Metabolic Routes in Inflammation: The Citrate Pathway and its Potential as Therapeutic Target

Author(s): Vittoria Infantino, Ciro Leonardo Pierri, Vito Iacobazzi*

Journal Name: Current Medicinal Chemistry

Volume 26 , Issue 40 , 2019

  Journal Home
Translate in Chinese
Become EABM
Become Reviewer


Significant metabolic changes occur in inflammation to respond to the new energetic needs of cells. Mitochondria are addressed not only to produce ATP, but also to supply substrates, such citrate, to produce pro-inflammatory molecules. In this context, most of the citrate is diverted from Krebs cycle and channeled into the “citrate pathway” leading to the increase in the export of citrate into cytosol by the Mitochondrial Citrate Carrier (CIC) followed by its cleavage into acetyl-CoA and oxaloacetate by ATP Citrate Lyase (ACLY). Acetyl- CoA is used to produce PGE2 and oxaloacetate to make NADPH needed for NO and ROS production. In addition, cytosolic citrate also provides precursors for itaconate synthesis. Citrate- derived itaconate acts as a negative regulator of inflammation by modulating the synthesis of the inflammatory mediators. Inhibition of CIC or ACLY by different synthetic and natural molecules results in the reduction of NO, ROS and PGE2 levels suggesting that the citrate pathway can be a new target to be addressed in inflammation. Beneficial effects can be obtained also in the oxidative stress and inflammatory conditions observed in Down syndrome.

Keywords: Citrate pathway, mitochondrial citrate carrier, ATP citrate lyase, inflammation, inhibition, ROS, NO, PGE2.

