting it for drug development is hampered by incomplete knowledge about the characteristics of its physiological vs. pathological actions. This review summarizes the current status of extracellular succinate in health and disease and discusses the underlying mechanisms and therapeutic implications.
Topics: Humans; Succinic Acid; Succinates; Signal Transduction; Cell Membrane; Fibrosis
PubMed: 37446354
DOI: 10.3390/ijms241311165 -
Journal of Immunology (Baltimore, Md. :... Aug 2023Immunometabolism is an interdisciplinary field that focuses on the relationship between metabolic pathways and immune responses. Dysregulated immunometabolism... (Review)
Review
Immunometabolism is an interdisciplinary field that focuses on the relationship between metabolic pathways and immune responses. Dysregulated immunometabolism contributes to many pathological settings, such as cytokine storm or immune tolerance. Aconitate decarboxylase 1 (ACOD1, also known as immunoresponsive gene 1), the mitochondrial enzyme responsible for catalyzing itaconate production, was originally identified as a bacterial LPS-inducible gene involved in innate immunity in mouse macrophages. We now know that the upregulation of ACOD1 expression in immune or nonimmune cells plays a context-dependent role in metabolic reprogramming, signal transduction, inflammasome regulation, and protein modification. The emerging function of ACOD1 in inflammation and infection is a double-edged sword. In this review, we discuss how ACOD1 regulates anti-inflammatory or proinflammatory responses in an itaconate-dependent or -independent manner. Further understanding of ACOD1 expression and function may pave the way for the development of precision therapies for inflammatory diseases.
Topics: Animals; Mice; Immunity, Innate; Inflammation; Macrophages; Succinates
PubMed: 37549395
DOI: 10.4049/jimmunol.2300101 -
Cell Metabolism Mar 2024Severe forms of malaria are associated with systemic inflammation and host metabolism disorders; however, the interplay between these outcomes is poorly understood....
Severe forms of malaria are associated with systemic inflammation and host metabolism disorders; however, the interplay between these outcomes is poorly understood. Using a Plasmodium chabaudi model of malaria, we demonstrate that interferon (IFN) γ boosts glycolysis in splenic monocyte-derived dendritic cells (MODCs), leading to itaconate accumulation and disruption in the TCA cycle. Increased itaconate levels reduce mitochondrial functionality, which associates with organellar nucleic acid release and MODC restraint. We hypothesize that dysfunctional mitochondria release degraded DNA into the cytosol. Once mitochondrial DNA is sensitized, the activation of IRF3 and IRF7 promotes the expression of IFN-stimulated genes and checkpoint markers. Indeed, depletion of the STING-IRF3/IRF7 axis reduces PD-L1 expression, enabling activation of CD8+ T cells that control parasite proliferation. In summary, mitochondrial disruption caused by itaconate in MODCs leads to a suppressive effect in CD8+ T cells, which enhances parasitemia. We provide evidence that ACOD1 and itaconate are potential targets for adjunct antimalarial therapy.
Topics: Humans; Monocytes; DNA, Mitochondrial; B7-H1 Antigen; Plasmodium; Malaria; Mitochondria; Dendritic Cells; Succinates
PubMed: 38325373
DOI: 10.1016/j.cmet.2024.01.008 -
Current Opinion in Biotechnology Dec 2023The tumor microenvironment (TME) consists of a network of metabolically interconnected tumor and immune cell types. Macrophages influence the metabolic composition... (Review)
Review
The tumor microenvironment (TME) consists of a network of metabolically interconnected tumor and immune cell types. Macrophages influence the metabolic composition within the TME, which directly impacts the metabolic state and drug response of tumors. The accumulation of oncometabolites, such as succinate, fumarate, and 2-hydroxyglutarate, represents metabolic vulnerabilities in cancer that can be targeted therapeutically. Immunometabolites are emerging as metabolic regulators of the TME impacting immune cell functions and cancer cell growth. Here, we discuss recent discoveries on the potential impact of itaconate on the TME. We highlight how itaconate influences metabolic pathways relevant to immune responses and cancer cell proliferation. We also consider the therapeutic implications of manipulating itaconate metabolism as an immunotherapeutic strategy to constrain tumor growth.
Topics: Humans; Tumor Microenvironment; Succinates; Neoplasms; Succinic Acid
PubMed: 37806082
DOI: 10.1016/j.copbio.2023.102996 -
Journal of Neuroinflammation Dec 2023Pathological neovascularization is a pivotal biological process in wet age-related macular degeneration (AMD), retinopathy of prematurity (ROP) and proliferative...
