The DOI matches its Crossref record; 65 of the 65 references it cites were found in a registry or an index.
Abolition of mitochondrial substrate‐level phosphorylation by itaconic acid produced by LPS‐induced Irg1 expression in cells of murine macrophage lineage
Abstract
Itaconate is a nonamino organic acid exhibiting antimicrobial effects. It has been recently identified in cells of macrophage lineage as a product of an enzyme encoded by immunoresponsive gene 1 ( Irg1 ), acting on the citric acid cycle intermediate cis‐aconitate. In mitochondria, itaconate can be converted by succinate‐coenzyme A (CoA) ligase to itaconyl‐CoA at the expense of ATP (or GTP), and is also a weak competitive inhibitor of complex II. Here, we investigated specific bioenergetic effects of increased itaconate production mediated by LPS‐induced stimulation of Irg1 in murine bone marrow‐derived macrophages (BMDM) and RAW‐264.7 cells. In rotenone‐treated macrophage cells, stimulation by LPS led to impairment in substrate‐level phosphorylation (SLP) of in situ mitochondria, deduced by a reversal in the directionality of the adenine nucleotide translocase operation. In RAW‐264.7 cells, the LPS‐induced impairment in SLP was reversed by short‐interfering RNA(siRNA)—but not scrambled siRNA—treatment directed against Irg1. LPS dose‐dependently inhibited oxygen consumption rates (61‐91%) and elevated glycolysis rates (>21%) in BMDM but not RAW‐264.7 cells, studied under various metabolic conditions. In isolated mouse liver mitochondria treated with rotenone, itaconate dose‐dependently (0.5‐2 mM) reversed the operation of adenine nucleotide translocase, implying impairment in SLP, an effect that was partially mimicked by malonate. However, malonate yielded greater ADP‐induced depolarizations (3‐19%) than itaconate. We postulate that itaconate abolishes SLP due to 1) a “CoA trap” in the form of itaconyl‐CoA that negatively affects the upstream supply of succinyl‐CoA from the α‐ketoglutarate dehydrogenase complex; 2) depletion of ATP (or GTP), which are required for the thioesterification by succinate‐CoA ligase; and 3) inhibition of complex II leading to a buildup of succinate which shifts succinate‐CoA ligase equilibrium toward ATP (or GTP) utilization. Our results support the notion that Irg1 ‐expressing cells of macrophage lineage lose the capacity of mitochondrial SLP for producing itaconate during mounting of an immune defense.—Németh, B., Doczi, J., Csete, D., Kacso, G., Ravasz, D., Adams, D., Kiss, G., Nagy, A. M., Horvath, G., Tretter, L., Mócsai, A., Csépányi‐Kömi, R., Iordanov, I., Adam‐Vizi, V., Chinopoulos, C. Abolition of mitochondrial substrate‐level phosphorylation by itaconic acid produced by LPS‐induced Irg1 expression in cells of murine macrophage lineage. FASEB J. 30, 286‐300 (2016). www.fasebj.org
Overview
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
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
“In 2014 Lee and colleagues demonstrated that acetyl-CoA levels and histone acetylation in tumors are regulated by oncogenic activation of Akt and subsequent ACLY phosphorylation58.”
From Coupling Krebs cycle metabolites to signalling in immunity and cancer (2018) · cites this paper as [58]
In the citing paper
“levels of histone acetylation have been shown to be predictive of which patients would later exhibit biochemical failure, with lower levels predictive of worse outcome.”
From Coupling Krebs cycle metabolites to signalling in immunity and cancer (2018) · cites this paper as [58]
In the citing paper
“histone acetylation and phosphorylated Akt levels correlate significantly in human glioma and human prostate cancer”
From Coupling Krebs cycle metabolites to signalling in immunity and cancer (2018) · cites this paper as [58]
Citations
Cites
1 retracted
Garedew, A., Henderson, S. O., & Moncada, S. (2010) · Cell Death and Differentiation · doi:10.1038/cdd.2010.27 · Cited by 124
RetractedUnderstanding the Warburg Effect: The Metabolic Requirements of Cell Proliferation
Vander Heiden, M. G., Cantley, L. C., & Thompson, C. B. (2009) · Science · doi:10.1126/science.1160809 · Cited by 16,197
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
A new collection method for the evaluation of nasal mucus proteins
Ruocco, L. A., Fattori, Romanelli, Martelloni, L., Casani, Samolewska, & Rezzonico (1998) · Clinical & Experimental Allergy · doi:10.1046/j.1365-2222.1998.00312.x · Cited by 1,296
Toll-like receptor–induced changes in glycolytic metabolism regulate dendritic cell activation
