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Immunoresponsive Gene 1 and Itaconate Inhibit Succinate Dehydrogenase to Modulate Intracellular Succinate Levels
Open accessAbstract
Metabolic reprogramming is emerging as a hallmark of the innate immune response, and the dynamic control of metabolites such as succinate serves to facilitate the execution of inflammatory responses in macrophages and other immune cells. Immunoresponsive gene 1 (Irg1) expression is induced by inflammatory stimuli, and its enzyme product cis-aconitate decarboxylase catalyzes the production of itaconate from the tricarboxylic acid cycle. Here we identify an immunometabolic regulatory pathway that links Irg1 and itaconate production to the succinate accumulation that occurs in the context of innate immune responses. Itaconate levels and Irg1 expression correlate strongly with succinate during LPS exposure in macrophages and non-immune cells. We demonstrate that itaconate acts as an endogenous succinate dehydrogenase inhibitor to cause succinate accumulation. Loss of itaconate production in activated macrophages from Irg1(-/-) mice decreases the accumulation of succinate in response to LPS exposure. This metabolic network links the innate immune response and tricarboxylic acid metabolism to function of the electron transport chain.
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TL;DR
This paper identifies an immunometabolic pathway in which Irg1/CAD-derived itaconate inhibits succinate dehydrogenase (SDH), causing succinate accumulation during LPS exposure. Loss of Irg1 in macrophages reduces itaconate and succinate, linking innate immune metabolism to TCA cycle and electron transport chain function.
Key findings
- In LPS-activated RAW 264.7 macrophages, itaconate and succinate levels showed similar trends over 6 h, unlike citrate, α-ketoglutarate, fumarate, and malate; basal oxygen consumption rate remained unchanged.
- Exogenous itaconate (0–25 mM, 6 h) increased intracellular itaconate dose-dependently and correlated strongly with succinate in resting and LPS-activated RAW 264.7 macrophages (r = 0.99) and in A549 cells (r = 0.99), while other TCA intermediates correlated poorly or negatively.
- Itaconate was not metabolized to succinate: [1-13C]glutamine labeling produced ~65% M1 itaconate but no succinate labeling, and prelabeling with [U-13C6]glucose/[U-13C5]glutamine left succinate labeling ~90% after unlabeled itaconate.
- Itaconate inhibited SDH/complex II: dose-dependent OCR inhibition in permeabilized RAW 264.7 macrophages and BMDMs with succinate, >75% reduction with 10 mM itaconate plus succinate/rotenone, and no effect on complex I or IV substrates; Irg1 KO BMDMs failed to produce itaconate and had significantly lower succinate than WT after LPS, while Irg1 overexpression in A549 cells increased succinate.
Methods
- Cell models and treatments: RAW 264.7 macrophages, A549 lung adenocarcinoma cells, and primary BMDMs from C57BL/6J and Irg1 KO mice; LPS at 10 ng/ml; itaconate at 5, 10, and 25 mM for 6 h; A549 cells transfected with pCMV6-Irg1 or empty vector.
- Metabolite and isotope analysis: GC-MS quantification of itaconate and TCA intermediates using external standard curves; isotopic labeling with [1-13C]glutamine, [U-13C6]glucose, and [U-13C5]glutamine; mass isotopomer distributions corrected for natural abundance.
- Respiration and statistics: Seahorse XF96 oxygen consumption measurements in intact and permeabilized cells (perfringolysin O) with succinate/rotenone, glutamate/malate, pyruvate/malate, or ascorbate/TMPD/antimycin A; Pearson correlation and two-tailed Student’s t tests.
Limitations
- Stated: The authors note variability in succinate accumulation between RAW 264.7 macrophages and BMDMs, likely due to cell, medium, and LPS variability; they also state that the physiological role of itaconate and Irg1 requires further investigation, particularly in macrophage development and differentiation.
- Stated: It is not known whether downstream inflammatory responses are mediated directly by succinate or itaconate or through other mechanisms; no mammalian mitochondrial or plasma membrane itaconate transporters have been described, and other succinate-producing pathways (GABA shunt, glutaminolysis) could compensate.
- Evident from the text: Most mechanistic experiments use cultured cells and exogenous itaconate up to 25 mM, whereas endogenous macrophage itaconate is cited as up to 8 mM; no in vivo inflammation or disease model is presented.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“We observed a dose depen- dent inhibition of OCRs by itaconate in RAW 264.7 macrophages (Fig. 5a) and BMDMs (Fig. 5b)”
§ Immunoresponsive Gene 1 and Itaconate Inhibit Succinate Dehydrogenase to Modulate Intracellular Succinate Levels * > Itaconate and Irg1-induced Succinate Accumulation Is Not
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Itaconate also failed to impact this complex IV-mediated respiration.”
§ Immunoresponsive Gene 1 and Itaconate Inhibit Succinate Dehydrogenase to Modulate Intracellular Succinate Levels * > Itaconate and Irg1-induced Succinate Accumulation Is Not
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Notably, basal oxygen consumption rates (OCR) remained unchanged compared with resting macrophages (Fig. 1b).”
§ Immunoresponsive Gene 1 and Itaconate Inhibit Succinate Dehydrogenase to Modulate Intracellular Succinate Levels * > Succinate and Itaconate Accumulate in LPS-activated RAW 264.7 Macrophages-To better understand the relationship between
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“However, medium itaconate levels were not appreciably affected (Fig. 2g).”