Pathological neovascularization is a pivotal biological process in wet age-related macular degeneration (AMD), retinopathy of prematurity (ROP) and proliferative diabetic retinopathy (PDR), in which macrophages (Mφs) play a key role. Tip cell specialization is critical in angiogenesis; however, its interconnection with the surrounding immune environment remains unclear. Succinate is an intermediate in the tricarboxylic acid (TCA) cycle and was significantly elevated in patients with wet AMD by metabolomics. Advanced experiments revealed that SUCNR1 expression in Mφ and M2 polarization was detected in abnormal vessels of choroidal neovascularization (CNV) and oxygen-induced retinopathy (OIR) models. Succinate-induced M2 polarization via SUCNR1, which facilitated vascular endothelial cell (EC) migration, invasion, and tubulation, thus promoting angiogenesis in pathological neovascularization. Furthermore, evidence indicated that succinate triggered the release of RBP4 from Mφs into the surroundings to regulate endothelial sprouting and pathological angiogenesis via VEGFR2, a marker of tip cell formation. In conclusion, our results suggest that succinate represents a novel class of vasculature-inducing factors that modulate Mφ polarization and the RBP4/VEGFR2 pathway to induce pathological angiogenic signaling through tip cell specialization.
Topics: Infant, Newborn; Humans; Animals; Succinic Acid; Eye; Choroidal Neovascularization; Retinopathy of Prematurity; Macrophages; Disease Models, Animal; Retinol-Binding Proteins, Plasma
PubMed: 38129891
DOI: 10.1186/s12974-023-02998-1 -
Cell Metabolism Mar 2024Itaconate is a metabolite that synthesized from cis-aconitate in mitochondria and transported into the cytosol to exert multiple regulatory effects in macrophages....
Itaconate is a metabolite that synthesized from cis-aconitate in mitochondria and transported into the cytosol to exert multiple regulatory effects in macrophages. However, the mechanism by which itaconate exits from macrophages remains unknown. Using a genetic screen, we reveal that itaconate is exported from cytosol to extracellular space by ATP-binding cassette transporter G2 (ABCG2) in an ATPase-dependent manner in human and mouse macrophages. Elevation of transcription factor TFEB-dependent lysosomal biogenesis and antibacterial innate immunity are observed in inflammatory macrophages with deficiency of ABCG2-mediated itaconate export. Furthermore, deficiency of ABCG2-mediated itaconate export in macrophages promotes antibacterial innate immune defense in a mouse model of S. typhimurium infection. Thus, our findings identify ABCG2-mediated itaconate export as a key regulatory mechanism that limits TFEB-dependent lysosomal biogenesis and antibacterial innate immunity in inflammatory macrophages, implying the potential therapeutic utility of blocking itaconate export in treating human bacterial infections.
Topics: Animals; Humans; Mice; Anti-Bacterial Agents; ATP Binding Cassette Transporter, Subfamily G, Member 2; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; Immunity, Innate; Lysosomes; Neoplasm Proteins; Succinates
PubMed: 38181789
DOI: 10.1016/j.cmet.2023.12.015 -
Proceedings of the National Academy of... Apr 2024Atherosclerosis is fueled by a failure to resolve lipid-driven inflammation within the vasculature that drives plaque formation. Therapeutic approaches to reverse...
Atherosclerosis is fueled by a failure to resolve lipid-driven inflammation within the vasculature that drives plaque formation. Therapeutic approaches to reverse atherosclerotic inflammation are needed to address the rising global burden of cardiovascular disease (CVD). Recently, metabolites have gained attention for their immunomodulatory properties, including itaconate, which is generated from the tricarboxylic acid-intermediate cis-aconitate by the enzyme Immune Responsive Gene 1 (IRG1/ACOD1). Here, we tested the therapeutic potential of the IRG1-itaconate axis for human atherosclerosis. Using single-cell RNA sequencing (scRNA-seq), we found that is up-regulated in human coronary atherosclerotic lesions compared to patient-matched healthy vasculature, and in mouse models of atherosclerosis, where it is primarily expressed by plaque monocytes, macrophages, and neutrophils. Global or hematopoietic -deficiency in mice increases atherosclerosis burden, plaque macrophage and lipid content, and expression of the proatherosclerotic cytokine interleukin (IL)-1β. Mechanistically, absence of increased macrophage lipid accumulation, and accelerated inflammation via increased neutrophil extracellular trap (NET) formation and NET-priming of the NLRP3-inflammasome in macrophages, resulting in increased IL-1β release. Conversely, supplementation of the -itaconate axis using 4-octyl itaconate (4-OI) beneficially remodeled advanced plaques and reduced lesional IL-1β levels in mice. To investigate the effects of 4-OI in humans, we leveraged an ex vivo systems-immunology approach for CVD drug discovery. Using CyTOF and scRNA-seq of peripheral blood mononuclear cells treated with plasma from CVD patients, we showed that 4-OI attenuates proinflammatory phospho-signaling and mediates anti-inflammatory rewiring of macrophage populations. Our data highlight the relevance of pursuing IRG1-itaconate axis supplementation as a therapeutic approach for atherosclerosis in humans.