Waguri-Nagaya, Y.; Otsuka, T.; Sugimura, I.; Matsui, N.; Asai, K.; Nakajima, K.; Tada, T.; Akiyama, S.; Kato, T. Synovial inflammation and hyperplasia induced by gliostatin/platelet-derived endothelial cell growth factor in rabbit knees. Rheumatol. Int., 2000, 20(1), 13-19.
[] [PMID: 11149655]
O’Neill, L.A.; Hardie, D.G. Metabolism of inflammation limited by AMPK and pseudo-starvation. Nature, 2013, 493(7432), 346-355.
[] [PMID: 23325217]
Akiyama, H.; Barger, S.; Barnum, S.; Bradt, B.; Bauer, J.; Cole, G.M.; Cooper, N.R.; Eikelenboom, P.; Emmerling, M.; Fiebich, B.L.; Finch, C.E.; Frautschy, S.; Griffin, W.S.; Hampel, H.; Hull, M.; Landreth, G.; Lue, L.; Mrak, R.; Mackenzie, I.R.; McGeer, P.L.; O’Banion, M.K.; Pachter, J.; Pasinetti, G.; Plata-Salaman, C.; Rogers, J.; Rydel, R.; Shen, Y.; Streit, W.; Strohmeyer, R.; Tooyoma, I.; Van Muiswinkel, F.L.; Veerhuis, R.; Walker, D.; Webster, S.; Wegrzyniak, B.; Wenk, G.; Wyss-Coray, T. Inflammation and Alzheimer’s disease. Neurobiol. Aging, 2000, 21(3), 383-421.
[] [PMID: 10858586]
Chandel, N.S. Mitochondria as signaling organelles. BMC Biol., 2014, 12, 34.
[] [PMID: 24884669]
Murphy, M.P. How mitochondria produce reactive oxygen species. Biochem. J., 2009, 417(1), 1-13.
[] [PMID: 19061483]
Metallo, C.M.; Vander Heiden, M.G. Metabolism strikes back: metabolic flux regulates cell signaling. Genes Dev., 2010, 24(24), 2717-2722.
[] [PMID: 21159812]
Nazaret, C.; Heiske, M.; Thurley, K.; Mazat, J.P. Mitochondrial energetic metabolism: a simplified model of TCA cycle with ATP production. J. Theor. Biol., 2009, 258(3), 455-464.
[] [PMID: 19007794]
Iacobazzi, V.; Infantino, V. Citrate - new functions for an old metabolite. Biol. Chem., 2014, 395(4), 387-399.
[] [PMID: 24445237]
Ryan, D.G.; O’Neill, L.A.J. Krebs cycle rewired for macrophage and dendritic cell effector functions. FEBS Lett., 2017, 591(19), 2992-3006.
[] [PMID: 28685841]
Iacobazzi, V.; Infantino, V.; Castegna, A.; Menga, A.; Palmieri, E.M.; Convertini, P.; Palmieri, F. Mitochondrial carriers in inflammation induced by bacterial endotoxin and cytokines. Biol. Chem., 2017, 398(3), 303-317.
[] [PMID: 27727142]
Jha, A.K.; Huang, S.C.; Sergushichev, A.; Lampropoulou, V.; Ivanova, Y.; Loginicheva, E.; Chmielewski, K.; Stewart, K.M.; Ashall, J.; Everts, B.; Pearce, E.J.; Driggers, E.M.; Artyomov, M.N. Network integration of parallel metabolic and transcriptional data reveals metabolic modules that regulate macrophage polarization. Immunity, 2015, 42(3), 419-430.
[] [PMID: 25786174]
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.; Zheng, L.; Gardet, A.; Tong, Z.; Jany, S.S.; Corr, S.C.; Haneklaus, M.; Caffrey, B.E.; Pierce, K.; Walmsley, S.; Beasley, F.C.; Cummins, E.; Nizet, V.; Whyte, M.; Taylor, C.T.; Lin, H.; Masters, S.L.; Gottlieb, E.; Kelly, V.P.; Clish, C.; Auron, P.E.; Xavier, R.J.; O’Neill, L.A. Succinate is an inflammatory signal that induces IL-1β through HIF-1α. Nature, 2013, 496(7444), 238-242.
[] [PMID: 23535595]
Infantino, V.; Convertini, P.; Cucci, L.; Panaro, M.A.; Di Noia, M.A.; Calvello, R.; Palmieri, F.; Iacobazzi, V. The mitochondrial citrate carrier: a new player in inflammation. Biochem. J., 2011, 438(3), 433-436.
[] [PMID: 21787310]