§ Immunoresponsive Gene 1 and Itaconate Inhibit Succinate Dehydrogenase to Modulate Intracellular Succinate Levels * > Succinate and Itaconate Accumulate in LPS-activated RAW 264.7 Macrophages-To better understand the relationship between
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Because labeling of succinate after exposure to exogenous, unlabeled itaconate was unchanged (even in the physi-ological concentration used here) (Fig. 4d)”
§ Immunoresponsive Gene 1 and Itaconate Inhibit Succinate Dehydrogenase to Modulate Intracellular Succinate Levels * > Itaconate and Irg1-induced Succinate Accumulation Is Not
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“we observed that intracellular itaconate levels correlated strongly with succinate levels in resting (r ϭ 0.99) as well as LPS-activated macrophages (r ϭ 0.99)”
§ Immunoresponsive Gene 1 and Itaconate Inhibit Succinate Dehydrogenase to Modulate Intracellular Succinate Levels * > Succinate and Itaconate Accumulate in LPS-activated RAW 264.7 Macrophages-To better understand the relationship between
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Intriguingly, the levels of itaconate and succinate exhibited similar trends upon activation, in contrast to the dynamics of citrate, ␣-ketoglutarate, fumarate, and malate (Fig. 1a)”
§ Immunoresponsive Gene 1 and Itaconate Inhibit Succinate Dehydrogenase to Modulate Intracellular Succinate Levels * > Succinate and Itaconate Accumulate in LPS-activated RAW 264.7 Macrophages-To better understand the relationship between
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“the levels of other TCA intermediates, including citrate, ␣-ketoglutarate, fumarate, and malate correlated poorly (or in some cases negatively) with intracellular itaconate levels (Fig. 2, a, b, d, and f).”
§ Immunoresponsive Gene 1 and Itaconate Inhibit Succinate Dehydrogenase to Modulate Intracellular Succinate Levels * > Succinate and Itaconate Accumulate in LPS-activated RAW 264.7 Macrophages-To better understand the relationship between
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Loss of itaconate production in activated macrophages from Irg1 ؊/؊ mice decreases the accumulation of succinate in response to LPS exposure.”
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“oxygen consumption rates in permeabilized cells in the presence of either pyruvate with malate or glutamate with malate, substrates that drive respiration via complex I activity, were not affected by itaconate supplementation.”
§ Immunoresponsive Gene 1 and Itaconate Inhibit Succinate Dehydrogenase to Modulate Intracellular Succinate Levels * > Itaconate and Irg1-induced Succinate Accumulation Is Not
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Exposure to exogenous itaconate resulted in increasing intracellular itaconate levels in a dose-dependent manner (Fig. 2c)”
§ Immunoresponsive Gene 1 and Itaconate Inhibit Succinate Dehydrogenase to Modulate Intracellular Succinate Levels * > Succinate and Itaconate Accumulate in LPS-activated RAW 264.7 Macrophages-To better understand the relationship between
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“When the succinate concentration was lowered to 2.5 mM, itaconate had a greater proportional inhibitory effect.”
§ Immunoresponsive Gene 1 and Itaconate Inhibit Succinate Dehydrogenase to Modulate Intracellular Succinate Levels * > Itaconate and Irg1-induced Succinate Accumulation Is Not
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Itaconate levels and Irg1 expression correlate strongly with succinate during LPS exposure in macrophages and non-immune cells.”
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Itaconate was only produced at detectable levels in pCMV6 Irg1-overexpressing A549 cells (pmIrg1) compared with vector (pCMV6) controls (Fig. 3c).”
§ Immunoresponsive Gene 1 and Itaconate Inhibit Succinate Dehydrogenase to Modulate Intracellular Succinate Levels * > Itaconate and Irg1-induced Succinate Accumulation Is Not
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“itaconate supplementation significantly reduced respiration (Ͼ75%) in the presence of succinate (SDH substrate) and rotenone (complex I inhibitor).”
§ Immunoresponsive Gene 1 and Itaconate Inhibit Succinate Dehydrogenase to Modulate Intracellular Succinate Levels * > Itaconate and Irg1-induced Succinate Accumulation Is Not
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“pmIrg1 cells accumulated significantly higher amounts of succinate compared with pCMV6 controls (Fig. 3d)”
§ Immunoresponsive Gene 1 and Itaconate Inhibit Succinate Dehydrogenase to Modulate Intracellular Succinate Levels * > Itaconate and Irg1-induced Succinate Accumulation Is Not
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Substrate-specific respirometry studies in permeabilized cells confirmed that itaconate acts as an SDH inhibitor.”
- Also stated in: § Discussion · plain
“Itaconate inhibits SDH.”
- Also stated in: § Loss of Irg1 Influences Succinate Levels in · plain
“Taken together, our data highlight a mechanistic function of itaconate whereby this metabolite acts as a SDH inhibitor to influence TCA cycle metabolism by driving succinate accumulation (Fig. 7).”
§ Immunoresponsive Gene 1 and Itaconate Inhibit Succinate Dehydrogenase to Modulate Intracellular Succinate Levels * > Discussion
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Also stated in: § Discussion · plain
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“FIGURE 2. Exogenous itaconate drives succinate accumulation.”