Topics: Animals; Humans; Mice; Atherosclerosis; Cholesterol; Inflammation; Leukocytes, Mononuclear; Lipids; Plaque, Atherosclerotic; Succinates
PubMed: 38564634
DOI: 10.1073/pnas.2400675121 -
Basic Research in Cardiology Oct 2023A hallmark of heart failure is a metabolic switch away from fatty acids β-oxidation (FAO) to glycolysis. Here, we show that succinate dehydrogenase (SDH) is required...
A hallmark of heart failure is a metabolic switch away from fatty acids β-oxidation (FAO) to glycolysis. Here, we show that succinate dehydrogenase (SDH) is required for maintenance of myocardial homeostasis of FAO/glycolysis. Mice with cardiomyocyte-restricted deletion of subunit b or c of SDH developed a dilated cardiomyopathy and heart failure. Hypertrophied hearts displayed a decrease in FAO, while glucose uptake and glycolysis were augmented, which was reversed by enforcing FAO fuels via a high-fat diet, which also improved heart failure of mutant mice. SDH-deficient hearts exhibited an increase in genome-wide DNA methylation associated with accumulation of succinate, a metabolite known to inhibit DNA demethylases, resulting in changes of myocardial transcriptomic landscape. Succinate induced DNA hypermethylation and depressed the expression of FAO genes in myocardium, leading to imbalanced FAO/glycolysis. Inhibition of succinate by α-ketoglutarate restored transcriptional profiles and metabolic disorders in SDH-deficient cardiomyocytes. Thus, our findings reveal the essential role for SDH in metabolic remodeling of failing hearts, and highlight the potential of therapeutic strategies to prevent cardiac dysfunction in the setting of SDH deficiency.
Topics: Mice; Animals; Succinate Dehydrogenase; Myocardium; Myocytes, Cardiac; Heart Failure; Homeostasis; Succinates; DNA; Epigenesis, Genetic
PubMed: 37819607
DOI: 10.1007/s00395-023-01015-z -
International Journal of Toxicology Dec 2023The Expert Panel for Cosmetic Ingredient Safety reviewed newly available studies since their original assessment in 2002, along with updated information regarding...
The Expert Panel for Cosmetic Ingredient Safety reviewed newly available studies since their original assessment in 2002, along with updated information regarding product types and concentrations of use, and confirmed that Aluminum Starch Octenylsuccinate is safe as a cosmetic ingredient in the practices of use and concentration as described in this report.
Topics: Consumer Product Safety; Aluminum; Starch; Succinates; Cosmetics
PubMed: 37774506
DOI: 10.1177/10915818231204281 -
Cellular & Molecular Biology Letters Dec 2023Metabolic states greatly influence functioning and differentiation of immune cells. Regulating the metabolism of immune cells can effectively modulate the host immune... (Review)
Review
Metabolic states greatly influence functioning and differentiation of immune cells. Regulating the metabolism of immune cells can effectively modulate the host immune response. Itaconate, an intermediate metabolite derived from the tricarboxylic acid (TCA) cycle of immune cells, is produced through the decarboxylation of cis-aconitate by cis-aconitate decarboxylase in the mitochondria. The gene encoding cis-aconitate decarboxylase is known as immune response gene 1 (IRG1). In response to external proinflammatory stimulation, macrophages exhibit high IRG1 expression. IRG1/itaconate inhibits succinate dehydrogenase activity, thus influencing the metabolic status of macrophages. Therefore, itaconate serves as a link between macrophage metabolism, oxidative stress, and immune response, ultimately regulating macrophage function. Studies have demonstrated that itaconate acts on various signaling pathways, including Keap1-nuclear factor E2-related factor 2-ARE pathways, ATF3-IκBζ axis, and the stimulator of interferon genes (STING) pathway to exert antiinflammatory and antioxidant effects. Furthermore, several studies have reported that itaconate affects cancer occurrence and development through diverse signaling pathways. In this paper, we provide a comprehensive review of the role IRG1/itaconate and its derivatives in the regulation of macrophage metabolism and functions. By furthering our understanding of itaconate, we intend to shed light on its potential for treating inflammatory diseases and offer new insights in this field.
Topics: Kelch-Like ECH-Associated Protein 1; NF-E2-Related Factor 2; Succinates; Immunity
PubMed: 38042791
DOI: 10.1186/s11658-023-00503-3