Infantino, V.; Iacobazzi, V.; Palmieri, F.; Menga, A. ATP-citrate lyase is essential for macrophage inflammatory response. Biochem. Biophys. Res. Commun., 2013, 440(1), 105-111.
[] [PMID: 24051091]
Infantino, V.; Iacobazzi, V.; Menga, A.; Avantaggiati, M.L.; Palmieri, F. A key role of the mitochondrial citrate carrier (SLC25A1) in TNFα- and IFNγ-triggered inflammation. Biochim. Biophys. Acta, 2014, 1839(11), 1217-1225.
[] [PMID: 25072865]
Sharif, O.; Bolshakov, V.N.; Raines, S.; Newham, P.; Perkins, N.D. Transcriptional profiling of the LPS induced NF-kappaB response in macrophages. BMC Immunol., 2007, 8, 1.
[] [PMID: 17222336]
Assmann, N.; O’Brien, K.L.; Donnelly, R.P.; Dyck, L.; Zaiatz-Bittencourt, V.; Loftus, R.M.; Heinrich, P.; Oefner, P.J.; Lynch, L.; Gardiner, C.M.; Dettmer, K.; Finlay, D.K. Srebp-controlled glucose metabolism is essential for NK cell functional responses. Nat. Immunol., 2017, 18(11), 1197-1206.
[] [PMID: 28920951]
Infantino, V.; Iacobazzi, V.; De Santis, F.; Mastrapasqua, M.; Palmieri, F. Transcription of the mitochondrial citrate carrier gene: role of SREBP-1, upregulation by insulin and downregulation by PUFA. Biochem. Biophys. Res. Commun., 2007, 356(1), 249-254.
[] [PMID: 17350599]
Moon, Y.A.; Park, S.W.; Kim, K.S. Characterization of cis-acting elements in the rat ATP citrate-lyase gene promoter. Exp. Mol. Med., 2002, 34(1), 60-68.
[] [PMID: 11989980]
Babior, B.M. NADPH oxidase. Curr. Opin. Immunol., 2004, 16(1), 42-47.
[] [PMID: 14734109]
Lee, I.T.; Yang, C.M. Role of NADPH oxidase/ROS in pro-inflammatory mediators-induced airway and pulmonary diseases. Biochem. Pharmacol., 2012, 84(5), 581-590.
[] [PMID: 22587816]
Rodríguez, M.; Domingo, E.; Municio, C.; Alvarez, Y.; Hugo, E.; Fernández, N.; Sánchez Crespo, M. Polarization of the innate immune response by prostaglandin E2: a puzzle of receptors and signals. Mol. Pharmacol., 2014, 85(1), 187-197.
[] [PMID: 24170779]
Park, J.Y.; Pillinger, M.H.; Abramson, S.B. Prostaglandin E2 synthesis and secretion: the role of PGE2 synthases. Clin. Immunol., 2006, 119(3), 229-240.
[] [PMID: 16540375]
Zasłona, Z.; Pålsson-McDermott, E.M.; Menon, D.; Haneklaus, M.; Flis, E.; Prendeville, H.; Corcoran, S.E.; Peters-Golden, M.; O’Neill, L.A.J. The Induction of Pro-IL-1β by lipopolysaccharide requires endogenous prostaglandin E2 production. J. Immunol., 2017, 198(9), 3558-3564.
[] [PMID: 28298525]
Everts, B.; Amiel, E.; Huang, S.C.; Smith, A.M.; Chang, C.H.; Lam, W.Y.; Redmann, V.; Freitas, T.C.; Blagih, J.; van der Windt, G.J.; Artyomov, M.N.; Jones, R.G.; Pearce, E.L.; Pearce, E.J. TLR-driven early glycolytic reprogramming via the kinases TBK1-IKKɛ supports the anabolic demands of dendritic cell activation. Nat. Immunol., 2014, 15(4), 323-332.
[] [PMID: 24562310]
Cader, M.Z.; Boroviak, K.; Zhang, Q.; Assadi, G.; Kempster, S.L.; Sewell, G.W.; Saveljeva, S.; Ashcroft, J.W.; Clare, S.; Mukhopadhyay, S.; Brown, K.P.; Tschurtschenthaler, M.; Raine, T.; Doe, B.; Chilvers, E.R.; Griffin, J.L.; Kaneider, N.C.; Floto, R.A.; D’Amato, M.; Bradley, A.; Wakelam, M.J.; Dougan, G.; Kaser, A. C13orf31 (FAMIN) is a central regulator of immunometabolic function. Nat. Immunol., 2016, 17(9), 1046-1056.
[] [PMID: 27478939]
