Coupling Krebs cycle metabolites to signalling in immunity and cancer

In the paper

“Treatment of mouse fibroblasts with the SDH inhibitor 3-nitropropionic acid increases succinylation38.”

What the sources say

• ?Could not verify

  The Results section reports effects of mitochondrial complex I deficiency in mouse macrophages and pups, not treatment of fibroblasts with an SDH inhibitor. Searches for 3-nitropropionic acid, SDH inhibition, fibroblasts, and succinylation found no passage in our copy addressing the claimed effect. (LLM, conf=0.76)

  cites [38] Jin, Z., Wei, W., Yang, M., Du, Y. & Wan, Y. Mitochondrial complex I activity suppresses inflammation and enhances bone resorption by shifting macrophage-osteoclast polarization. Cell. Metab. 20, 483–498 (2014). sourceExperimental — accuracy not yet measured

In the paper

“IRG1 has also been shown to mediate the immunomodulatory effects of CO releasing molecule 2 (CORM2)-induced HMOX1 on TNF-αproduction in both LPS-activated macrophages and in a murine endotoxin shock model69”

What the sources say

• Partly supported

  The Results and discussion reports that Irg1 has been found to suppress TLR-triggered TNF-α production, citing Jamal Uddin et al. (2016). The References identifies that study as concerning heme oxygenase-1/carbon monoxide and LPS-mediated sepsis. This paper does not establish the claimed CORM2-induced mechanism or its effects in both LPS-activated macrophages and a murine endotoxin shock model; its own experiments concern M. tuberculosis infection. (LLM, conf=0.82)

  cites [69] Nair, S. et al. Irg1 expression in myeloid cells prevents immunopathology during M. tuberculosis infection. J. Exp. Med. 215, 1035–1045 (2018). sourceExperimental — accuracy not yet measured

In the paper

“Most recently, an intriguing study in peritoneal tumours (B16 melanoma and ID8 ovarian carcinoma) has demonstrated that tumour-infiltrating macrophages release itaconate which potentiates tumour growth74.”

What the sources say

• ?Could not verify

  The Methods describe collecting thioglycolate-elicited peritoneal macrophages, and the Results use them to study Keap1–Nrf2 stress sensing. Searches for itaconate and for B16 melanoma and ID8 ovarian carcinoma found no passage about tumour-infiltrating macrophages releasing itaconate or promoting tumour growth. (LLM, conf=0.78)

  cites [74] Saito, R. et al. Characterizations of three major cysteine sensors of Keap1 in stress response. Mol. Cell Biol. 36, 271–284 (2015). sourceExperimental — accuracy not yet measured

In the paper

“Importantly, inhibition of aerobic glycolysis by the specific GAPDH inhibitor heptelidic acid (HA) and 2-deoxyglucose (2-DG) recapitulated the immunomodulatory effects of DMF in vitro, while in vivo administration of HA inhibited the development of experimental autoimmune encephalomyelitis (EAE), a murine model of MS99.”

What the sources say

• ?Could not verify

  The Results and Discussion describe GAPDH succination and enzyme activity in diabetic rats, not treatment of EAE. Searches for heptelidic acid, HA, EAE, and multiple sclerosis found no passage addressing whether in vivo HA administration inhibits EAE development. (LLM, conf=0.78)

  cites [99] Blatnik, M., Thorpe, S. R. & Baynes, J. W. Succination of proteins by fumarate: mechanism of inactivation of glyceraldehyde-3-phosphate dehydrogenase in diabetes. Ann. NY Acad. Sci. 1126, 272–275 (2008). sourceExperimental — accuracy not yet measured

In the paper

“These data are consistent with previous reports demonstrating that Irg1 acts as an oncogene, driving glioma pathogenesis171.”

What the sources say

• ?Could not verify

  The cited paper’s supplied Abstract passage discusses IL-2-mediated T-cell proliferation, and the retrieved Methods and References passages concern ACLY and related signaling; no page numbers were provided. Searches for “Irg1 acts as an oncogene driving glioma pathogenesis” and “Irg1 glioma oncogene” found no passage addressing Irg1 or glioma pathogenesis. (LLM, conf=0.76)

  cites [171] Osinalde, N. et al. Nuclear phosphoproteomic screen uncovers ACLY as mediator of IL-2-induced proliferation of CD4+ T lymphocytes. Mol. Cell. Proteomics 15, 2076–2092 (2016). sourceExperimental — accuracy not yet measured

In the paper

“As mentioned, fumarate also inhibits a variety of α-KGDDs, enzymes involved in multiple cellular processes, from metabolism to signalling and epigenetics90-92”

What the sources say

• ?Could not verify

  The Introduction discusses dimethyl fumarate’s proposed effects on cysteine-containing proteins, and the Results report inhibition of T-cell activation by dimethyl fumarate. Searches for α-KGDD, dioxygenase, and 2-oxoglutarate-dependent dioxygenases found no passage in our copy addressing whether fumarate inhibits those enzymes. (LLM, conf=0.74)

  cites [90] Blewett, M. M. et al. Chemical proteomic map of dimethyl fumarate-sensitive cysteines in primary human T cells. Sci. Signal. 9, rs10 (2016). sourceExperimental — accuracy not yet measured
• ?Could not verify

  The paper’s discussion of protein succination (pp. 613–615) says fumarate can modify many proteins and describes inhibition of GAPDH. Searches for α-KGDDs and α-ketoglutarate-dependent dioxygenases found no passage addressing whether fumarate inhibits that enzyme class. (LLM, conf=0.78)

  cites [91] Angiari, S. & O’Neill, L. A. Dimethyl fumarate: targeting glycolysis to treat MS. Cell Res. 28, 613–615 (2018). sourceExperimental — accuracy not yet measured
• ?Could not verify

  The supplied passages and searches for α-KGDDs and α-ketoglutarate-dependent dioxygenases found no discussion of that enzyme class. The paper instead discusses fumarate-mediated inactivation of GAPDH and inhibition of GAPDH by dimethyl fumarate (Abstract; page not provided). That does not establish whether fumarate inhibits α-KGDDs. (LLM, conf=0.72)

  cites [92] Kornberg, M. D. et al. Dimethyl fumarate targets GAPDH and aerobic glycolysis to modulate immunity. Science 360, 449–453 (2018). sourceExperimental — accuracy not yet measured

In the paper

“Lastly, AOAA ameliorated disease progression in EAE, a disease in which TH17 cells mediate pathology143.”

