Cellular Citrate Levels Establish a Regulatory Link Between Energy Metabolism and the Hepatic Iron Hormone Hepcidin

Overview

Journal J Mol Med (Berl)

Specialty General Medicine

Date 2017 Jun 7

PMID 28585096

Citations 6

Authors

Ana Rita da Silva

Joana Neves

Katarzyna Mleczko-Sanecka

Amol Tandon

Sven W Sauer

Matthias W Hentze

Martina U Muckenthaler

Affiliations

Soon will be listed here.

Abstract

Key Messages: • Elevated citrate levels increase hepcidin mRNA expression in primary hepatocytes. • Citrate treatment in primary hepatocytes activates hepcidin expression. • Intravenous injection of citrate in mice increases hepcidin mRNA levels. • The hepcidin response to citrate involves the BMP/SMAD signaling pathway.

Citing Articles

Ferric Ammonium Citrate Reduces Claudin-5 Abundance and Function in Primary Mouse Brain Endothelial Cells.

Runwal P, Pyun J, Newman S, Mawal C, Bush A, Koehn L Pharm Res. 2025; 42(2):319-334.

PMID: 39939558 PMC: 11880181. DOI: 10.1007/s11095-025-03826-2.

Binding of Citrate-Fe to Plastic Culture Dishes, an Artefact Useful as a Simple Technique to Screen for New Iron Chelators.

Ogura J, Sato T, Higuchi K, Sivaprakasam S, Kopel J, Bhutia Y Int J Mol Sci. 2022; 23(12).

PMID: 35743100 PMC: 9223814. DOI: 10.3390/ijms23126657.

A Potential Citrate Shunt in Erythrocytes of PKAN Patients Caused by Mutations in Pantothenate Kinase 2.

Werning M, Dobretzberger V, Brenner M, Mullner E, Mlynek G, Djinovic-Carugo K Biomolecules. 2022; 12(2).

PMID: 35204826 PMC: 8869601. DOI: 10.3390/biom12020325.

The Effect of STAT3 Signal Pathway Activation on Retinopathy of Prematurity.

Ren J, Jiang J, Ou W, Luo X, Xiang J, Liu G Front Pediatr. 2021; 9:638432.

PMID: 34858895 PMC: 8631452. DOI: 10.3389/fped.2021.638432.

Silica-coated magnetic-nanoparticle-induced cytotoxicity is reduced in microglia by glutathione and citrate identified using integrated omics.

Shin T, Manavalan B, Lee D, Basith S, Seo C, Paik M Part Fibre Toxicol. 2021; 18(1):42.

PMID: 34819099 PMC: 8614058. DOI: 10.1186/s12989-021-00433-y.

References

Kim W, Flamm S, Di Bisceglie A, Bodenheimer H . Serum activity of alanine aminotransferase (ALT) as an indicator of health and disease. Hepatology. 2008; 47(4):1363-70. DOI: 10.1002/hep.22109. View

Tapryal N, G V, Mukhopadhyay C . Catecholamine stress hormones regulate cellular iron homeostasis by a posttranscriptional mechanism mediated by iron regulatory protein: implication in energy homeostasis. J Biol Chem. 2015; 290(12):7634-46. PMC: 4367267. DOI: 10.1074/jbc.M114.592519. View

BEINERT H, Kennedy M . Aconitase, a two-faced protein: enzyme and iron regulatory factor. FASEB J. 1993; 7(15):1442-9. DOI: 10.1096/fasebj.7.15.8262329. View

Taylor W, Halperin M . Regulation of pyruvate dehydrogenase in muscle. Inhibition by citrate. J Biol Chem. 1973; 248(17):6080-3. View

Muckenthaler M, Rivella S, Hentze M, Galy B . A Red Carpet for Iron Metabolism. Cell. 2017; 168(3):344-361. PMC: 5706455. DOI: 10.1016/j.cell.2016.12.034. View

La P, Yang G, Dennery P . Mammalian target of rapamycin complex 1 (mTORC1)-mediated phosphorylation stabilizes ISCU protein: implications for iron metabolism. J Biol Chem. 2013; 288(18):12901-9. PMC: 3642333. DOI: 10.1074/jbc.M112.424499. View