Norris, K.L.; Lee, J.Y.; Yao, T.P. Acetylation goes global: the emergence of acetylation biology. Sci. Signal., 2009, 2(97), pe76.
[] [PMID: 19920250]
Wang, B.; Rao, Y.H.; Inoue, M.; Hao, R.; Lai, C.H.; Chen, D.; McDonald, S.L.; Choi, M.C.; Wang, Q.; Shinohara, M.L.; Yao, T.P. Microtubule acetylation amplifies p38 kinase signalling and anti-inflammatory IL-10 production. Nat. Commun., 2014, 5, 3479.
[] [PMID: 24632940]
Hu, L.; Yu, Y.; Huang, H.; Fan, H.; Hu, L.; Yin, C.; Li, K.; Fulton, D.J.; Chen, F. Epigenetic regulation of interleukin 6 by histone acetylation in macrophages and its role in paraquat-induced pulmonary fibrosis. Front. Immunol., 2017, 7, 696.
[] [PMID: 28194150]
Palmieri, E.M.; Spera, I.; Menga, A.; Infantino, V.; Porcelli, V.; Iacobazzi, V.; Pierri, C.L.; Hooper, D.C.; Palmieri, F.; Castegna, A. Acetylation of human mitochondrial citrate carrier modulates mitochondrial citrate/malate exchange activity to sustain NADPH production during macrophage activation. Biochim. Biophys. Acta, 2015, 1847(8), 729-738.
[] [PMID: 25917893]
Covarrubias, A.J.; Aksoylar, H.I.; Yu, J.; Snyder, N.W.; Worth, A.J.; Iyer, S.S.; Wang, J.; Ben-Sahra, I.; Byles, V.; Polynne-Stapornkul, T.; Espinosa, E.C.; Lamming, D.; Manning, B.D.; Zhang, Y.; Blair, I.A.; Horng, T. Akt-mTORC1 signaling regulates Acly to integrate metabolic input to control of macrophage activation. eLife, 2016, 5, 5.
[] [PMID: 26894960]
Michelucci, A.; Cordes, T.; Ghelfi, J.; Pailot, A.; Reiling, N.; Goldmann, O.; Binz, T.; Wegner, A.; Tallam, A.; Rausell, A.; Buttini, M.; Linster, C.L.; Medina, E.; Balling, R.; Hiller, K. Immune-responsive gene 1 protein links metabolism to immunity by catalyzing itaconic acid production. Proc. Natl. Acad. Sci. USA, 2013, 110(19), 7820-7825.
[] [PMID: 23610393]
Convertini, P.; Menga, A.; Andria, G.; Scala, I.; Santarsiero, A.; Castiglione Morelli, M.A.; Iacobazzi, V.; Infantino, V. The contribution of the citrate pathway to oxidative stress in down syndrome. Immunology, 2016, 149(4), 423-431.
[] [PMID: 27502741]
Pearce, N.J.; Yates, J.W.; Berkhout, T.A.; Jackson, B.; Tew, D.; Boyd, H.; Camilleri, P.; Sweeney, P.; Gribble, A.D.; Shaw, A.; Groot, P.H. The role of ATP citrate-lyase in the metabolic regulation of plasma lipids. Hypolipidaemic effects of SB-204990, a lactone prodrug of the potent ATP citrate-lyase inhibitor SB-201076. Biochem. J., 1998, 334(Pt 1), 113-119.
[] [PMID: 9693110]
Abramson, H.N. The lipogenesis pathway as a cancer target. J. Med. Chem., 2011, 54(16), 5615-5638.
[] [PMID: 21726077]
O’Neill, L.A. A broken krebs cycle in macrophages. Immunity, 2015, 42(3), 393-394.
[] [PMID: 25786167]
Valenti, D.; Manente, G.A.; Moro, L.; Marra, E.; Vacca, R.A. Deficit of complex I activity in human skin fibroblasts with chromosome 21 trisomy and overproduction of reactive oxygen species by mitochondria: involvement of the cAMP/PKA signalling pathway. Biochem. J., 2011, 435(3), 679-688.
[] [PMID: 21338338]
Aluvila, S.; Sun, J.; Harrison, D.H.; Walters, D.E.; Kaplan, R.S. Inhibitors of the mitochondrial citrate transport protein: validation of the role of substrate binding residues and discovery of the first purely competitive inhibitor. Mol. Pharmacol., 2010, 77(1), 26-34.
[] [PMID: 19843634]