What the sources say

• ?Could not verify

  The Results (Sequence Analysis; page not available) concern IDH mutations and outcomes in glioma patients, not AOAA treatment or EAE. Searches for AOAA, experimental autoimmune encephalomyelitis, and TH17 found no passage addressing the attributed claim. (LLM, conf=0.78)

  cites [143] Yan, H. et al. IDH1 and IDH2 mutations in gliomas. N. Engl. J. Med. 360, 765–773 (2009). sourceExperimental — accuracy not yet measured

In the paper

“Finally, it was shown that fumarate can drive succination of several members of the family of Iron Sulfur (Fe-S) cluster biogenesis proteins, causing a depletion of Fe-S clusters required for the activity of mitochondrial enzymes, including complex I88.”

What the sources say

• Partly supported

  The Discussion (page not available in our copy) says fumarate can cause aberrant succination of many proteins, including KEAP1. It does not identify Fe-S cluster biogenesis proteins as targets or report Fe-S cluster depletion or an effect on mitochondrial complex I activity. (LLM, conf=0.83)

  cites [88] Xiao, M. et al. Inhibition of α-KG-dependent histone and DNA demethylases by fumarate and succinate that are accumulated in mutations of FH and SDH tumor suppressors. Genes Dev. 26, 1326–1338 (2012). sourceExperimental — accuracy not yet measured

In the paper

“D-2-HG produced by mIDH1/2 has been shown to drive a CpG island methylator phenotype (G-CIMP) in both glioma and ICC tumours to promote tumorigenesis, and has also been found to occupy the active site of histone demethylases thereby increasing histone methylation in primary gliomas121,123-125.”

What the sources say

• Not checked yetcites [121] Duran, M., Kamerling, J. P., Bakker, H. D., van Gennip, A. H. & Wadman, S. K. l-2-Hydroxyglutaric aciduria: an inborn error of metabolism? J. Inherit. Metab. Dis. 3, 109–112 (1980). source
• ?Could not verify

  The paper’s Pathophysiological Implications section discusses accumulation and possible toxicity of L-2-hydroxyglutarate in L-2-hydroxyglutaric aciduria (page not available in our copy). Searches for mutant IDH, CpG island methylation, glioma, ICC, and histone demethylation found no passage addressing the attributed tumour mechanism. (LLM, conf=0.78)

  cites [123] Rzem, R. et al. A gene encoding a putative FAD-dependent l-2-hydroxyglutarate dehydrogenase is mutated in l-2-hydroxyglutaric aciduria. Proc. Natl. Acad. Sci. USA 101, 16849–16854 (2004). sourceExperimental — accuracy not yet measured
• Not checked yetcites [124] Struys, E. A. et al. Mutations in the d-2-hydroxyglutarate dehydrogenase gene cause D-2-hydroxyglutaric aciduria. Am. J. Hum. Genet. 76, 358–360 (2005). source
• Not checked yetcites [125] Topçu, M. et al. l-2-Hydroxyglutaric aciduria: identification of a mutant gene C14orf160, localized on chromosome 14q22.1. Hum. Mol. Genet. 13, 2803–2811 (2004). source

In the paper

“It has been reported that under conditions of hypoxia L-2HG is selectively produced by mammalian cells 51.”

What the sources say

• ?Could not verify

  The supplied passages on Sirt5 activity and lysine succinylation (section labeled Abstract; page unavailable) do not address L-2HG production under hypoxia. Searches for hypoxic L-2HG production returned no passage in our copy that speaks to the claim. (LLM, conf=0.76)

  cites [51] Du, J. et al. Sirt5 is a NAD-dependent protein lysine demalonylase and desuccinylase. Science 334, 806–809 (2011). sourceExperimental — accuracy not yet measured

In the paper

“DMM could also decrease inflammation in a mouse model of sepsis28.”

What the sources say

• ?Could not verify

  The section on TRAP1, respiration, and cancer discusses succinate accumulation and tumor growth, not DMM or sepsis. Searches for DMM and dimethyl malonate in relation to inflammation in a mouse sepsis model found no passage addressing the claim in our copy. (LLM, conf=0.78)

  cites [28] Rasola, A., Neckers, L. & Picard, D. Mitochondrial oxidative phosphorylation TRAP(1)ped in tumor cells. Trends Cell Biol. 24, 455–463 (2014). sourceExperimental — accuracy not yet measured

In the paper

“A selective antagonist for human and rat has been shown to be protective in hypertension, a disease in which succinate is elevated11.”

What the sources say

• Not checked yetcites [11] Hollander, A. P., Corke, K. P., Freemont, A. J. & Lewis, C. E. Expression of hypoxia-inducible factor 1α by macrophages in the rheumatoid synovium: implications for targeting of therapeutic genes to the inflamed joint. Arthritis Rheum. 44, 1540–1544 (2001). source

In the paper

“LPS can also stabilize HIF-1α indirectly, by increasing succinate levels.”

In the paper

“It transcriptionally directs a switch in metabolism from oxidative phosphorylation to glycolysis, which allows rapid ATP production without the need for oxygen15.”

What the sources say

• Not checked yetcites [15] Lewis, G. D. et al. Metabolic signatures of exercise in human plasma. Sci. Transl. Med. 2, 33ra37 (2010). source

In the paper

“HIF-1α is tightly regulated by prolyl hydroxylases (PHD), a class of α-ketoglutarate (α-KG)-dependent dioxygenases (α-KGDDs) that convert α-KG to succinate and use molecular oxygen to hydroxylate HIF-1α.”

In the paper

“Priming of DCs with succinate and antigen simultaneously, elevates antigen-specific T cell activation, increasing TNFα and IFN-γproduction from these cells4.”

What the sources say

• Not checked yetcites [4] Chouchani, E. T. et al. A unifying mechanism for mitochondrial superoxide production during ischemia–reperfusion injury. Cell. Metab. 23, 254–263 (2016). source

In the paper

“More recently, however, it has been demonstrated that succinate accumulation in tumours promotes angiogenesis via upregulation of vascular endothelial growth factor (VEGF) in a HIF-1α-independent manner.”

What the sources say

• Not checked yetcites [23] Maxwell, P. H. et al. The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis. Nature 399, 271–275 (1999). source

In the paper

“SUCNR1 ligation on MoDC or the U937 macrophage cell line induces cell migration, suggesting that succinate can act as a chemokine4.”

