Mitochondrial dicarboxylate carrier explained

The mitochondrial dicarboxylate carrier (DIC) is an integral membrane protein encoded by the SLC25A10 gene in humans that catalyzes the transport of dicarboxylates such as malonate, malate, and succinate across the inner mitochondrial membrane in exchange for phosphate, sulfate, and thiosulfate by a simultaneous antiport mechanism, thus supplying substrates for the Krebs cycle, gluconeogenesis, urea synthesis, fatty acid synthesis, and sulfur metabolism.^{[1] [2] [3] [4] [5]}

Structure

The SLC25A10 gene is located on the q arm of chromosome 17 in position 25.3 and spans 8,781 base pairs.^[4] The gene has 11 exons and produces a 31.3 kDa protein composed of 287 amino acids.^{[6] [7]} Intron 1 of this gene has five short Alu sequences.^[8] Mitochondrial dicarboxylate carriers are dimers, each consisting of six transmembrane domains with both the N- and C- terminus exposed to the cytoplasm.^[9] Like all mitochondrial carriers, dicarboxylate carriers features a tripartite structure with three repeats of about 100 amino acid residues, each of which contains a conserved sequence motif.^[10] These three tandem sequences fold into two anti-parallel transmembrane α-helices linked by hydrophilic sequences.

Function

A crucial function of dicarboxylate carriers is to export malate from the mitochondria in exchange for inorganic phosphate. Dicarboxylate carriers are highly abundant in the adipose tissue and play a central role in supplying cytosolic malate for the citrate transporter, which then exchanges cytosolic malate for mitochondrial citrate to begin fatty acid synthesis.^[11] Abundant levels of DIC are also detected in the kidneys and liver, whereas lower levels are found in the lung, spleen, heart, and brain. Dicarboxylate carriers are involved in glucose-stimulated insulin secretion through pyruvate cycling, which mediates NADPH production, and by providing cytosolic malate as a counter-substrate for citrate export.^[12] It is also involved in reactive oxygen species (ROS) production through hyperpolarization of mitochondria and increases ROS levels when overexpressed.^[13] Furthermore, dicarboxylate carriers are crucial for cellular respiration, and inhibition of DIC impairs complex I activity in mitochondria.^[14]

Regulation

Insulin causes a dramatic (approximately 80%) reduction of DIC expression in mice, whereas free fatty acids induces DIC expression. Cold exposure, which increases energy expenditure and decreases fatty acid biosynthesis, resulted in a significant (approximately 50%) reduction of DIC expression. DIC is inhibited by some dicarboxylate analogues, such as butylmalonate, as well as bathophenanthroline and thiol reagents such as Mersalyl and p-hydroxymercuribenzoate.^{[15] [16] [17]} The activity of dicarboxylate carriers has also been found to be upregulated in plants in response to stress.^[18] The rate of malonate uptake is inhibited by 2-oxoglutarate and unaffected by citrate, whereas the rates of succinate and malate uptake are inhibited by both 2-oxoglutarate and citrate.

Disease relevance

Suppression of SLC25A10 down-regulated fatty acid synthesis in mice, resulting in decreased lipid accumulation in adipocytes. Additionally, knockout of SLC25A10 inhibited insulin-stimulated lipogenesis in adipocytes. These findings presents a possible target for anti-obesity treatments.^[19] It is also upregulated in tumors, which is likely because it regulates energy metabolism and redox homeostasis, both of which are frequently altered in tumor cells. In non-small cell lung cancer (NSCLC) cells, inhibition of SLC25A10 was found to increase the sensitivity to traditional anticancer drugs, and thus may present a potential target for anti-cancer strategies.^[20] Furthermore, overexpression of dicarboxylate carriers in renal proximal tubular cells has been found to cause a reversion to a non-diabetic state and protect cells from oxidative injury. This finding supports the dicarboxylate carriers as a potential therapeutic target to correct underlying metabolic disturbances in diabetic nephropathy.^[21]

Interactions

This protein has binary interactions with NOTCH2NL, KRTAP5-9, KRTAP4-2, KRTAP10-8, MDFI, and KRT40.^{[22] [23]}