Klingenberg, M. Kinetic study of the tricarboxylate carrier in rat liver mitochondria. Eur. J. of Biochem., 1972, 26(4), p.587-594.
[] [PMID: 5025933]
Stipani, I.; Krämer, R.; Palmieri, F.; Klingenberg, M. Citrate transport in liposomes reconstituted with triton extracts from mitochondria. Biochem. Biophys. Res. Commun., 1980, 97(3), 1206-1214.
[] [PMID: 7470147]
Zara, V.; Palmieri, L.; Franco, M.R.; Perrone, M.; Gnoni, G.V.; Palmieri, F. Kinetics of the reconstituted tricarboxylate carrier from eel liver mitochondria. J. Bioenerg. Biomembr., 1998, 30(6), 555-563.
[] [PMID: 10206475]
Ma, C.; Remani, S.; Sun, J.; Kotaria, R.; Mayor, J.A.; Walters, D.E.; Kaplan, R.S. Identification of the substrate binding sites within the yeast mitochondrial citrate transport protein. J. Biol. Chem., 2007, 282(23), 17210-17220.
[] [PMID: 17400551]
Pierri, C.L.; Palmieri, F.; De Grassi, A. Single-nucleotide evolution quantifies the importance of each site along the structure of mitochondrial carriers. Cell. Mol. Life Sci., 2014, 71(2), 349-364.
[] [PMID: 23800987]
Remani, S.; Sun, J.; Kotaria, R.; Mayor, J.A.; Brownlee, J.M.; Harrison, D.H.; Walters, D.E.; Kaplan, R.S. The yeast mitochondrial citrate transport protein: identification of the Lysine residues responsible for inhibition mediated by Pyridoxal 5′-phosphate. J. Bioenerg. Biomembr., 2008, 40(6), 577-585.
[] [PMID: 19002576]
Genchi, G.; Spagnoletta, A.; De Santis, A.; Stefanizzi, L.; Palmieri, F. Purification and characterization of the reconstitutively active citrate carrier from maize mitochondria. Plant Physiol., 1999, 120(3), 841-848.
[] [PMID: 10398720]
Palmieri, F. Mitochondrial transporters of the SLC25 family and associated diseases: a review. J. Inherit. Metab. Dis., 2014, 37(4), 565-575.
[] [PMID: 24797559]
Chaouch, A.; Porcelli, V.; Cox, D.; Edvardson, S.; Scarcia, P.; De Grassi, A.; Pierri, C.L.; Cossins, J.; Laval, S.H.; Griffin, H.; Müller, J.S.; Evangelista, T.; Töpf, A.; Abicht, A.; Huebner, A.; von der Hagen, M.; Bushby, K.; Straub, V.; Horvath, R.; Elpeleg, O.; Palace, J.; Senderek, J.; Beeson, D.; Palmieri, L.; Lochmüller, H. Mutations in the mitochondrial citrate carrier SLC25A1 are associated with impaired neuromuscular transmission. J. Neuromuscul. Dis., 2014, 1(1), 75-90.
[] [PMID: 26870663]
Edvardson, S.; Porcelli, V.; Jalas, C.; Soiferman, D.; Kellner, Y.; Shaag, A.; Korman, S.H.; Pierri, C.L.; Scarcia, P.; Fraenkel, N.D.; Segel, R.; Schechter, A.; Frumkin, A.; Pines, O.; Saada, A.; Palmieri, L.; Elpeleg, O. Agenesis of corpus callosum and optic nerve hypoplasia due to mutations in SLC25A1 encoding the mitochondrial citrate transporter. J. Med. Genet., 2013, 50(4), 240-245.
[] [PMID: 23393310]
Palmieri, F.; Pierri, C.L. Structure and function of mitochondrial carriers - role of the transmembrane helix P and G residues in the gating and transport mechanism. FEBS Lett., 2010, 584(9), 1931-1939.
[] [PMID: 19861126]
Todisco, S.; Di Noia, M.A.; Onofrio, A.; Parisi, G.; Punzi, G.; Redavid, G.; De Grassi, A.; Pierri, C.L. Identification of new highly selective inhibitors of the human ADP/ATP carriers by molecular docking and in vitro transport assays. Biochem. Pharmacol., 2016, 100, 112-132.
[] [PMID: 26616220]
