# Mitochondrial citrate transport protein
The mitochondrial citrate transport protein, also called the citrate/isocitrate carrier (CIC) and encoded by the **SLC25A1** gene, is a nuclear-encoded transporter of the mitochondrial inner membrane that exports citrate and isocitrate from the mitochondrial matrix to the cytosol in exchange for malate.[1](https://pmc.ncbi.nlm.nih.gov/articles/PMC7912299/) It is the only known human mitochondrial transporter for citrate, which makes its activity central to linking mitochondrial metabolism with cytosolic biosynthesis and regulation.[1](https://pmc.ncbi.nlm.nih.gov/articles/PMC7912299/)
| Key fact | Detail |
|---|---|
| Names and gene | SLC25A1, also citrate transporter protein (CTP), citrate/isocitrate carrier (CIC), or tricarboxylate carrier protein; gene on chromosome 22q11.2[1](https://pmc.ncbi.nlm.nih.gov/articles/PMC7912299/) • [2](https://www.sciencedirect.com/science/article/pii/S1043661820314407) |
| Transport reaction | Electroneutral exchange of citrate (or isocitrate) out of the matrix for cytosolic malate; in vitro Km approximately 0.76 mM for citrate and 0.13 mM for malate[3](https://pmc.ncbi.nlm.nih.gov/articles/PMC9792894/) |
| Structure | Mature protein of 298 amino acids in three homologous domains of about 100 amino acids, each with two alpha-helices; synthesized with a 13-amino-acid N-terminal presequence[4](https://pmc.ncbi.nlm.nih.gov/articles/PMC7504413/) |
| Discovery | First identified in 1967 by Chappell and Haarhoff in rat liver mitochondria; later purified and reconstituted from rat, bovine, yeast, eel, and maize mitochondria[5](https://pmc.ncbi.nlm.nih.gov/articles/PMC9288958/) |
| Cytosolic fate of citrate | ATP-citrate lyase cleaves exported citrate into oxaloacetate and acetyl-CoA, the starting block for fatty acid and sterol synthesis[4](https://pmc.ncbi.nlm.nih.gov/articles/PMC7504413/) • [6](https://pmc.ncbi.nlm.nih.gov/articles/PMC3806213/) |
| Congenital disease | At least 12 SLC25A1 mutations cause combined D,L-2-hydroxyglutaric aciduria, a severe infantile brain disorder[7](https://medlineplus.gov/genetics/gene/slc25a1/) |
| Inhibitors | BTA (first generation), CTPI-1 (Kₑ 63.6 µM), and CTPI-2 (Kₑ 3.5 µM, roughly 20-fold better binding)[8](https://pmc.ncbi.nlm.nih.gov/articles/PMC6030199/) |
## Function and transport mechanism
CIC sits in the inner mitochondrial membrane, which is impermeable to ions and metabolites, and catalyzes the exchange of matrix citrate or isocitrate for cytosolic malate.[1](https://pmc.ncbi.nlm.nih.gov/articles/PMC7912299/) When reconstituted in vitro, transport is dependent on ΔpH and is electroneutral, exchanging H⁺ + citrate³⁻ for malate²⁻; phosphoenolpyruvate is an additional substrate at least in vitro.[3](https://pmc.ncbi.nlm.nih.gov/articles/PMC9792894/) By moving these substrates in both directions, the carrier connects reactions inside mitochondria with cytosolic ones, and malate re-entering the matrix can influence mitochondrial respiration, membrane potential stability, glycolysis, and lipogenesis.[5](https://pmc.ncbi.nlm.nih.gov/articles/PMC9288958/)
The kinetic mechanism has been debated. Earlier work described SLC25A1 as a dimer operating with a sequential mechanism in which both substrates bind concurrently in a ternary complex.[3](https://pmc.ncbi.nlm.nih.gov/articles/PMC9792894/) A 2024 reanalysis of the citrate, dicarboxylate, oxoglutarate, and aspartate/glutamate carriers concluded instead that these human SLC25 carriers function as monomers with a single central substrate-binding site and a ping-pong (alternating access) mechanism, in which one substrate is imported and released before the counter-substrate binds and is exported.[9](https://pubmed.ncbi.nlm.nih.gov/38937634/)