What the sources say

• Not checked yetcites [4] Chouchani, E. T. et al. A unifying mechanism for mitochondrial superoxide production during ischemia–reperfusion injury. Cell. Metab. 23, 254–263 (2016). source

In the paper

“Tissue and circulating succinate is also elevated in other chronic inflammatory settings such as models of diet-induced obesity8.”

What the sources say

• Not checked yetcites [8] Schneider, C. et al. A metabolite-triggered tuft cell–ILC2 circuit drives small intestinal remodeling. Cell 174, 271–284.e14 (2018). source

In the paper

“It was demonstrated that brown adipocytes possess a unique capacity to sequester extracellular succinate, which serves to increase UCP1 activity as a consequence of elevated mtROS160.”

What the sources say

• Not checked yetcites [160] Chesnelong, C. et al. Lactate dehydrogenase A silencing in IDH mutant gliomas. Neuro-Oncol. 16, 686–695 (2014). source

In the paper

“Succinate instead activates extracellular regulated kinase (ERK) 1/2 and signal transducer and activator of transcription 3 (STAT3) in a SUCNR1-dependent manner23.”

What the sources say

• Not checked yetcites [23] Maxwell, P. H. et al. The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis. Nature 399, 271–275 (1999). source

In the paper

“This correlates with an observed increase in succinate in synovial fluids from rheumatoid arthritis (RA) patients suggesting that chronically elevated succinate is pathological in this setting6.”

What the sources say

• Not checked yetcites [6] Lei, W. et al. Activation of intestinal tuft cell-expressed Sucnr1 triggers type 2 immunity in the mouse small intestine. Proc. Natl Acad. Sci. USA. 115, 5552–5557 (2018). source

In the paper

“Ligation of TLR4 by LPS can transcriptionally induce HIF-1α and the induction of a range of HIF-1α target genes under hypoxic and also normoxic conditions2, in an NF-κB-dependent manner19.”

What the sources say

• Not checked yetcites [2] Tannahill, G. M. et al. Succinate is an inflammatory signal that induces IL-1β through HIF-1α. Nature 496, 238–242 (2013). source
• Not checked yetcites [19] Tannahill, G. M. & O’Neill, L. A. The emerging role of metabolic regulation in the functioning of Toll-like receptors and the NOD-like receptor Nlrp3. FEBS Lett. 585, 1568–1572 (2011). source

In the paper

“Macrophage activation and IL-1β production are decreased in the absence of SUCR1 both following LPS treatment and in a model of antigen-induced arthritis.”

What the sources say

• Not checked yetcites [5] Rubic, T. et al. Triggering the succinate receptor GPR91 on dendritic cells enhances immunity. Nat. Immunol. 9, 1261–1269 (2008). source

In the paper

“Intriguingly, HIF-1α expression is also increased in synovial joints of RA patients7 suggesting that succinate may act in two ways to increase inflammation in RA: via SUCNR1 and HIF-1α.”

What the sources say

• Not checked yetcites [7] Nadjsombati, M. S. et al. Detection of succinate by intestinal tuft cells triggers a type 2 innate immune circuit. Immunity 49, 33–41.e7 (2018). source

In the paper

“HIF-1α is vital for the switch to glycolysis observed in M1 macrophages and DCs following stimulation.”

In the paper

“Littlewood-Evans and colleagues (2016) have demonstrated that succinate can act in an autocrine and paracrine manner to increase IL-1β production in macrophages5.”

What the sources say

• Not checked yetcites [5] Rubic, T. et al. Triggering the succinate receptor GPR91 on dendritic cells enhances immunity. Nat. Immunol. 9, 1261–1269 (2008). source

In the paper

“As such, following ischemia/hypoxia, or when SDH operation is affected by genetic aberrations (such a tumors harboring SDH mutations) elevated succinate can potentiate the hypoxic phenotype by leading to further HIF-1α stabilization.”

In the paper

“DI was shown to significantly and acutely deplete GSH levels, confirming it was indeed an activated Michael acceptor59.”

What the sources say

• Not checked yetcites [59] Okabe, M., Lies, D., Kanamasa, S. & Park, E. Y. Biotechnological production of itaconic acid and its biosynthesis in Aspergillus terreus. Appl. Microbiol. Biotechnol. 84, 597–606 (2009). source

In the paper

“Lampropoulou and colleagues (2016) reported an upregulation of genes involved in Phase II conjugation, glutathione conjugation and biological oxidations from an RNA-seq screen performed in DI-treated BMDMs50.”

What the sources say

• Not checked yetcites [50] Xie, Z. et al. Lysine succinylation and lysine malonylation in histones. Mol. Cell. Proteomics 11, 100–107 (2012). source

In the paper

“Importantly, Lampropoulou and colleagues (2016) first demonstrated that bone-marrow derived macrophages (BMDMs) activated by LPS and pre-treated with a cell permeable methyl ester derivative of itaconate, dimethyl itaconate (DI), exhibited potent inhibition of pro-inflammatory mediators including nitic oxide (NO), ROS and the cytokines IL-6, IL-12p70 and IL-1β13,50.”

What the sources say

• Not checked yetcites [13] van Diepen, J. A. et al. SUCNR1-mediated chemotaxis of macrophages aggravates obesity-induced inflammation and diabetes. Diabetologia 60, 1304–1313 (2017). source
• Not checked yetcites [50] Xie, Z. et al. Lysine succinylation and lysine malonylation in histones. Mol. Cell. Proteomics 11, 100–107 (2012). source

In the paper

“ROS production in this setting is believed to be as a result of reverse electron transport (RET) at complex I of the electron transport chain.”

In the paper

“In this way succinate, and α-KG, can remodel the epigenome.”

In the paper

“A critical consequence of succinate elevation in response to LPS is the potentiation of inflammatory signalling and in particular IL-1β, in a HIF-1α-dependent manner2.”

What the sources say

• Not checked yetcites [2] Tannahill, G. M. et al. Succinate is an inflammatory signal that induces IL-1β through HIF-1α. Nature 496, 238–242 (2013). source

In the paper

“The finding that hypoxia was capable of inducing IL-1β production in astrocytes in an NF-κB-independent, HIF-1α-dependent, mechanism 28 led to the discovery of a HRE in the IL-1β promoter 2.”