Krawczyk, C. M., Holowka, T., Sun, J., Blagih, J., Amiel, E., DeBerardinis, R. J., Cross, J. R., Jung, E., Thompson, C. B., Jones, R. G., et al. (2010) · Blood · doi:10.1182/blood-2009-10-249540 · Cited by 1,246
Identification of Lps2 as a key transducer of MyD88-independent TIR signalling
Hoebe, K. H. N., Du, X., Georgel, P., Janssen, E. M., Tabeta, K., Kim, S. O., Goode, J., Lin, P., Mann, N., Mudd, S., et al. (2003) · Nature · doi:10.1038/nature01889 · Cited by 1,232
Immune-responsive gene 1 protein links metabolism to immunity by catalyzing itaconic acid production
Michelucci, A., Cordes, T., Ghelfi, J., Pailot, A., Reiling, N., Goldmann, O., Binz, T., Wegner, A., Tallam, A., Rausell, A., et al. (2013) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1218599110 · Cited by 1,191
Rodríguez-Prados, J.-C., Través, P. G., Cuenca, J., Rico, D., Aragonés, J., Martín-Sanz, P., Cascante, M., & Boscá, L. (2010) · The Journal of Immunology · doi:10.4049/jimmunol.0901698 · Cited by 1,022
Safranine as a probe of the mitochondrial membrane potential
Åkerman, K. E. O., & Wikström, M. K. F. (1976) · FEBS Letters · doi:10.1016/0014-5793(76)80434-6 · Cited by 793
Succinate: a metabolic signal in inflammation
Mills, E., & O’Neill, L. A. J. (2014) · Trends in Cell Biology · doi:10.1016/j.tcb.2013.11.008 · Cited by 741
Cited by
Sorted by citations
Immunometabolism governs dendritic cell and macrophage function
O'Neill, L. A. J., & Pearce, E. J. (2015) · The Journal of Experimental Medicine · doi:10.1084/jem.20151570 · Cited by 1,779
Lampropoulou, V., Sergushichev, A., Bambousková, M., Nair, S., Vincent, E. E., Loginicheva, E., Cervantes‐Barragán, L., Ma, X., Huang, S. C., Griss, T., et al. (2016) · Cell Metabolism · doi:10.1016/j.cmet.2016.06.004 · Cited by 1,583
Macrophage Immunometabolism: Where Are We (Going)?
den Bossche, J. V., O'Neill, L. A. J., & Menon, D. (2017) · Trends in Immunology · doi:10.1016/j.it.2017.03.001 · Cited by 1,187
HIF1α and metabolic reprogramming in inflammation
Corcoran, S. E., & O'Neill, L. A. J. (2016) · Journal of Clinical Investigation · doi:10.1172/jci84431 · Cited by 814
Glycolysis – a key player in the inflammatory response
Soto‐Heredero, G., Heras, M. M. G. D. L., Gabandé‐Rodríguez, E., Oller, J., & Mittelbrunn, M. (2020) · FEBS Journal · doi:10.1111/febs.15327 · Cited by 660
Metadata
- Authors
- Németh, B., Doczi, J., Csete, D., Kacso, G., Ravasz, D., Adams, D., Kiss, G., Nagy, A. M., Horvath, G., Tretter, L., Mócsai, A., Csépáinyi‐Kömi, R., Iordanov, I., Adam‐Vizi, V., & Chinopoulos, C.
- Affiliations
- Department of Medical Biochemistry Semmelweis University Budapest Hungary
- Department of Physiology Semmelweis University Budapest Hungary
- Semmelweis University (HU)
- Corresponding author
- Chinopoulos, Christos
- Venue
- The FASEB Journal
- Publisher
- Wiley
- Published
- 2015-09-10
- Volume
- 30
- Issue
- 1
- Pages
- 286-300
- ISSN
- 0892-6638 (ISSN-L)
- 1530-6860
- OpenAlex
- W2232390838
- Cited by
- 136
- References
- 65
- Citations by year
- 2026: 7 · 2025: 13 · 2024: 9 · 2023: 7 · 2022: 20 · 2021: 14 · 2020: 15 · 2019: 15 · 2018: 11 · 2017: 15 · 2016: 9 · 2015: 1
- FWCI
- 5.90
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- The FASEB Journal (publishedVersion)
- PubMed (publishedVersion)
- Repository of the Academy's Library (Library of the Hungarian Academy of Sciences) (acceptedVersion)
- Semmelweis University Repository (Semmelweis University) (submittedVersion)
- Funders
- Magyar Tudományos Akadémia (02001)
- Hungarian Scientific Research Fund (K 100918)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Keywords
- itaconic acid, IRG1, substrate-level phosphorylation, macrophages, LPS, complex II inhibition, succinic acid, adenine nucleotide translocase, mitochondrial bioenergetics, glycolysis, rotenone, malonate, alpha-ketoglutarate dehydrogenase complex, succinyl-CoA, ATP depletion, bone marrow-derived macrophages, RAW 264.7 macrophages
- MeSH terms
- Mitochondrial ADP, ATP Translocases, Animals, Cell Line, Chlorocebus aethiops, Female, Glycolysis, Hydro-Lyases, Lipopolysaccharides, Macrophages, Male, Malonates, Mice, Inbred C57BL, Mitochondria, Liver, Oxidative Phosphorylation, Rotenone, Succinates, Succinate-CoA Ligases, COS Cells, Mice, Membrane Potential, Mitochondrial
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.
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 ›
Are you an author, or do you see a problem with this page? Request a review