Pierri, C.L.; Parisi, G.; Porcelli, V. Computational approaches for protein function prediction: a combined strategy from multiple sequence alignment to molecular docking-based virtual screening. Biochim. Biophys. Acta, 2010, 1804(9), 1695-1712.
[] [PMID: 20433957]
Sun, J.; Aluvila, S.; Kotaria, R.; Mayor, J.A.; Walters, D.E.; Kaplan, R.S. Mitochondrial and plasma membrane citrate transporters: discovery of selective inhibitors and application to structure/function analysis. Mol. Cell. Pharmacol., 2010, 2(3), 101-110.
[PMID: 20686672]
So, J.S. Roles of endoplasmic reticulum stress in immune responses. Mol. Cells, 2018, 41(8), 705-716.
[] [PMID: 30078231]
Catalina-Rodriguez, O.; Kolukula, V.K.; Tomita, Y.; Preet, A.; Palmieri, F.; Wellstein, A.; Byers, S.; Giaccia, A.J.; Glasgow, E.; Albanese, C.; Avantaggiati, M.L. The mitochondrial citrate transporter, CIC, is essential for mitochondrial homeostasis. Oncotarget, 2012, 3(10), 1220-1235.
[] [PMID: 23100451]
Triscari, J.; Sullivan, A.C. Comparative effects of (--)-hydroxycitrate and (+)-allo-hydroxycitrate on acetyl CoA carboxylase and fatty acid and cholesterol synthesis in vivo. Lipids, 1977, 12(4), 357-363.
[] [PMID: 16191]
Berkhout, T.A.; Havekes, L.M.; Pearce, N.J.; Groot, P.H. The effect of (-)-hydroxycitrate on the activity of the low-density-lipoprotein receptor and 3-hydroxy-3-methylglutaryl-CoA reductase levels in the human hepatoma cell line Hep G2. Biochem. J., 1990, 272(1), 181-186.
[] [PMID: 2176080]
Sullivan, A.C.; Triscari, J.; Spiegel, J.E. Metabolic regulation as a control for lipid disorders. II. Influence of (--)-hydroxycitrate on genetically and experimentally induced hypertriglyceridemia in the rat. Am. J. Clin. Nutr., 1977, 30(5), 777-784.
[] [PMID: 857644]
Zaidi, N.; Swinnen, J.V.; Smans, K. ATP-citrate lyase: a key player in cancer metabolism. Cancer Res., 2012, 72(15), 3709-3714.
[] [PMID: 22787121]
Bilen, O.; Ballantyne, C.M. Bempedoic Acid (ETC-1002): an investigational inhibitor of ATP citrate lyase. Curr. Atheroscler. Rep., 2016, 18(10), 61.
[] [PMID: 27663902]
Pinkosky, S.L.; Filippov, S.; Srivastava, R.A.; Hanselman, J.C.; Bradshaw, C.D.; Hurley, T.R.; Cramer, C.T.; Spahr, M.A.; Brant, A.F.; Houghton, J.L.; Baker, C.; Naples, M.; Adeli, K.; Newton, R.S. AMP-activated protein kinase and ATP-citrate lyase are two distinct molecular targets for ETC-1002, a novel small molecule regulator of lipid and carbohydrate metabolism. J. Lipid Res., 2013, 54(1), 134-151.
[] [PMID: 23118444]
Lott, I.T.; Doran, E.; Nguyen, V.Q.; Tournay, A.; Head, E.; Gillen, D.L. Down syndrome and dementia: a randomized, controlled trial of antioxidant supplementation. Am. J. Med. Genet. A., 2011, 155A(8), 1939-1948.
[] [PMID: 21739598]
Chypre, M.; Zaidi, N.; Smans, K. ATP-citrate lyase: a mini-review. Biochem. Biophys. Res. Commun., 2012, 422(1), 1-4.
[] [PMID: 22575446]
Hu, J.; Komakula, A.; Fraser, M.E. Binding of hydroxycitrate to human ATP-citrate lyase. Acta Crystallogr. D Struct. Biol., 2017, 73(Pt 8), 660-671.
[] [PMID: 28777081]

Rights & PermissionsPrintExport Cite as

Article Details

Year: 2019
Page: [7104 - 7116]
Pages: 13
DOI: 10.2174/0929867325666180510124558
Price: $65

Article Metrics

PDF: 50
HTML: 13
PRC: 1