## Structure and biogenesis
The SLC25A1 gene spans 2.8 kb of human DNA and encodes a precursor with a 13-amino-acid N-terminal presequence followed by the 298-amino-acid mature protein.[4](https://pmc.ncbi.nlm.nih.gov/articles/PMC7504413/) The mature protein has three homologous domains of roughly 100 amino acids, each forming two alpha-helices, the tripartite architecture typical of the SLC25 mitochondrial carrier family.[4](https://pmc.ncbi.nlm.nih.gov/articles/PMC7504413/) • [10](https://pmc.ncbi.nlm.nih.gov/articles/PMC13140495/) Unusually for the family, whose members generally lack N-terminal presequences and carry internal targeting elements, the CIC presequence facilitates protein solubility but does not itself confer mitochondrial targeting information.[10](https://pmc.ncbi.nlm.nih.gov/articles/PMC13140495/) A variant called pmCiC has been reported at the plasma membrane of human prostatic epithelial cells.[4](https://pmc.ncbi.nlm.nih.gov/articles/PMC7504413/)
## Role in metabolism
Cytosolic citrate has three principal uses. First, ATP-citrate lyase converts it into oxaloacetate and acetyl-CoA; the acetyl-CoA feeds fatty acid and sterol synthesis, while the oxaloacetate is reduced to malate and then decarboxylated by malic enzyme to pyruvate, generating NADPH.[4](https://pmc.ncbi.nlm.nih.gov/articles/PMC7504413/) Second, citrate is an allosteric regulator: it inhibits the glycolytic enzyme phosphofructokinase (PFK) and activates fructose 1,6-bisphosphatase (Fbp1) and acetyl-CoA carboxylase alpha ([ACACA](https://www.edgepedia.org/acaca)), which serve gluconeogenesis and lipid synthesis respectively.[1](https://pmc.ncbi.nlm.nih.gov/articles/PMC7912299/) Third, citrate-derived acetyl-CoA supports protein acetylation, including histone acetylation, so the carrier contributes to epigenetic regulation and genome integrity maintenance.[1](https://pmc.ncbi.nlm.nih.gov/articles/PMC7912299/) • [11](https://www.frontiersin.org/journals/cell-and-developmental-biology/articles/10.3389/fcell.2019.00003/full)
In plants, a related carrier, the dicarboxylate-tricarboxylate carrier (DTC), transports a broad spectrum of dicarboxylates and tricarboxylates and participates in processes such as nitrogen assimilation and fruit ripening.[5](https://pmc.ncbi.nlm.nih.gov/articles/PMC9288958/)
## Disease associations
**Congenital deficiency.** At least 12 mutations in SLC25A1 cause combined [D,L-2-hydroxyglutaric aciduria](https://www.edgepedia.org/d-l-2-hydroxyglutaric-aciduria), a condition with severe brain abnormalities apparent in early infancy.[7](https://medlineplus.gov/genetics/gene/slc25a1/) Each known mutation greatly reduces transporter function, so citrate and malate can no longer be exchanged across the inner membrane; D- and L-2-hydroxyglutarate accumulate to levels that damage cells, with brain cells the most vulnerable.[7](https://medlineplus.gov/genetics/gene/slc25a1/) The gene lies at chromosome 22q11.2, a region whose microdeletions cause the Velo-cardio-facial and DiGeorge syndromes.[12](https://www.nature.com/articles/s41418-020-0491-6)
**Cancer.** SLC25A1 is upregulated in non-small cell lung cancer, colorectal cancer, and metastatic sites, and promotes tumor growth and survival by reprogramming energy metabolism; high expression in lung cancer stem cell spheres enhanced mitochondrial citrate uptake and respiration.[13](https://pmc.ncbi.nlm.nih.gov/articles/PMC10266237/pdf/nihms-1904789.pdf) In pancreatic models, oncogenic KRASᴳ¹²ᴰ upregulates SLC25A1 as part of lipid metabolism reprogramming that drives tumorigenesis.[14](https://pmc.ncbi.nlm.nih.gov/articles/PMC10840918/pdf/nihms-1931822.pdf) In acute myeloid leukemia, the carrier supports de novo lipogenesis and protein acetylation by regulating cytoplasmic acetyl-CoA levels and promotes cancer cell growth and resistance to energy-stress-induced apoptosis.[15](https://haematologica.org/article/view/12250/78784)
**Fatty liver disease.** Slc25a1 expression is elevated in human NASH livers and in mice fed a high-fat diet. In preclinical models, the inhibitor CTPI-2 (50 mg/kg on alternate days, intraperitoneal) reverted steatosis, prevented progression to steatohepatitis, reduced inflammatory macrophage infiltration in liver and adipose tissue, and mitigated obesity, while genetic ablation of one gene copy or a liver-targeted knockout recapitulated parts of these effects.[12](https://www.nature.com/articles/s41418-020-0491-6)
## Inhibitors as research tools and drug candidates
The first-generation inhibitor benzenetricarboxylate (BTA) is a non-cleavable citrate analog widely used in vitro on reconstituted liposomes, but in vivo it requires very high concentrations (5 mM) and can interfere with other citrate-binding proteins.