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Last Updated: 2019-09-20
The Krebs cycle, also known as the citric acid cycle (CAC) or tricarboxylic acid cycle (TCA cycle) occurs in the mitochondria, and it involves the oxidation of acetyl-CoA from glycolysis to form molecules of ATP, as well as NADH, which will later be used to form more ATP. Intermediates from the Krebs cycle can be used as inflammatory signals in the body, specifically in immune cells such as macrophages. Succinic acid, or its anion succinate, can leave the mitochondria and can directly inhibit the prolyl 4-hydroxylase subunit alpha-3 protein, which then allows for additional activation of the hypoxia-inducible factor 1-alpha (HF-1α). The higher levels of HF-1α enhance the expression of genes, including those for interleukin-1 beta (IL-1β). Succinic acid is also necessary for the succinylation of proteins, leading to changes in their structure and function. Another intermediate of the Krebs cycle, NAD, activates the NAD-dependent protein deacetylase sirtuin-3, which is involved in the deacetylase of proteins in the cell, regulating ATP levels and promoting mtDNA transcription when needed. Activated sirtuin-3 inhibits NACHT, LRR and PYD domains-containing protein 3, which works to activate the inflammasome, and thus the increase in NAD+ leads to anti-inflammatory actions in the body. Citric acid is another intermediate of the Krebs cycle, and it activates the production of reactive oxygen species, nitric oxide, which is the precursor for reactive nitrogen species, and prostaglandins. Prostaglandins can act as vasodilators, and as such are involved in the inflammation response. Finally, glutamine is important for immune cells to carry out their functions, and when LPS binds to the Toll-like receptor 4 (TLR4) on the cell surface, activating this response, extra L-glutamine can be transported into the cell to fill this need. The L-glutamine can then be converted to oxoglutaric acid, which is important in the Krebs cycle, leading to the effects from its intermediates on the rest of the inflammatory response.
Succinate Signalling References
Mills E, O'Neill LA: Succinate: a metabolic signal in inflammation. Trends Cell Biol. 2014 May;24(5):313-20. doi: 10.1016/j.tcb.2013.11.008. Epub 2013 Dec 19.Pubmed: 24361092
O'Neill LA, Pearce EJ: Immunometabolism governs dendritic cell and macrophage function. J Exp Med. 2016 Jan 11;213(1):15-23. doi: 10.1084/jem.20151570. Epub 2015 Dec 22.Pubmed: 26694970
Cruzat V, Macedo Rogero M, Noel Keane K, Curi R, Newsholme P: Glutamine: Metabolism and Immune Function, Supplementation and Clinical Translation. Nutrients. 2018 Oct 23;10(11). pii: nu10111564. doi: 10.3390/nu10111564.Pubmed: 30360490
Smirnova I, Poltorak A, Chan EK, McBride C, Beutler B: Phylogenetic variation and polymorphism at the toll-like receptor 4 locus (TLR4). Genome Biol. 2000;1(1):RESEARCH002. doi: 10.1186/gb-2000-1-1-research002. Epub 2000 Apr 27.Pubmed: 11104518
Arbour NC, Lorenz E, Schutte BC, Zabner J, Kline JN, Jones M, Frees K, Watt JL, Schwartz DA: TLR4 mutations are associated with endotoxin hyporesponsiveness in humans. Nat Genet. 2000 Jun;25(2):187-91. doi: 10.1038/76048.Pubmed: 10835634
da Silva Correia J, Soldau K, Christen U, Tobias PS, Ulevitch RJ: Lipopolysaccharide is in close proximity to each of the proteins in its membrane receptor complex. transfer from CD14 to TLR4 and MD-2. J Biol Chem. 2001 Jun 15;276(24):21129-35. doi: 10.1074/jbc.M009164200. Epub 2001 Mar 26.Pubmed: 11274165
Kukkola L, Hieta R, Kivirikko KI, Myllyharju J: Identification and characterization of a third human, rat, and mouse collagen prolyl 4-hydroxylase isoenzyme. J Biol Chem. 2003 Nov 28;278(48):47685-93. doi: 10.1074/jbc.M306806200. Epub 2003 Sep 18.Pubmed: 14500733
Van Den Diepstraten C, Papay K, Bolender Z, Brown A, Pickering JG: Cloning of a novel prolyl 4-hydroxylase subunit expressed in the fibrous cap of human atherosclerotic plaque. Circulation. 2003 Aug 5;108(5):508-11. doi: 10.1161/01.CIR.0000080883.53863.5C. Epub 2003 Jul 21.Pubmed: 12874193