What the sources say

• Not checked yetcites [2] Tannahill, G. M. et al. Succinate is an inflammatory signal that induces IL-1β through HIF-1α. Nature 496, 238–242 (2013). source
• Not checked yetcites [28] Rasola, A., Neckers, L. & Picard, D. Mitochondrial oxidative phosphorylation TRAP(1)ped in tumor cells. Trends Cell Biol. 24, 455–463 (2014). source

In the paper

“itaconate and 4-OI were shown to have a similar thiol reactivity profile”

What the sources say

• Not checked yetcites [59] Okabe, M., Lies, D., Kanamasa, S. & Park, E. Y. Biotechnological production of itaconic acid and its biosynthesis in Aspergillus terreus. Appl. Microbiol. Biotechnol. 84, 597–606 (2009). source

In the paper

“At a molecular level this involves epigenetic modifications, leading to stronger gene transcription upon re-stimulation, as opposed to gene recombination that occurs in the adaptive memory response.”

What the sources say

• Not checked yetcites [35] Peyssonnaux, C. et al. Cutting edge: essential role of hypoxia inducible factor-1α in development of lipopolysaccharide-induced sepsis. J. Immunol. 178, 7516–7519 (2007). source

In the paper

“Inhibition of HIF-1α with ascorbate impaired the training effect induced by β-glucan and decreased TNF-α production in these cells, demonstrating a requirement for HIF-1α in the training effect induced by β-glucan.”

What the sources say

• Not checked yetcites [37] El-Khoury, R. et al. Engineering the alternative oxidase gene to better understand and counteract mitochondrial defects: state of the art and perspectives. Br. J. Pharmacol. 171, 2243–2249 (2014). source

In the paper

“It should be noted that hypoxia and ischemia, as well as decreased oxidative phosphorylation, drive succinate accumulation in the mitochondrial matrix26,27.”

What the sources say

• Not checked yetcites [26] Wu, W. & Zhao, S. Metabolic changes in cancer: beyond the Warburg effect. Acta Biochim. Biophys. Sin. (Shanghai) 45, 18–26 (2013). source
• Not checked yetcites [27] Selak, M. A. et al. Succinate links TCA cycle dysfunction to oncogenesis by inhibiting HIF-α prolyl hydroxylase. Cancer Cell. 7, 77–85 (2005). source

In the paper

“α-KG and succinate can regulate the activity of other members of the α-KGDD family of enzymes, in particular those involved in the regulation of histone and DNA demethylation, the α-KG-dependent Jumonji C-domain containing histone demethylases (JMJDs) and the Ten eleven translocation (TET) family of 5mC hydroxylases, which play a role in DNA demethylation.”

What the sources say

• Not checked yetcites [33] Chouchani, E. T. et al. Ischaemic accumulation of succinate controls reperfusion injury through mitochondrial ROS. Nature 515, 431–435 (2014). source

In the paper

“However, it must also be noted that, compared with malonate, itaconate is a relatively weak competitive inhibitor of SDH47,49, which raised the question as to whether any additional mechanisms could contribute to the anti-inflammatory effects of itaconate.”

What the sources say

• Not checked yetcites [47] Xie, L. et al. First succinyl-proteome profiling of extensively drug-resistant Mycobacterium tuberculosis revealed involvement of succinylation in cellular physiology. J. Proteome Res. 14, 107–119 (2015). source
• Not checked yetcites [49] He, D. et al. Global proteome analyses of lysine acetylation and succinylation reveal the widespread involvement of both modification in metabolism in the embryo of germinating rice seed. J. Proteome Res. 15, 879–890 (2016). source

In the paper

“this effect was independent of its ability to act as an anti-bactericidal agent73.”

What the sources say

• Not checked yetcites [73] Brennan, M. S. et al. Dimethyl fumarate and monoethyl fumarate exhibit differential effects on KEAP1, NRF2 activation, and glutathione depletion in vitro. PLoS One 10, e0120254 (2015). source

In the paper

“Further supporting the hypothesis that itaconate was a thiol reactive metabolite, a significant increase in the levels of the metabolite 2,3-dicarboxypropyl cysteine (itaconate-cysteine adduct), akin to (S)-2-succinocysteine (2SC) a breakdown product of fumarate-mediated protein succination, was observed in LPS-activated BMDMs59.”

What the sources say

• Not checked yetcites [59] Okabe, M., Lies, D., Kanamasa, S. & Park, E. Y. Biotechnological production of itaconic acid and its biosynthesis in Aspergillus terreus. Appl. Microbiol. Biotechnol. 84, 597–606 (2009). source

In the paper

“no differences were observed in IκBξ levels between Irg1-/- and wildtype macrophages stimulated with LPS60.”

What the sources say

• Not checked yetcites [60] Lee, C. G., Jenkins, N. A., Gilbert, D. J., Copeland, N. G. & O’Brien, W. E. Cloning and analysis of gene regulation of a novel LPS-inducible cDNA. Immunogenetics 41, 263–270 (1995). source

In the paper

“These data suggest that itaconate may dampen the immune response of Mtb-infected mice to limit immunopathology.”

In the paper

“an effect shown to be mediated through inhibition of IκBξ the major transcription factor governing secondary transcriptional responses to TLR activation60.”

What the sources say

• Not checked yetcites [60] Lee, C. G., Jenkins, N. A., Gilbert, D. J., Copeland, N. G. & O’Brien, W. E. Cloning and analysis of gene regulation of a novel LPS-inducible cDNA. Immunogenetics 41, 263–270 (1995). source

In the paper

“1EI (an activated Michael acceptor) could also inhibit IκBξ”

What the sources say

• Not checked yetcites [60] Lee, C. G., Jenkins, N. A., Gilbert, D. J., Copeland, N. G. & O’Brien, W. E. Cloning and analysis of gene regulation of a novel LPS-inducible cDNA. Immunogenetics 41, 263–270 (1995). source

In the paper

“an effect that was at least partially dependent on Nrf259.”

What the sources say

• Not checked yetcites [59] Okabe, M., Lies, D., Kanamasa, S. & Park, E. Y. Biotechnological production of itaconic acid and its biosynthesis in Aspergillus terreus. Appl. Microbiol. Biotechnol. 84, 597–606 (2009). source

In the paper

“Bambouskova and colleagues (2018) demonstrated that DI could induce electrophilic stress and Nrf2 in macrophages via depletion of intracellular GSH to form a DI-GSH adduct”

What the sources say

• Not checked yetcites [60] Lee, C. G., Jenkins, N. A., Gilbert, D. J., Copeland, N. G. & O’Brien, W. E. Cloning and analysis of gene regulation of a novel LPS-inducible cDNA. Immunogenetics 41, 263–270 (1995). source

In the paper

“IRG1 suppresses the production of the pro-inflammatory cytokines TNF-α, IL-6 and IFN-β in LPS-tolerised BMDMs67.”