[1](https://pmc.ncbi.nlm.nih.gov/articles/PMC7912299/) CTPI-1, discovered from a homology model of the *Caenorhabditis elegans* carrier, was the first competitive inhibitor but binds suboptimally (Kₑ 63.6 µM).[8](https://pmc.ncbi.nlm.nih.gov/articles/PMC6030199/) • [1](https://pmc.ncbi.nlm.nih.gov/articles/PMC7912299/) Structure-guided optimization produced CTPI-2, with an experimental Kₑ of 3.5 µM, roughly 20-fold better binding than CTPI-1, and inhibition of citrate transport and tumor proliferation at doses tenfold lower.[8](https://pmc.ncbi.nlm.nih.gov/articles/PMC6030199/) • [12](https://www.nature.com/articles/s41418-020-0491-6) CTPI-2 binds residues involved in citrate recognition, including Lys190, Lys245, Arg282, and Arg285, and largely phenocopies SLC25A1 deficiency in gene-expression profiling, supporting SLC25A1 as its principal intracellular target.[8](https://pmc.ncbi.nlm.nih.gov/articles/PMC6030199/)
## References
1. [The Mitochondrial Citrate Carrier SLC25A1/CIC and the Fundamental Role of Citrate in Cancer, Inflammation and Beyond, Biomolecules (2021)](https://pmc.ncbi.nlm.nih.gov/articles/PMC7912299/)
2. [Advances into Understanding the Vital Role of the Mitochondrial Citrate Carrier (CIC) in Metabolic Diseases, Pharmacological Research](https://www.sciencedirect.com/science/article/pii/S1043661820314407)
3. [Intracellular Citrate/acetyl-CoA flux and endoplasmic reticulum acetylation, PMC](https://pmc.ncbi.nlm.nih.gov/articles/PMC9792894/)
4. [Drosophila melanogaster Mitochondrial Carriers: Similarities and Differences with the Human Carriers, PMC](https://pmc.ncbi.nlm.nih.gov/articles/PMC7504413/)
5. [Multiple roles played by the mitochondrial citrate carrier in cellular metabolism and physiology, PMC](https://pmc.ncbi.nlm.nih.gov/articles/PMC9288958/)
6. [Physiological and pathological roles of mitochondrial SLC25 carriers, PMC](https://pmc.ncbi.nlm.nih.gov/articles/PMC3806213/)
7. [SLC25A1 gene, MedlinePlus Genetics](https://medlineplus.gov/genetics/gene/slc25a1/)
8. [The mitochondrial citrate carrier, SLC25A1, drives stemness and therapy resistance in non-small cell lung cancer, PMC](https://pmc.ncbi.nlm.nih.gov/articles/PMC6030199/)
9. [Human mitochondrial carriers of the SLC25 family function as monomers exchanging substrates with a ping-pong kinetic mechanism, PubMed](https://pubmed.ncbi.nlm.nih.gov/38937634/)
10. [From the cytosol to the inner membrane: biogenesis of the mitochondrial carrier family, Protein Science (2026)](https://pmc.ncbi.nlm.nih.gov/articles/PMC13140495/)
11. [Emerging Roles in the Biogenesis of Cytochrome c Oxidase for Members of the Mitochondrial Carrier Family, Frontiers in Cell and Developmental Biology](https://www.frontiersin.org/journals/cell-and-developmental-biology/articles/10.3389/fcell.2019.00003/full)
12. [Inhibition of the mitochondrial citrate carrier, Slc25a1, reverts steatosis, glucose intolerance, and inflammation in preclinical models of NAFLD/NASH, Cell Death & Differentiation (2020)](https://www.nature.com/articles/s41418-020-0491-6)
13. [Nutrient transporters: connecting cancer metabolism to therapeutic opportunities, PMC](https://pmc.ncbi.nlm.nih.gov/articles/PMC10266237/pdf/nihms-1904789.pdf)
14. [Oncogenic KRASᴳ¹²ᴰ reprograms lipid metabolism by upregulating SLC25A1 to drive pancreatic tumorigenesis, PMC](https://pmc.ncbi.nlm.nih.gov/articles/PMC10840918/pdf/nihms-1931822.pdf)
15. [SLC25A1 is essential in AML, Haematologica](https://haematologica.org/article/view/12250/78784)
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*Topic: Encyclopedia › Life and health › Biological foundations › Biochemistry and metabolism › Metabolism and metabolic pathways › Carbohydrate and energy metabolism › Citric acid cycle › Citrate synthesis and citrate chemistry*
*Initially written Sep 17, 2026 · Reviewed: Sep 30, 2026; Oct 21, 2026 · Edited: Sep 30, 2026; Oct 21, 2026 · Last review: Oct 21, 2026*
*Copyright 2026 EdgeChat AI, a subsidiary of Biostate AI.*
License: Edgepedia Community License 1.0, https://www.edgepedia.org/edgepedia/license