Clark HF, Gurney AL, Abaya E, Baker K, Baldwin D, Brush J, Chen J, Chow B, Chui C, Crowley C, Currell B, Deuel B, Dowd P, Eaton D, Foster J, Grimaldi C, Gu Q, Hass PE, Heldens S, Huang A, Kim HS, Klimowski L, Jin Y, Johnson S, Lee J, Lewis L, Liao D, Mark M, Robbie E, Sanchez C, Schoenfeld J, Seshagiri S, Simmons L, Singh J, Smith V, Stinson J, Vagts A, Vandlen R, Watanabe C, Wieand D, Woods K, Xie MH, Yansura D, Yi S, Yu G, Yuan J, Zhang M, Zhang Z, Goddard A, Wood WI, Godowski P, Gray A: The secreted protein discovery initiative (SPDI), a large-scale effort to identify novel human secreted and transmembrane proteins: a bioinformatics assessment. Genome Res. 2003 Oct;13(10):2265-70. doi: 10.1101/gr.1293003. Epub 2003 Sep 15.Pubmed: 12975309
Iyer NV, Leung SW, Semenza GL: The human hypoxia-inducible factor 1alpha gene: HIF1A structure and evolutionary conservation. Genomics. 1998 Sep 1;52(2):159-65. doi: 10.1006/geno.1998.5416.Pubmed: 9782081
Wang GL, Jiang BH, Rue EA, Semenza GL: Hypoxia-inducible factor 1 is a basic-helix-loop-helix-PAS heterodimer regulated by cellular O2 tension. Proc Natl Acad Sci U S A. 1995 Jun 6;92(12):5510-4. doi: 10.1073/pnas.92.12.5510.Pubmed: 7539918
Hogenesch JB, Chan WK, Jackiw VH, Brown RC, Gu YZ, Pray-Grant M, Perdew GH, Bradfield CA: Characterization of a subset of the basic-helix-loop-helix-PAS superfamily that interacts with components of the dioxin signaling pathway. J Biol Chem. 1997 Mar 28;272(13):8581-93. doi: 10.1074/jbc.272.13.8581.Pubmed: 9079689
Auron PE, Webb AC, Rosenwasser LJ, Mucci SF, Rich A, Wolff SM, Dinarello CA: Nucleotide sequence of human monocyte interleukin 1 precursor cDNA. Proc Natl Acad Sci U S A. 1984 Dec;81(24):7907-11. doi: 10.1073/pnas.81.24.7907.Pubmed: 6083565
March CJ, Mosley B, Larsen A, Cerretti DP, Braedt G, Price V, Gillis S, Henney CS, Kronheim SR, Grabstein K, et al.: Cloning, sequence and expression of two distinct human interleukin-1 complementary DNAs. Nature. 1985 Jun 20-26;315(6021):641-7. doi: 10.1038/315641a0.Pubmed: 2989698
Clark BD, Collins KL, Gandy MS, Webb AC, Auron PE: Genomic sequence for human prointerleukin 1 beta: possible evolution from a reverse transcribed prointerleukin 1 alpha gene. Nucleic Acids Res. 1986 Oct 24;14(20):7897-914. doi: 10.1093/nar/14.20.7897.Pubmed: 3490654
Schwer B, North BJ, Frye RA, Ott M, Verdin E: The human silent information regulator (Sir)2 homologue hSIRT3 is a mitochondrial nicotinamide adenine dinucleotide-dependent deacetylase. J Cell Biol. 2002 Aug 19;158(4):647-57. doi: 10.1083/jcb.200205057. Epub 2002 Aug 19.Pubmed: 12186850
Onyango P, Celic I, McCaffery JM, Boeke JD, Feinberg AP: SIRT3, a human SIR2 homologue, is an NAD-dependent deacetylase localized to mitochondria. Proc Natl Acad Sci U S A. 2002 Oct 15;99(21):13653-8. doi: 10.1073/pnas.222538099. Epub 2002 Oct 8.Pubmed: 12374852
Peserico A, Chiacchiera F, Grossi V, Matrone A, Latorre D, Simonatto M, Fusella A, Ryall JG, Finley LW, Haigis MC, Villani G, Puri PL, Sartorelli V, Simone C: A novel AMPK-dependent FoxO3A-SIRT3 intramitochondrial complex sensing glucose levels. Cell Mol Life Sci. 2013 Jun;70(11):2015-29. doi: 10.1007/s00018-012-1244-6. Epub 2013 Jan 3.Pubmed: 23283301
McCall SH, Sahraei M, Young AB, Worley CS, Duncan JA, Ting JP, Marriott I: Osteoblasts express NLRP3, a nucleotide-binding domain and leucine-rich repeat region containing receptor implicated in bacterially induced cell death. J Bone Miner Res. 2008 Jan;23(1):30-40. doi: 10.1359/jbmr.071002.Pubmed: 17907925
Lo YH, Huang YW, Wu YH, Tsai CS, Lin YC, Mo ST, Kuo WC, Chuang YT, Jiang ST, Shih HM, Lai MZ: Selective inhibition of the NLRP3 inflammasome by targeting to promyelocytic leukemia protein in mouse and human. Blood. 2013 Apr 18;121(16):3185-94. doi: 10.1182/blood-2012-05-432104. Epub 2013 Feb 21.Pubmed: 23430110
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