Li J, Wang H, Tino J, Robl J, Herpin T, Lawrence R . 2-hydroxy-N-arylbenzenesulfonamides as ATP-citrate lyase inhibitors. Bioorg Med Chem Lett. 2007; 17(11):3208-11. DOI: 10.1016/j.bmcl.2007.03.017. View

Casanovas G, Mleczko-Sanecka K, Altamura S, Hentze M, Muckenthaler M . Bone morphogenetic protein (BMP)-responsive elements located in the proximal and distal hepcidin promoter are critical for its response to HJV/BMP/SMAD. J Mol Med (Berl). 2009; 87(5):471-80. DOI: 10.1007/s00109-009-0447-2. View

Hines J, Fromm H, Honzatko R . Structures of activated fructose-1,6-bisphosphatase from Escherichia coli. Coordinate regulation of bacterial metabolism and the conservation of the R-state. J Biol Chem. 2007; 282(16):11696-704. DOI: 10.1074/jbc.M611104200. View

10.

SRERE P . The citrate cleavage enzyme. I. Distribution and purification. J Biol Chem. 1959; 234:2544-7. View

11.

Livak K, Schmittgen T . Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods. 2002; 25(4):402-8. DOI: 10.1006/meth.2001.1262. View

12.

Van De Wier B, Balk J, Haenen G, Giamouridis D, Bakker J, Bast B . Elevated citrate levels in non-alcoholic fatty liver disease: the potential of citrate to promote radical production. FEBS Lett. 2013; 587(15):2461-6. DOI: 10.1016/j.febslet.2013.06.019. View

13.

Oexle H, Gnaiger E, Weiss G . Iron-dependent changes in cellular energy metabolism: influence on citric acid cycle and oxidative phosphorylation. Biochim Biophys Acta. 1999; 1413(3):99-107. DOI: 10.1016/s0005-2728(99)00088-2. View

14.

Verga Falzacappa M, Casanovas G, Hentze M, Muckenthaler M . A bone morphogenetic protein (BMP)-responsive element in the hepcidin promoter controls HFE2-mediated hepatic hepcidin expression and its response to IL-6 in cultured cells. J Mol Med (Berl). 2008; 86(5):531-40. DOI: 10.1007/s00109-008-0313-7. View

15.

Besson-Fournier C, Latour C, Kautz L, Bertrand J, Ganz T, Roth M . Induction of activin B by inflammatory stimuli up-regulates expression of the iron-regulatory peptide hepcidin through Smad1/5/8 signaling. Blood. 2012; 120(2):431-9. DOI: 10.1182/blood-2012-02-411470. View

16.

Dandekar T, Stripecke R, Gray N, Goossen B, Constable A, Johansson H . Identification of a novel iron-responsive element in murine and human erythroid delta-aminolevulinic acid synthase mRNA. EMBO J. 1991; 10(7):1903-9. PMC: 452865. DOI: 10.1002/j.1460-2075.1991.tb07716.x. View

17.

Costello L, Liu Y, Franklin R, Kennedy M . Zinc inhibition of mitochondrial aconitase and its importance in citrate metabolism of prostate epithelial cells. J Biol Chem. 1997; 272(46):28875-81. DOI: 10.1074/jbc.272.46.28875. View

18.

Galvez T, Teruel M, Heo W, Jones J, Kim M, Liou J . siRNA screen of the human signaling proteome identifies the PtdIns(3,4,5)P3-mTOR signaling pathway as a primary regulator of transferrin uptake. Genome Biol. 2007; 8(7):R142. PMC: 2323231. DOI: 10.1186/gb-2007-8-7-r142. View

19.

HILLAR M, Lott V, Lennox B . Correlation of the effects of citric acid cycle metabolites on succinate oxidation by rat liver mitochondria and submitochondrial particles. J Bioenerg. 1975; 7(1):1-16. DOI: 10.1007/BF01558459. View

20.

Sam A, Busbridge M, Amin A, Webber L, White D, Franks S . Hepcidin levels in diabetes mellitus and polycystic ovary syndrome. Diabet Med. 2013; 30(12):1495-9. PMC: 4232927. DOI: 10.1111/dme.12262. View