§ Immunoresponsive Gene 1 and Itaconate Inhibit Succinate Dehydrogenase to Modulate Intracellular Succinate Levels * > Discussion
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesThe paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Finally, modulation of endogenous itaconate production in LPS-activated primary macrophages from Irg1 KO mice reduces succinate levels.”
§ Immunoresponsive Gene 1 and Itaconate Inhibit Succinate Dehydrogenase to Modulate Intracellular Succinate Levels * > Discussion
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Notably, succinate concentrations in stimulated BMDMs from Irg1 KO mice were significantly lower than those quantified in BMDMs from WT mice, suggesting that CAD-derived itaconate influences succinate accumulation in LPS-induced macrophages (Fig. 6c).”
§ Immunoresponsive Gene 1 and Itaconate Inhibit Succinate Dehydrogenase to Modulate Intracellular Succinate Levels * > Loss of Irg1 Influences Succinate Levels in
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“We confirmed that Irg1 mRNA was not expressed in LPS-stimulated KO-derived BMDMs (Fig. 6a).”
§ Immunoresponsive Gene 1 and Itaconate Inhibit Succinate Dehydrogenase to Modulate Intracellular Succinate Levels * > Loss of Irg1 Influences Succinate Levels in
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“FIGURE 3. Itaconate-and Irg1-induced succinate accumulation is not specific to immune cells.”
§ Immunoresponsive Gene 1 and Itaconate Inhibit Succinate Dehydrogenase to Modulate Intracellular Succinate Levels * > Discussion
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“FIGURE 1. Succinate and itaconate accumulate in LPS-activated murine RAW 264.7 macrophages.”
§ Immunoresponsive Gene 1 and Itaconate Inhibit Succinate Dehydrogenase to Modulate Intracellular Succinate Levels * > Discussion
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Consistent with this result, LPS-stimulated BMDMs from Irg1 KO mice failed to produce significant levels of itaconate (Fig. 6b).”
§ Immunoresponsive Gene 1 and Itaconate Inhibit Succinate Dehydrogenase to Modulate Intracellular Succinate Levels * > Loss of Irg1 Influences Succinate Levels in
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“However, we consistently observed increased succinate downstream of itaconate production or administration in a variety of cell types.”
§ Immunoresponsive Gene 1 and Itaconate Inhibit Succinate Dehydrogenase to Modulate Intracellular Succinate Levels * > Discussion
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In the cells studied, exogenous and endogenous, CAD-produced itaconate strongly correlated with succinate accumulation.”
§ Immunoresponsive Gene 1 and Itaconate Inhibit Succinate Dehydrogenase to Modulate Intracellular Succinate Levels * > Discussion
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIn the paper
“In mammals, itaconate is pro-duced through the decarboxylation of the TCA cycle intermediate cis-aconitate, which is catalyzed by mammalian cis-aconitate decarboxylase (CAD, also known as immune-responsive gene 1 (IRG1) protein) encoded by immunoresponsive gene 1 (IRG1) (20).”
What the sources say
- Not checked yetcites [20] Michelucci, 2013, Immune-responsive gene 1 protein links metabolism to immunity by catalyzing itaconic acid production, Proc. Natl. Acad. Sci. U.S.A source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesNone of the sources cited for this claim have been checked yet.
In the paper
“Succinate inhibits the hydroxylation of HIF-1␣ by EGLN1, resulting in pseudohypoxic HIF-1␣ stabilization under normoxic conditions (10 -12).”
What the sources say
- Not checked yetcites [10] Selak, 2005, Succinate links TCA cycle dysfunction to oncogenesis by inhibiting HIF-alpha prolyl hydroxylase, Cancer Cell source
- Not checked yetcites [11] Epstein, 2001, C. elegans EGL-9 and mammalian homologs define a family of dioxygenases that regulate HIF by prolyl hydroxylation, Cell source
- Not checked yetcites [12] Losman, 2013, What a difference a hydroxyl makes: mutant IDH, (R)-2-hydroxyglutarate, and cancer, Genes Dev source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Collectively, these observations provide strong evidence that itaconate functions as metabolic trigger to modulate succinate levels.”
§ Immunoresponsive Gene 1 and Itaconate Inhibit Succinate Dehydrogenase to Modulate Intracellular Succinate Levels * > Itaconate and Irg1-induced Succinate Accumulation Is Not
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“indicating that cells have the capacity to take up itaconate from medium.”
§ Immunoresponsive Gene 1 and Itaconate Inhibit Succinate Dehydrogenase to Modulate Intracellular Succinate Levels * > Succinate and Itaconate Accumulate in LPS-activated RAW 264.7 Macrophages-To better understand the relationship between
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“indicating that ectopic expression of CAD alone is sufficient to impact succinate levels.”
§ Immunoresponsive Gene 1 and Itaconate Inhibit Succinate Dehydrogenase to Modulate Intracellular Succinate Levels * > Itaconate and Irg1-induced Succinate Accumulation Is Not
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Together, these data provide evidence that itaconate contributes to succinate accumulation in macrophages by acting as an endogenous SDH inhibitor.”
§ Immunoresponsive Gene 1 and Itaconate Inhibit Succinate Dehydrogenase to Modulate Intracellular Succinate Levels * > Itaconate and Irg1-induced Succinate Accumulation Is Not
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“these data therefore confirm that itaconate is not metabolized to succinate in these mammalian cells.”