What the sources say

• Not checked yetcites [67] Bambouskova, M. et al. Electrophilic properties of itaconate and derivatives regulate the IκBξ–ATF3 inflammatory axis. Nature 556, 501–504 (2018). source

In the paper

“an effect thought to be a consequence of itaconate-mediated transcriptional regulation of the inflammatory response73.”

What the sources say

• Not checked yetcites [73] Brennan, M. S. et al. Dimethyl fumarate and monoethyl fumarate exhibit differential effects on KEAP1, NRF2 activation, and glutathione depletion in vitro. PLoS One 10, e0120254 (2015). source

In the paper

“Irg1 was shown to specifically impair neutrophil recruitment to the lungs to curtail excessive lung inflammation and pathology”

What the sources say

• Not checked yetcites [73] Brennan, M. S. et al. Dimethyl fumarate and monoethyl fumarate exhibit differential effects on KEAP1, NRF2 activation, and glutathione depletion in vitro. PLoS One 10, e0120254 (2015). source

In the paper

“4-OI was shown to alkylate KEAP1 on several cysteine residues, namely cysteine 151 (C151), a principal redox sensing cysteine important for activation of Nrf259,66.”

What the sources say

• Not checked yetcites [59] Okabe, M., Lies, D., Kanamasa, S. & Park, E. Y. Biotechnological production of itaconic acid and its biosynthesis in Aspergillus terreus. Appl. Microbiol. Biotechnol. 84, 597–606 (2009). source
• Not checked yetcites [66] Williams, J. O., Roche, T. E. & McFadden, B. A. Mechanism of action of isocitrate lyase from Pseudomonas indigofera. Biochemistry 10, 1384–1390 (1971). source

In the paper

“the induction of Irg1 and itaconate was largely dependent on autocrine/paracrine type I interferon signalling59.”

What the sources say

• Not checked yetcites [59] Okabe, M., Lies, D., Kanamasa, S. & Park, E. Y. Biotechnological production of itaconic acid and its biosynthesis in Aspergillus terreus. Appl. Microbiol. Biotechnol. 84, 597–606 (2009). source

In the paper

“Bambouskova and colleagues (2018) who demonstrated a decrease in LPS-induced Nrf2 stabilisation in Irg1-deficient BMDMs”

What the sources say

• Not checked yetcites [60] Lee, C. G., Jenkins, N. A., Gilbert, D. J., Copeland, N. G. & O’Brien, W. E. Cloning and analysis of gene regulation of a novel LPS-inducible cDNA. Immunogenetics 41, 263–270 (1995). source

In the paper

“it also appears to play a major role in embryo implantation in the womb, a process thought to require immunosuppression70–72.”

What the sources say

• Not checked yetcites [70] Ackermann, W. W. & Potter, V. R. Enzyme inhibition in relation to chemotherapy. Proc. Soc. Exp. Biol. Med. 72, 1–9 (1949). source
• Not checked yetcites [71] El Azzouny, M. et al. Dimethyl itaconate is not metabolized into itaconate intracellularly. J. Biol. Chem. 292, 4766–4769 (2017). source
• Not checked yetcites [72] Kobayashi, E. H. et al. Nrf2 suppresses macrophage inflammatory response by blocking proinflammatory cytokine transcription. Nat. Commun. 7, 11624 (2016). source

In the paper

“the ability of 4-OI to induce NQO1 activity remained unaffected59.”

What the sources say

• Not checked yetcites [59] Okabe, M., Lies, D., Kanamasa, S. & Park, E. Y. Biotechnological production of itaconic acid and its biosynthesis in Aspergillus terreus. Appl. Microbiol. Biotechnol. 84, 597–606 (2009). source

In the paper

“the profound levels to which it is produced in macrophages suggest that it is likely to be central to macrophage function.”

In the paper

“4EI (which has similar reactivity to endogenous itaconate) could not inhibit IκBξ unless GSH synthesis was inhibited by buthionine sulfoximine (BSO)60.”

What the sources say

• Not checked yetcites [60] Lee, C. G., Jenkins, N. A., Gilbert, D. J., Copeland, N. G. & O’Brien, W. E. Cloning and analysis of gene regulation of a novel LPS-inducible cDNA. Immunogenetics 41, 263–270 (1995). source

In the paper

“Furthermore, using a quantitative unbiased proteomic screen performed in both LPS (which will drive intracellular itaconate accumulation) and 4-OI-treated macrophages, several metabolic and inflammatory proteins were found to be alkylated representing the first demonstration of this novel post-translational modification (PTM), termed 2,3-dicarboxypropylation59.”

What the sources say

• Not checked yetcites [59] Okabe, M., Lies, D., Kanamasa, S. & Park, E. Y. Biotechnological production of itaconic acid and its biosynthesis in Aspergillus terreus. Appl. Microbiol. Biotechnol. 84, 597–606 (2009). source

In the paper

“pre-treatment of LPS-activated macrophages with 4-OI resulted in a significant attenuation of IFN-β levels and interferon-stimulated genes (ISGs), namely ISG20”

What the sources say

• Not checked yetcites [59] Okabe, M., Lies, D., Kanamasa, S. & Park, E. Y. Biotechnological production of itaconic acid and its biosynthesis in Aspergillus terreus. Appl. Microbiol. Biotechnol. 84, 597–606 (2009). source

In the paper

“Pre-treatment of LPS-activated BMDMs with 4-OI also resulted in a significant attenuation of IL-1β levels”

What the sources say

• Not checked yetcites [59] Okabe, M., Lies, D., Kanamasa, S. & Park, E. Y. Biotechnological production of itaconic acid and its biosynthesis in Aspergillus terreus. Appl. Microbiol. Biotechnol. 84, 597–606 (2009). source

In the paper

“confirming that endogenous itaconate stabilizes Nrf260.”

What the sources say

• Not checked yetcites [60] Lee, C. G., Jenkins, N. A., Gilbert, D. J., Copeland, N. G. & O’Brien, W. E. Cloning and analysis of gene regulation of a novel LPS-inducible cDNA. Immunogenetics 41, 263–270 (1995). source

In the paper

“an effect that was largely abrogated in Nrf2-deficent macrophages59.”

