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Cited by 136Immune cells in cancerMitochondrial Function and PathologyCancer, Hypoxia, and Metabolism

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

Németh, Beata, Doczi, Judit, Csete, Daniel, Kacso, Gergely, Ravasz, Dora, Adams, Daniel, Kiss, Gergely, Nagy, Adam M., Horvath, Gergo, Tretter, Laszlo, Mócsai, Attila, Csépáinyi‐Kömi, Roland, Iordanov, Iordan, Adam‐Vizi, Vera, Chinopoulos, Christos·2016·The FASEB Journal
DOI 10.1096/fj.15-279398
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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

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Crossref · 10.1096/fj.15-279398

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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
ORCID
Venue
The FASEB Journal
Publisher
Wiley
Published
2015-09-10
Volume
30
Issue
1
Pages
286-300
ISSN
  • 0892-6638 (ISSN-L)
  • 1530-6860
DOI
10.1096/fj.15-279398
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
Licence
onlinelibrary.wiley.com/termsAndConditions#vor (vor)
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

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