§ Immunoresponsive Gene 1 and Itaconate Inhibit Succinate Dehydrogenase to Modulate Intracellular Succinate Levels * > Itaconate and Irg1-induced Succinate Accumulation Is Not
Load-bearingStrength:boosted· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIn the paper
“Increased succinate levels in macrophages are important mediators of the inflammatory response, linking metabolism to innate immunity.”
What the sources say
- Not checked yetcites [9] Tannahill, 2013, Succinate is an inflammatory signal that induces IL-1β through HIF-1α, Nature source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIn the paper
“succinate acts as a regulatory signal enhancing Il-1 expression through stabilization of HIF-1␣, which, in turn, influences the function of various other metabolic pathways (9).”
What the sources say
- Not checked yetcites [9] Tannahill, 2013, Succinate is an inflammatory signal that induces IL-1β through HIF-1α, Nature source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIn the paper
“they suggest that itaconate-mediated succinate accumulation occurs even in the absence of an active inflammatory signaling cascade.”
§ Immunoresponsive Gene 1 and Itaconate Inhibit Succinate Dehydrogenase to Modulate Intracellular Succinate Levels * > Itaconate and Irg1-induced Succinate Accumulation Is Not
What the sources say
- Not checked yetcites [20] Michelucci, 2013, Immune-responsive gene 1 protein links metabolism to immunity by catalyzing itaconic acid production, Proc. Natl. Acad. Sci. U.S.A source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“We demonstrate that itaconate acts as an endogenous succinate dehydrogenase inhibitor to cause succinate accumulation.”
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesNone of the sources cited for this claim have been checked yet.
In the paper
“Itaconate exhibits an antibiotic function (20) via inhibition of isocitrate lyase, a key enzyme of the glyoxylate shunt needed by many bacteria to survive during infection (21)(22)(23).”
What the sources say
- Not checked yetcites [20] Michelucci, 2013, Immune-responsive gene 1 protein links metabolism to immunity by catalyzing itaconic acid production, Proc. Natl. Acad. Sci. U.S.A source
- Not checked yetcites [21] Patel, 1978, Caenorhabditis elegans and Ascaris suum: inhibition of isocitrate lyase by itaconate, Exp. Parasitol. source
- Not checked yetcites [22] Williams, 1971, Mechanism of action of isocitrate lyase from Pseudomonas indigofera, Biochemistry source
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIn the paper
“Mammalian CAD is localized to mitochondria in murine macrophages (38)”
§ Immunoresponsive Gene 1 and Itaconate Inhibit Succinate Dehydrogenase to Modulate Intracellular Succinate Levels * > Itaconate and Irg1-induced Succinate Accumulation Is Not
What the sources say
- Not checked yetcites [38] Degrandi, 2009, The proinflammatory cytokine-induced IRG1 protein associates with mitochondria, J. Interferon Cytokine Res source
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIn the paper
“because A549 cells do not express IRG1 (20)”
§ Immunoresponsive Gene 1 and Itaconate Inhibit Succinate Dehydrogenase to Modulate Intracellular Succinate Levels * > Itaconate and Irg1-induced Succinate Accumulation Is Not
What the sources say
- Not checked yetcites [20] Michelucci, 2013, Immune-responsive gene 1 protein links metabolism to immunity by catalyzing itaconic acid production, Proc. Natl. Acad. Sci. U.S.A source
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“This metabolic network links the innate immune response and tricarboxylic acid metabolism to function of the electron transport chain.”
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“suggesting a regulatory role of itaconate for SDH activity.”
§ Immunoresponsive Gene 1 and Itaconate Inhibit Succinate Dehydrogenase to Modulate Intracellular Succinate Levels * > Itaconate and Irg1-induced Succinate Accumulation Is Not
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“suggesting that itaconate and succinate (or the enzymes metabolizing them) are regulated in a coordinated manner.”
§ Immunoresponsive Gene 1 and Itaconate Inhibit Succinate Dehydrogenase to Modulate Intracellular Succinate Levels * > Succinate and Itaconate Accumulate in LPS-activated RAW 264.7 Macrophages-To better understand the relationship between
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIn the paper
“LPS-activated murine macrophages produced up to 8 mM intracellular itaconate (20)”
What the sources say
- Not checked yetcites [20] Michelucci, 2013, Immune-responsive gene 1 protein links metabolism to immunity by catalyzing itaconic acid production, Proc. Natl. Acad. Sci. U.S.A source
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“indicating that the mechanism through which itaconate acts is independent of other inflammatory signaling events.”
§ Immunoresponsive Gene 1 and Itaconate Inhibit Succinate Dehydrogenase to Modulate Intracellular Succinate Levels * > Succinate and Itaconate Accumulate in LPS-activated RAW 264.7 Macrophages-To better understand the relationship between
Load-bearingStrength:hedged· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIn the paper
“Recently, synthesis of the antimicrobial metabolite itaconate was identified in mammalian immune cells as being selectively up-regulated under proinflammatory conditions (19).”
What the sources say
- Not checked yetcites [19] Strelko, 2011, Itaconic acid is a mammalian metabolite induced during macrophage activation, J. Am. Chem. Soc. source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesNone of the sources cited for this claim have been checked yet.
In the paper
“our data suggest that itaconate acts as a competitive SDH inhibitor in immune cells”
§ Immunoresponsive Gene 1 and Itaconate Inhibit Succinate Dehydrogenase to Modulate Intracellular Succinate Levels * > Itaconate and Irg1-induced Succinate Accumulation Is Not
What the sources say
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Our results suggest that Irg1mediated itaconate production may influence downstream inflammatory responses in macrophages (e.g.expression of Il-1 or associated inflammatory genes).”