What the sources say

• Not checked yetcites [59] Okabe, M., Lies, D., Kanamasa, S. & Park, E. Y. Biotechnological production of itaconic acid and its biosynthesis in Aspergillus terreus. Appl. Microbiol. Biotechnol. 84, 597–606 (2009). source

In the paper

“IRG1 was also found to be significantly increased in A20-deficient macrophages”

What the sources say

• Not checked yetcites [68] Mills, E. L. et al. Itaconate is an anti-inflammatory metabolite that activates Nrf2 via alkylation of KEAP1. Nature 556, 113–117 (2018). source

In the paper

“Nair and colleagues (2018) convincingly demonstrated an increase in pro-inflammatory cytokine production, including IL-6 and IL-1β, in Mtb-infected Irg1-deficent mice”

What the sources say

• Not checked yetcites [73] Brennan, M. S. et al. Dimethyl fumarate and monoethyl fumarate exhibit differential effects on KEAP1, NRF2 activation, and glutathione depletion in vitro. PLoS One 10, e0120254 (2015). source

In the paper

“Yingke and colleagues (2013) also observed increased IFN-β and IRF3 signaling in LPS-tolerized Irg1-silenced macrophages”

What the sources say

• Not checked yetcites [67] Bambouskova, M. et al. Electrophilic properties of itaconate and derivatives regulate the IκBξ–ATF3 inflammatory axis. Nature 556, 501–504 (2018). source

In the paper

“Nrf2 can also limit LPS-induced inflammatory gene transcription, in a redox-independent manner, through direct ligation of these genes and inhibition of RNA polymerse II recruitment47.”

What the sources say

• Not checked yetcites [47] Xie, L. et al. First succinyl-proteome profiling of extensively drug-resistant Mycobacterium tuberculosis revealed involvement of succinylation in cellular physiology. J. Proteome Res. 14, 107–119 (2015). source

In the paper

“Yingke and colleagues (2013) attributed the effect of IRG1 on cytokine production to ROS-mediated induction of A20”

What the sources say

• Not checked yetcites [67] Bambouskova, M. et al. Electrophilic properties of itaconate and derivatives regulate the IκBξ–ATF3 inflammatory axis. Nature 556, 501–504 (2018). source

In the paper

“pre-treatment of control and LPS-activated macrophages with 4-OI still resulted in a significant increase in Nrf2 and Nrf2 target genes, namely Heme oxygenase 1 (HMOX1)”

What the sources say

• Not checked yetcites [59] Okabe, M., Lies, D., Kanamasa, S. & Park, E. Y. Biotechnological production of itaconic acid and its biosynthesis in Aspergillus terreus. Appl. Microbiol. Biotechnol. 84, 597–606 (2009). source

In the paper

“the ability of DI to induce NQO1 activity (a prototypical Nrf2 target gene) was diminished when pre-incubated with GSH”

What the sources say

• Not checked yetcites [59] Okabe, M., Lies, D., Kanamasa, S. & Park, E. Y. Biotechnological production of itaconic acid and its biosynthesis in Aspergillus terreus. Appl. Microbiol. Biotechnol. 84, 597–606 (2009). source

In the paper

“it is unlikely to have any physiological relevance to this canonical pathway.”

In the paper

“To determine the role of increased fumarate levels on the epigenetic landscape, Arts and colleagues (2016) used the cell permeable fumaric acid ester, monomethyl fumarate (MMF), which was shown to alter histone methylation with similarities to β-glucan induced training97.”

What the sources say

• Not checked yetcites [97] Rustin, P. et al. Inborn errors of the Krebs cycle: a group of unusual mitochondrial diseases in human. Biochim. Biophys. Acta 1361, 185–197 (1997). source

In the paper

“The first insights into the relevance of succination in HRLCC patients was proposed in 2011, when it was shown that fumarate could bind reactive thiol residues and inactivate KEAP1, the negative regulator of the master antioxidant transcription factor Nrf2, leading to a powerful antioxidant response81,82”

What the sources say

• Not checked yetcites [81] Weiss, J. M. et al. Itaconic acid mediates crosstalk between macrophage metabolism and peritoneal tumors. J. Clin. Invest. 128, 3794–3805 (2018). source
• Not checked yetcites [82] Hall, C. J. et al. Immunoresponsive gene 1 augments bactericidal activity of macrophage-lineage cells by regulating β-oxidation-dependent mitochondrial ROS production. Cell. Metab. 18, 265–278 (2013). source

In the paper

“Furthermore, Weiss and colleagues (2018) demonstrated that ROS production in response to itaconate regulates Nrf2”

What the sources say

• Not checked yetcites [75] Li, Y. et al. Immune responsive gene 1 (IRG1) promotes endotoxin tolerance by increasing A20 expression in macrophages through reactive oxygen species. J. Biol. Chem. 288, 16225–16234 (2013). source

In the paper

“Furthermore, IRG1 (and presumably itaconate) levels were also shown to be markedly increased in glioma tissue75.”

What the sources say

• Not checked yetcites [75] Li, Y. et al. Immune responsive gene 1 (IRG1) promotes endotoxin tolerance by increasing A20 expression in macrophages through reactive oxygen species. J. Biol. Chem. 288, 16225–16234 (2013). source

In the paper

“However, in 2002 it was shown that mutations of FH are the cause of Hereditary Leiomyomatosis and Renal Cell Cancer (HLRCC), a cancer predisposition syndrome characterised by benign tumours of the smooth muscle of skin and uterus, and a very aggressive form of renal cancer78.”

What the sources say

• Not checked yetcites [78] Cheon, Y. P., Xu, X., Bagchi, M. K. & Bagchi, I. C. Immune-responsive gene 1 is a novel target of progesterone receptor and plays a critical role during implantation in the mouse. Endocrinology 144, 5623–5630 (2003). source

In the paper

“Outside of trained immunity, fumarate has previously been reported to accumulate in LPS-activated macrophages1,13.”

What the sources say

• Not checked yetcites [1] Jha, A. K. et al. Network integration of parallel metabolic and transcriptional data reveals metabolic modules that regulate macrophage polarization. Immunity 42, 419–430 (2015). source
• Not checked yetcites [13] van Diepen, J. A. et al. SUCNR1-mediated chemotaxis of macrophages aggravates obesity-induced inflammation and diabetes. Diabetologia 60, 1304–1313 (2017). source

In the paper

“Furthermore, treatment with MMF augmented TNF and IL-6 secretion in β-glucan-trained macrophages stimulated with LPS97.”