§ Immunoresponsive Gene 1 and Itaconate Inhibit Succinate Dehydrogenase to Modulate Intracellular Succinate Levels * > Discussion
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Here we have demonstrated an important function of itaconate; it acts as a key regulatory metabolite to modulate TCA metabolism and succinate levels.”
§ Immunoresponsive Gene 1 and Itaconate Inhibit Succinate Dehydrogenase to Modulate Intracellular Succinate Levels * > Discussion
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Notably, succinate concentrations in stimulated BMDMs from Irg1 KO mice were significantly lower than those quantified in BMDMs from WT mice, suggesting that CAD-derived itaconate influences succinate accumulation in LPS-induced macrophages (Fig. 6c).”
§ Immunoresponsive Gene 1 and Itaconate Inhibit Succinate Dehydrogenase to Modulate Intracellular Succinate Levels * > Loss of Irg1 Influences Succinate Levels in
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Rests on an assumption: The Irg1 KO mouse model specifically abolishes itaconate production without other metabolic adaptations that affect succinate levels.
In the paper
“Succinate accumulation plays important roles during inflammation so that it contributes to the induction of Il-1 expression via HIF-1␣ stabilization (9).”
§ Immunoresponsive Gene 1 and Itaconate Inhibit Succinate Dehydrogenase to Modulate Intracellular Succinate Levels * > Discussion
What the sources say
- Not checked yetcites [9] Tannahill, 2013, Succinate is an inflammatory signal that induces IL-1β through HIF-1α, Nature source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Thus, itaconate alters mitochondrial metabolism to influence succinate accumulation in macrophages (Fig. 7).”
§ Immunoresponsive Gene 1 and Itaconate Inhibit Succinate Dehydrogenase to Modulate Intracellular Succinate Levels * > Discussion
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Rests on an assumption: The effects of exogenous itaconate on succinate accumulation reflect the physiological role of endogenous itaconate.
- Rests on an assumption: The cell models used are representative of macrophages in vivo for conclusions about immune cell metabolism.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“We have now identified a functional link between these nodes of the TCA cycle, where itaconate produced by mammalian CAD at the first break-point regulates SDH activity at the second break point.”
§ Immunoresponsive Gene 1 and Itaconate Inhibit Succinate Dehydrogenase to Modulate Intracellular Succinate Levels * > Discussion
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“These results provide evidence that Irg1-mediated itaconate production plays a role in succinate accumulation within immune cells.”
§ Immunoresponsive Gene 1 and Itaconate Inhibit Succinate Dehydrogenase to Modulate Intracellular Succinate Levels * > Loss of Irg1 Influences Succinate Levels in
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIn the paper
“Under inflammatory conditions, such as LPS stimulation, mammalian CAD catalyzes the decarboxylation of the TCA cycle intermediate cis-aconitate to produce itaconate.”
§ Immunoresponsive Gene 1 and Itaconate Inhibit Succinate Dehydrogenase to Modulate Intracellular Succinate Levels * > Discussion
What the sources say
- Not checked yetcites [20] Michelucci, 2013, Immune-responsive gene 1 protein links metabolism to immunity by catalyzing itaconic acid production, Proc. Natl. Acad. Sci. U.S.A source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesNone of the sources cited for this claim have been checked yet.
In the paper
“Notably, SDH inhibition protected against brain injury after ischemia/reperfusion (40,41), suggesting that inhibition of SDH by endogenously produced itaconate may buffer against potential oxidative damage that can occur under such conditions.”
§ Immunoresponsive Gene 1 and Itaconate Inhibit Succinate Dehydrogenase to Modulate Intracellular Succinate Levels * > Discussion
What the sources say
- Not checked yetcites [40] Chouchani, 2016, A unifying mechanism for mitochondrial superoxide production during ischemia-reperfusion injury, Cell Metab source
- Not checked yetcites [41] Chouchani, 2014, Ischaemic accumulation of succinate controls reperfusion injury through mitochondrial ROS, Nature source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Our findings provide critical new insights into the regulatory machinery governing TCA cycle function, with mammalian CAD-produced itaconate serving as a metabolic inhibitor to cause succinate accumulation.”
§ Immunoresponsive Gene 1 and Itaconate Inhibit Succinate Dehydrogenase to Modulate Intracellular Succinate Levels * > Discussion
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Rests on an assumption: The effects of exogenous itaconate on succinate accumulation reflect the physiological role of endogenous itaconate.
- It may state two separate claims as one. 10
- Probably not a substantial claim. 13
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Succinate levels increased linearly with itaconate levels and correlated strongly (r ϭ 0.99), whereas other TCA cycle intermediates, including citrate, ␣-ketoglutarate, fumarate, and malate, did not accumulate (Fig. 3a).”
§ Immunoresponsive Gene 1 and Itaconate Inhibit Succinate Dehydrogenase to Modulate Intracellular Succinate Levels * > Itaconate and Irg1-induced Succinate Accumulation Is Not
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Although we observed high fractions of M1 itaconate isotopologues (ϳ65%) because of itaconate production via reductive glutamine metabolism, no labeling was detected on succinate (Fig. 4b).”