What the sources say

• Not checked yetcites [97] Rustin, P. et al. Inborn errors of the Krebs cycle: a group of unusual mitochondrial diseases in human. Biochim. Biophys. Acta 1361, 185–197 (1997). source

In the paper

“Importantly, Arts and colleagues (2016) demonstrated that the accumulation of fumarate in β-glucan-treated monocytes was essential for trained immunity by enhancing cytokine production upon re-stimulation with LPS97.”

What the sources say

• Not checked yetcites [97] Rustin, P. et al. Inborn errors of the Krebs cycle: a group of unusual mitochondrial diseases in human. Biochim. Biophys. Acta 1361, 185–197 (1997). source

In the paper

“For instance, accumulated fumarate can bind and inactivate reactive thiol residues of proteins and peptides in a process called succination, a protein modification originally described in diabetes80.”

What the sources say

• Not checked yetcites [80] Sherwin, J. R. et al. Identification of genes regulated by leukemia-inhibitory factor in the mouse uterus at the time of implantation. Mol. Endocrinol. 18, 2185–2195 (2004). source

In the paper

“Itaconate was shown to boost OXPHOS and mtROS generation and subsequent MAPK activation in tumour-infiltrating macrophages (Figure 3).”

What the sources say

• Not checked yetcites [74] Saito, R. et al. Characterizations of three major cysteine sensors of Keap1 in stress response. Mol. Cell Biol. 36, 271–284 (2015). source

In the paper

“By employing a proteomic approach the authors discovered a range of proteins which regulate T cell function that are sensitive to covalent modification by DMF including protein kinase C θ (PKCθ).”

What the sources say

• Not checked yetcites [49] He, D. et al. Global proteome analyses of lysine acetylation and succinylation reveal the widespread involvement of both modification in metabolism in the embryo of germinating rice seed. J. Proteome Res. 15, 879–890 (2016). source

In the paper

“The defining biochemical feature of FH loss is the accumulation of fumarate, which has been implicated in tumorigenesis, acting as an oncometabolite79.”

What the sources say

• Not checked yetcites [79] Luan, H. H. & Medzhitov, R. Food fight: role of itaconate and other metabolites in antimicrobial defense. Cell. Metab. 24, 379–387 (2016). source

In the paper

“Using an integrated high-throughput transcriptional metabolic profiling and analysis pipeline (CoMBI-T), Jha and colleagues (2015) described the induction of an inflammatory argininosuccinate shunt, a metabolic pathway that links the Krebs cycle to the Urea cycle1.”

What the sources say

• Not checked yetcites [1] Jha, A. K. et al. Network integration of parallel metabolic and transcriptional data reveals metabolic modules that regulate macrophage polarization. Immunity 42, 419–430 (2015). source

In the paper

“Importantly, inhibition of aerobic glycolysis by the specific GAPDH inhibitor heptelidic acid (HA) and 2-deoxyglucose (2-DG) recapitulated the immunomodulatory effects of DMF in vitro, while in vivo administration of HA inhibited the development of experimental autoimmune encephalomyelitis (EAE), a murine model of MS99.”

What the sources say

• Not checked yetcites [99] Blatnik, M., Thorpe, S. R. & Baynes, J. W. Succination of proteins by fumarate: mechanism of inactivation of glyceraldehyde-3-phosphate dehydrogenase in diabetes. Ann. NY Acad. Sci. 1126, 272–275 (2008). source

In the paper

“As such, itaconate serves as another example of crosstalk between macrophages and tumours in the context of metabolic reprogramming.”

In the paper

“Two pro-inflammatory T cell subsets implicated in the pathogenesis of MS, namely TH1 and TH17 cells, rely heavily on aerobic glycolysis and treatment with DMF or MMF inhibited their development in vitro, as previously reported99,101,102, 49.”

What the sources say

• Not checked yetcites [99] Blatnik, M., Thorpe, S. R. & Baynes, J. W. Succination of proteins by fumarate: mechanism of inactivation of glyceraldehyde-3-phosphate dehydrogenase in diabetes. Ann. NY Acad. Sci. 1126, 272–275 (2008). source
• Not checked yetcites [101] Ooi, A. et al. An antioxidant response phenotype shared between hereditary and sporadic type 2 papillary renal cell carcinoma. Cancer Cell 20, 511–523 (2011). source
• Not checked yetcites [102] Sullivan, L. B. et al. The proto-oncometabolite fumarate binds glutathione to amplify ROS-dependent signaling. Mol. Cell 51, 236–248 (2013). source

In the paper

“Two pro-inflammatory T cell subsets implicated in the pathogenesis of MS, namely TH1 and TH17 cells, rely heavily on aerobic glycolysis and treatment with DMF or MMF inhibited their development in vitro, as previously reported99,101,102, 49.”

What the sources say

• Not checked yetcites [99] Blatnik, M., Thorpe, S. R. & Baynes, J. W. Succination of proteins by fumarate: mechanism of inactivation of glyceraldehyde-3-phosphate dehydrogenase in diabetes. Ann. NY Acad. Sci. 1126, 272–275 (2008). source
• Not checked yetcites [101] Ooi, A. et al. An antioxidant response phenotype shared between hereditary and sporadic type 2 papillary renal cell carcinoma. Cancer Cell 20, 511–523 (2011). source
• Not checked yetcites [102] Sullivan, L. B. et al. The proto-oncometabolite fumarate binds glutathione to amplify ROS-dependent signaling. Mol. Cell 51, 236–248 (2013). source

In the paper

“Intriguingly, endogenous fumarate was also found to succinate GAPDH in both mouse and human macrophages, suggesting that elevated fumarate levels may act as an endogenous anti-inflammatory signal to limit inflammation, however, the precise role of fumarate accumulation remains an open question to be explored.”

What the sources say

• Not checked yetcites [99] Blatnik, M., Thorpe, S. R. & Baynes, J. W. Succination of proteins by fumarate: mechanism of inactivation of glyceraldehyde-3-phosphate dehydrogenase in diabetes. Ann. NY Acad. Sci. 1126, 272–275 (2008). source

In the paper

“Furthermore, increased fumarate levels were shown to be driven by enhanced shunting of glutamine into the TCA cycle, otherwise referred to as glutamine anaplerosis, as ascertained by a combination of biochemical techniques and the use of the glutaminase inhibitor, BPTES97.”

What the sources say

• Not checked yetcites [97] Rustin, P. et al. Inborn errors of the Krebs cycle: a group of unusual mitochondrial diseases in human. Biochim. Biophys. Acta 1361, 185–197 (1997). source

In the paper

“Induction of this pathway occurred via an increase in the expression of argininosuccinate synthase (Ass1), which catalyses the formation of argininosuccinate from aspartate, citrulline and ATP98.”

What the sources say

• Not checked yetcites [1] Jha, A. K. et al. Network integration of parallel metabolic and transcriptional data reveals metabolic modules that regulate macrophage polarization. Immunity 42, 419–430 (2015). source

In the paper

“Succination is a hallmark of FH-deficient tumours and an antibody against succinate protein has been proposed as a diagnostic marker for HLRCC89.”

What the sources say

• Not checked yetcites [89] Delage, B. et al. Arginine deprivation and argininosuccinate synthetase expression in the treatment of cancer. Int. J. Cancer 126, 2762–2772 (2010). source

In the paper

“It has also recently been shown that FH loss in renal cancer cells leads to increased DNA damage and resistance to ionising radiation (IR), due to a fumarate-dependent inhibition of mitotic entry after IR, even in the presence of unrepaired damage179.”

What the sources say

• Not checked yetcites [179] Zhang, J. et al. accumulation of succinate in cardiac ischemia primarily occurs via canonical Krebs cycle activity. Cell Rep. 23, 2617–2628 (2018). source

In the paper

“Of note, fumarate-dependent oxidative stress was shown to drive renal cells to senescence in an FH-deficient mouse model, and its bypass by the co-ablation of p21 increased malignant transformation in the kidneys503.”

What the sources say

• Not checked yetcites [503]

In the paper

“In addition to CD4+ T cells, an unexpected role for L-2-HG in the promotion of tumour killing acting via CD8+ T cells, cytotoxic T lymphocytes important for anti-tumour immunity, has emerged149.”

What the sources say

• Not checked yetcites [149] Flavahan, W. A. et al. Insulator dysfunction and oncogene activation in IDH mutant gliomas. Nature 529, 110–114 (2016). source

In the paper

“Accordingly, fumarate causes HIF stabilisation, even under normoxic conditions, i.e. pseudohypoxia, a hallmark of FH-deficient tumours93.”

What the sources say

• Not checked yetcites [93] Brück, J., Dringen, R., Amasuno, A., Pau-Charles, I. & Ghoreschi, K. A review of the mechanisms of action of dimethylfumarate in the treatment of psoriasis. Exp. Dermatol. 27, 611–624 (2018). source

In the paper

“A third 2HGA that arises from germline mutations in the mitochondrial citrate carrier SLC25A1, in which both enantiomers accumulate, has also been discovered.”

What the sources say

• Not checked yetcites [111] Yang, M., Soga, T., Pollard, P. J. & Adam, J. The emerging role of fumarate as an oncometabolite. Front. Oncol. 2, 85 (2012). source

In the paper

“Of note, fumarate-dependent oxidative stress was shown to drive renal cells to senescence in an FH-deficient mouse model, and its bypass by the co-ablation of p21 increased malignant transformation in the kidneys503.”

What the sources say

• Not checked yetcites [503]

In the paper

“Mechanistically, D-2-HG production was driven by the conversion of glutamate to α-KG by the aspartate aminotransferase GOT1.”

What the sources say

• Not checked yetcites [143] Yan, H. et al. IDH1 and IDH2 mutations in gliomas. N. Engl. J. Med. 360, 765–773 (2009). source

In the paper

“Of note, FH-deficient renal cancers are characterised by a distinct DNA hypermethylation phenotype, which also affects the tumour suppressor CDK2NA85”

What the sources say

• Not checked yetcites [85] Frezza, C. Mitochondrial metabolites: undercover signalling molecules. Interface Focus 7, 20160100 (2017). source

In the paper

“and also iron-responsive element binding protein (IRP)2, promting the transcription of transferrin87.”

What the sources say

• Not checked yetcites [87] Tomlinson, I. P. et al. Germline mutations in FH predispose to dominantly inherited uterine fibroids, skin leiomyomata and papillary renal cell cancer. Nat. Genet. 30, 406–410 (2002). source

In the paper

“Succination is a hallmark of FH-deficient tumours and an antibody against succinate protein has been proposed as a diagnostic marker for HLRCC89.”

What the sources say

• Not checked yetcites [89] Delage, B. et al. Arginine deprivation and argininosuccinate synthetase expression in the treatment of cancer. Int. J. Cancer 126, 2762–2772 (2010). source

In the paper

“In recent years, two landmark genomic studies carried out in human glioma and acute myeloid leukaemia (AML) found mutations in IDH1/2 and it is now appreciated that these enzymes (which drive elevated production of D-2-HG) are the most frequently mutated metabolic genes in human cancer112-114.”

What the sources say

• Not checked yetcites [112] Sciacovelli, M. et al. Fumarate is an epigenetic modifier that elicits epithelial-to-mesenchymal transition. Nature 537, 544–547 (2016). source
• Not checked yetcites [113] Brabletz, T., Kalluri, R., Nieto, M. A. & Weinberg, R. A. EMT in cancer. Nat. Rev. Cancer 18, 128–134 (2018). source
• Not checked yetcites [114] Brat, D. J. et al. Comprehensive, integrative genomic analysis of diffuse lower-grade gliomas. N. Engl. J. Med. 372, 2481–2498 (2015). source

In the paper

“Interestingly, Xu and colleagues (2017) observed increased levels in of D-2-HG in TH17 cells, when compared to iTreg cells143.”

What the sources say

• Not checked yetcites [143] Yan, H. et al. IDH1 and IDH2 mutations in gliomas. N. Engl. J. Med. 360, 765–773 (2009). source

In the paper

“It has also been shown that fumarate accumulation leads to the inhibition of TET-dependent DNA demethylation of a class of antimetastatic miRNAs, the miR200 family, promoting an EMT95”

What the sources say

• Not checked yetcites [95] Zheng, L. et al. Fumarate induces redox-dependent senescence by modifying glutathione metabolism. Nat. Commun. 6, 6001 (2015). source

In the paper

“Fumarate was shown to cause succination of the mitochondrial aconitase, ACO2, leading to an additional truncation of the TCA cycle86”

What the sources say

• Not checked yetcites [86] Arts, R. J. et al. Glutaminolysis and fumarate accumulation integrate immunometabolic and epigenetic programs in trained immunity. Cell. Metab. 24, 807–819 (2016). source