§ Immunoresponsive Gene 1 and Itaconate Inhibit Succinate Dehydrogenase to Modulate Intracellular Succinate Levels * > Itaconate and Irg1-induced Succinate Accumulation Is Not
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“exposure to exogenous itaconate induces succinate accumulation in resting RAW 264.7 macrophages (Fig. 2e) as well as resting BMDMs (Fig. 2h)”
§ Immunoresponsive Gene 1 and Itaconate Inhibit Succinate Dehydrogenase to Modulate Intracellular Succinate Levels * > Succinate and Itaconate Accumulate in LPS-activated RAW 264.7 Macrophages-To better understand the relationship between
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Within our analyses, we did observe variability in succinate accumulation upon LPS stimulation when comparing RAW 264.7 macrophages and BMDMs.”
§ Immunoresponsive Gene 1 and Itaconate Inhibit Succinate Dehydrogenase to Modulate Intracellular Succinate Levels * > Discussion
Strength:plain· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“The first break occurs at isocitrate dehydrogenase, leading to the accumulation of citrate, the precursor for itaconate”
What the sources say
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Although itaconate has been shown previously to inhibit SDH ex vivo (26 -28)”
What the sources say
- Not checked yetcites [26] Booth, 1952, The inhibitory effects of itaconic acid in vitro and in vivo, J. Biol. Chem. source
- Not checked yetcites [27] Ackermann, 1949, Enzyme inhibition in relation to chemotherapy, Proc. Soc. Exp. Biol. Med. source
- Not checked yetcites [28] Dervartanian, 1964, Studies on succinate dehydrogenase: I: spectral properties of the purified enzyme and formation of enzyme-competitive inhibitor complexes, Biochim. Biophys. Acta.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim.
In the paper
“although glycolytic metabolism is a prerequisite (14).”
What the sources say
- Not checked yetcites [14] Palsson-McDermott, 2015, Pyruvate kinase M2 regulates Hif-1α activity and IL-1β induction and is a critical determinant of the Warburg effect in LPS-activated macrophages, Cell Metab source
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“the second break occurs at succinate dehydrogenase (SDH), which may allow for succinate accumulation.”
What the sources say
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The emerging role of itaconate as a regulatory molecule to reprogram immune cell metabolism provides an intriguing link between innate immunity, metabolism, and disease pathogenesis.”
§ Immunoresponsive Gene 1 and Itaconate Inhibit Succinate Dehydrogenase to Modulate Intracellular Succinate Levels * > Discussion
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim.
- Rests on an assumption: The cell models used are representative of macrophages in vivo for conclusions about immune cell metabolism.
In the paper
“Itaconate was only recently identified as an endogenous mammalian biochemical (19), and subsequent studies demonstrated that this molecule was produced by mammalian CAD activity on cis-aconitate (20).”
§ Immunoresponsive Gene 1 and Itaconate Inhibit Succinate Dehydrogenase to Modulate Intracellular Succinate Levels * > Discussion
What the sources say
- Not checked yetcites [20] Michelucci, 2013, Immune-responsive gene 1 protein links metabolism to immunity by catalyzing itaconic acid production, Proc. Natl. Acad. Sci. U.S.A source
Strength:boosted· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“Numerous metabolic pathways have been implicated in the metabolic reprogramming of immune cells, in particular those that regulate succinate levels, which, in turn, can influence HIF signaling or other pathways (13,25,40,41).”
§ Immunoresponsive Gene 1 and Itaconate Inhibit Succinate Dehydrogenase to Modulate Intracellular Succinate Levels * > Discussion
What the sources say
- Not checked yetcites [13] Mills, 2014, Succinate: a metabolic signal in inflammation, Trends Cell Biol source
- Not checked yetcites [25] Jha, 2015, Network integration of parallel metabolic and transcriptional data reveals metabolic modules that regulate macrophage polarization, Immunity source
- Not checked yetcites [40] Chouchani, 2016, A unifying mechanism for mitochondrial superoxide production during ischemia-reperfusion injury, Cell Metab source
- Not checked yetcites [41] Chouchani, 2014, Ischaemic accumulation of succinate controls reperfusion injury through mitochondrial ROS, Nature source
Strength:plain· not yet calibratedCausal:conditional· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
In the paper
“Intracellular signaling pathways also play key roles in macrophage polarization and likely sustain inflammation to some degree in the absence of Irg1 (44).”
§ Immunoresponsive Gene 1 and Itaconate Inhibit Succinate Dehydrogenase to Modulate Intracellular Succinate Levels * > Discussion
What the sources say
- Not checked yetcites [44] Sica, 2012, Macrophage plasticity and polarization: in vivo veritas, J. Clin. Invest. source
Strength:hedged· not yet calibratedCausal:conditional· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
In the paper
“Glutamine serves as a major carbon source for succinate production in LPSactivated macrophages via ␣-ketoglutarate or, alternatively, through the GABA shunt (9).”
§ Immunoresponsive Gene 1 and Itaconate Inhibit Succinate Dehydrogenase to Modulate Intracellular Succinate Levels * > Discussion
What the sources say
- Not checked yetcites [9] Tannahill, 2013, Succinate is an inflammatory signal that induces IL-1β through HIF-1α, Nature source
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“This variance is in the range of succinate accumulation levels reported by others and is likely a function of cell, medium formulation, and LPS variability (9).”
§ Immunoresponsive Gene 1 and Itaconate Inhibit Succinate Dehydrogenase to Modulate Intracellular Succinate Levels * > Discussion
What the sources say
- Not checked yetcites [9] Tannahill, 2013, Succinate is an inflammatory signal that induces IL-1β through HIF-1α, Nature source
Strength:hedged· not yet calibratedCausal:conditional· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“As such, itaconate may have pleiotropic effects on cells depending on the expression, K i , and compartment-specific impacts on succinate concentrations.”
§ Immunoresponsive Gene 1 and Itaconate Inhibit Succinate Dehydrogenase to Modulate Intracellular Succinate Levels * > Discussion
Strength:hedged· not yet calibratedCausal:conditional· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“As noted above, various other pathways (e.g.GABA shunt, glutaminolysis) contribute to succinate synthesis in macrophages and could allow compensation (9, 13, 14).”
§ Immunoresponsive Gene 1 and Itaconate Inhibit Succinate Dehydrogenase to Modulate Intracellular Succinate Levels * > Discussion
What the sources say
- Not checked yetcites [9] Tannahill, 2013, Succinate is an inflammatory signal that induces IL-1β through HIF-1α, Nature source
- Not checked yetcites [13] Mills, 2014, Succinate: a metabolic signal in inflammation, Trends Cell Biol source
- Not checked yetcites [14] Palsson-McDermott, 2015, Pyruvate kinase M2 regulates Hif-1α activity and IL-1β induction and is a critical determinant of the Warburg effect in LPS-activated macrophages, Cell Metab source
Strength:hedged· not yet calibratedCausal:conditional· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Given the regulatory role of itaconate in succinate accumulation described here, IRG1-mediated itaconate production may act as a signaling molecule in other inflammatory situations or cellular states.”
§ Immunoresponsive Gene 1 and Itaconate Inhibit Succinate Dehydrogenase to Modulate Intracellular Succinate Levels * > Discussion
Strength:hedged· not yet calibratedCausal:conditional· not yet calibratedTests✓ Asserted: passes✗ Checkable: fails✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. It may be too vague to check against evidence. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Taken together, our data highlight a mechanistic function of itaconate whereby this metabolite acts as a SDH inhibitor to influence TCA cycle metabolism by driving succinate accumulation (Fig. 7).”
- Also stated in: § Discussion · plain
“This metabolite contributes to succinate accumulation in macrophages by acting as an endogenous SDH inhibitor.”
§ Immunoresponsive Gene 1 and Itaconate Inhibit Succinate Dehydrogenase to Modulate Intracellular Succinate Levels * > Loss of Irg1 Influences Succinate Levels in
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
- Also stated in: § Discussion · plain
None of the sources cited for this claim have been checked yet.
In the paper
“Succinate inhibits HIF-1␣ signaling through inhibition of PHD2 but can also impact the activity of numerous ␣-ketoglutarate-dependent dioxygenases (42,43).”
§ Immunoresponsive Gene 1 and Itaconate Inhibit Succinate Dehydrogenase to Modulate Intracellular Succinate Levels * > Discussion
What the sources say
- Not checked yetcites [42] Xiao, 2012, 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 source
- Not checked yetcites [43] Metallo, 2013, Understanding metabolic regulation and its influence on cell physiology, Mol. Cell. source
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
The paper relies on this without support.
The specific driver(s) of succinate accumulation in inflammatory macrophages have not yet been identified.
“However, the specific driver(s) of this phenomenon has/have not yet been identified.”
The paper relies on this without support.
A potential role of endogenously produced itaconate in succinate accumulation under inflammatory conditions has not yet been addressed and is unknown.
“a potential role of endogenously produced itaconate in succinate accumulation under inflammatory conditions has not yet been addressed and is unknown.”
The paper relies on this without support.
The Irg1 KO mouse model specifically abolishes itaconate production without other metabolic adaptations that affect succinate levels.
“Notably, succinate concentrations in stimulated BMDMs from Irg1 KO mice were significantly lower than those quantified in BMDMs from WT mice, suggesting that CAD-derived itaconate influences succinate accumulation in LPS-induced macrophages (Fig. 6c).”
The paper relies on this without support.
The effects of exogenous itaconate on succinate accumulation reflect the physiological role of endogenous itaconate.
“In the cells studied, exogenous and endogenous, CAD-produced itaconate strongly correlated with succinate accumulation.”
The paper relies on this without support.
The cell models used are representative of macrophages in vivo for conclusions about immune cell metabolism.
“However, we consistently observed increased succinate downstream of itaconate production or administration in a variety of cell types.”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In the citing paper
“Mechanistically LDHA-deficient T cells showed decreased acetyl-CoA levels and decreased histone H3 acetylation at the lysine 9 residue (H3K9Ac), a histone mark associated with active transcription, on the Ifng promoter.”
From Coupling Krebs cycle metabolites to signalling in immunity and cancer (2018) · cites this paper as [55]
In the citing paper
“Mice with an T cell-specific LDHA deficiency produced less IFN-γ and were protected from immunopathology.”
From Coupling Krebs cycle metabolites to signalling in immunity and cancer (2018) · cites this paper as [55]
In the citing paper
“The authors demonstrate that LDA, an enzyme that catalyzes the reversible conversion of pyruvate and NADH to lactate and NAD+, is induced in activated T cells and enhances histone acetylation of interferon gamma (Ifng) via the maintenance of acetyl-CoA levels to promote its expression 55.”
From Coupling Krebs cycle metabolites to signalling in immunity and cancer (2018) · cites this paper as [55]
In the citing paper
“Furthermore, artificial acetyl-CoA reduction, through inhibition of ACLY, decreased IFN-γ expression and acetate supplementation, which augmented acetyl-CoA production, corrected H3K9Ac marks and IFN-γ expression in LDHA-deficient T cells.”
From Coupling Krebs cycle metabolites to signalling in immunity and cancer (2018) · cites this paper as [55]
In the citing paper
“The generation of itaconate from the Krebs Cycle intermediate cis-aconitate contrasts with most other metabolite signals emanating from mitochondria, in that it primarily acts as a protective, anti-inflammatory metabolite55,59,60.”
From Coupling Krebs cycle metabolites to signalling in immunity and cancer (2018) · cites this paper as [55]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
Inconsistent itaconate concentrations for respiration assays
MinorThe methods list four itaconate concentrations for the permeabilized-cell respiration assay, but the Figure 5 caption lists five, including 2.5 mM.
“increasing itaconate concentrations (0, 5, 10, and 25 mM)”
“increasing itaconate concentrations (0, 2.5, 5, 10, and 25 mM)”
Opposite claims about succinate's effect on HIF-1α signaling
MinorThe discussion says succinate inhibits HIF-1α signaling, whereas the earlier account says succinate stabilizes HIF-1α and enhances its downstream effect.
“Succinate inhibits HIF-1␣ signaling through inhibition of PHD2”
“succinate acts as a regulatory signal enhancing Il-1 expression through stabilization of HIF-1␣”
Citations
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Succinate is an inflammatory signal that induces IL-1β through HIF-1α
Tannahill, G. M., Curtis, A. M., Adamik, J., Palsson-McDermott, E. M., McGettrick, A. F., Goel, G., Frezza, C., Bernard, N. J., Kelly, B., Foley, N. H., et al. (2013) · Nature · doi:10.1038/nature11986 · Cited by 4,176
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Chouchani, E. T., Pell, V. R., Gaude, E., Aksentijević, D., Sundier, S. Y., Robb, E. L., Logan, A., Nadtochiy, S. M., Ord, E. N. J., Smith, A. C., et al. (2014) · Nature · doi:10.1038/nature13909 · Cited by 2,907 · cited 3×
“Numerous metabolic pathways have been implicated in the metabolic reprogramming of immune cells, in particular those that regulate succinate levels, which, in turn, can influence HIF signaling or other pathways (13, 25, 40, 41).”
BackgroundGiard, D. J., Aaronson, S. A., Todaro, G. J., Arnstein, P., Kersey, J. H., Dosik, H., & Parks, W. P. (1973) · JNCI Journal of the National Cancer Institute · doi:10.1093/jnci/51.5.1417 · Cited by 2,336
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Cited by
Sorted by citations
Mitochondrial TCA cycle metabolites control physiology and disease
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Defining trained immunity and its role in health and disease
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Itaconate is an anti-inflammatory metabolite that activates Nrf2 via alkylation of KEAP1
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Metadata
- Authors
- Cordes, T., Wallace, M., Michelucci, A., Divakaruni, A. S., Sapcariu, S. C., Sousa, C., Koseki, H., Cabrales, P., Murphy, A. N., Hiller, K., & Metallo, C. M.
- Affiliations
- University of California San Diego (US)
- University of Luxembourg (LU)
- RIKEN Center for Integrative Medical Sciences (JP)
- Corresponding author
- Metallo, Christian M.
- ORCID
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2016-07
- Volume
- 291
- Issue
- 27
- Pages
- 14274-14284
- ISSN
- 0021-9258 (ISSN-L)
- PMC
- PMC4933182
- OpenAlex
- W2361586644
- Semantic Scholar
- e5517dd16c4dff72218eace800e1b0913a233bce
- Cited by
- 526
- References
- 52
- Citations by year
- 2026: 55 · 2025: 60 · 2024: 68 · 2023: 55 · 2022: 58 · 2021: 69 · 2020: 64 · 2019: 42 · 2018: 27 · 2017: 23 · 2016: 5
- FWCI
- 19.57
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Open Repository and Bibliography (University of Luxembourg) (submittedVersion, cc-by-nc-sa)
- Funders
- National Institutes of Health (R01CA188652, P01DK054441)
- National Institute of Allergy and Infectious Diseases (R01AI082610)
- National Heart, Lung, and Blood Institute (R53HL123015, P01HL110900, R01HL052684)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
- Life Sciences › Immunology and Microbiology › Immunology › Immune responses and vaccinations
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Microbial metabolism and enzyme function
- Keywords
- IRG1, itaconate, succinate accumulation, succinate dehydrogenase inhibition, cis-aconitate decarboxylase, TCA cycle, metabolic reprogramming, innate immunity, macrophages, lipopolysaccharide, electron transport chain, immunometabolism
- MeSH terms
- Animals, Cell Line, Hydro-Lyases, Lipopolysaccharides, Macrophages, Succinate Dehydrogenase, Succinates, Succinic Acid, Mice
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.
A language model drew the claims from the paper on 2026-10-10, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).
A second model labelled each claim on 2026-10-10 (model jev-1.13-20260917, definition revision gold-guideline-v0.2).
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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