See also

• Solute carrier family

Further reading

• Fiermonte G, Dolce V, Arrigoni R, Runswick MJ, Walker JE, Palmieri F . Organization and sequence of the gene for the human mitochondrial dicarboxylate carrier: evolution of the carrier family . The Biochemical Journal . 344 . 3 . 953–60 . December 1999 . 10585886 . 1220721 . 10.1042/bj3440953 .
• Douglas MW, Diefenbach RJ, Homa FL, Miranda-Saksena M, Rixon FJ, Vittone V, Byth K, Cunningham AL . Herpes simplex virus type 1 capsid protein VP26 interacts with dynein light chains RP3 and Tctex1 and plays a role in retrograde cellular transport . The Journal of Biological Chemistry . 279 . 27 . 28522–30 . July 2004 . 15117959 . 10.1074/jbc.M311671200 . free .
• Mizuarai S, Miki S, Araki H, Takahashi K, Kotani H . Identification of dicarboxylate carrier Slc25a10 as malate transporter in de novo fatty acid synthesis . The Journal of Biological Chemistry . 280 . 37 . 32434–41 . September 2005 . 16027120 . 10.1074/jbc.M503152200 . free .
• Khanna H, Hurd TW, Lillo C, Shu X, Parapuram SK, He S, Akimoto M, Wright AF, Margolis B, Williams DS, Swaroop A . RPGR-ORF15, which is mutated in retinitis pigmentosa, associates with SMC1, SMC3, and microtubule transport proteins . The Journal of Biological Chemistry . 280 . 39 . 33580–7 . September 2005 . 16043481 . 1249479 . 10.1074/jbc.M505827200 . free .
• Rual JF, Venkatesan K, Hao T, Hirozane-Kishikawa T, Dricot A, Li N, Berriz GF, Gibbons FD, Dreze M, Ayivi-Guedehoussou N, Klitgord N, Simon C, Boxem M, Milstein S, Rosenberg J, Goldberg DS, Zhang LV, Wong SL, Franklin G, Li S, Albala JS, Lim J, Fraughton C, Llamosas E, Cevik S, Bex C, Lamesch P, Sikorski RS, Vandenhaute J, Zoghbi HY, Smolyar A, Bosak S, Sequerra R, Doucette-Stamm L, Cusick ME, Hill DE, Roth FP, Vidal M . Towards a proteome-scale map of the human protein-protein interaction network . Nature . 437 . 7062 . 1173–8 . October 2005 . 16189514 . 10.1038/nature04209 . Huda Zoghbi . 2005Natur.437.1173R . 4427026 .
• Otsuki T, Ota T, Nishikawa T, Hayashi K, Suzuki Y, Yamamoto J, Wakamatsu A, Kimura K, Sakamoto K, Hatano N, Kawai Y, Ishii S, Saito K, Kojima S, Sugiyama T, Ono T, Okano K, Yoshikawa Y, Aotsuka S, Sasaki N, Hattori A, Okumura K, Nagai K, Sugano S, Isogai T . Signal sequence and keyword trap in silico for selection of full-length human cDNAs encoding secretion or membrane proteins from oligo-capped cDNA libraries . DNA Research . 12 . 2 . 117–26 . 2007 . 16303743 . 10.1093/dnares/12.2.117 . free .

Notes and References

1. Dolce V, Cappello AR, Capobianco L . Mitochondrial tricarboxylate and dicarboxylate-tricarboxylate carriers: from animals to plants . IUBMB Life . 66 . 7 . 462–71 . September 1997 . 25045044. 10.1002/iub.1290. 21307218 . free .
2. Fiermonte G, Palmieri L, Dolce V, Lasorsa FM, Palmieri F, Runswick MJ, Walker JE . The sequence, bacterial expression, and functional reconstitution of the rat mitochondrial dicarboxylate transporter cloned via distant homologs in yeast and Caenorhabditis elegans . The Journal of Biological Chemistry . 273 . 38 . 24754–9 . September 1998 . 9733776 . 10.1074/jbc.273.38.24754 . free .
3. Pannone E, Fiermonte G, Dolce V, Rocchi M, Palmieri F . Assignment of the human dicarboxylate carrier gene (DIC) to chromosome 17 band 17q25.3 . Cytogenetics and Cell Genetics . 83 . 3–4 . 238–9 . Mar 1999 . 10072589 . 10.1159/000015190 . 38031823 .
4. Web site: Entrez Gene: SLC25A10 solute carrier family 25 (mitochondrial carrier; dicarboxylate transporter), member 10.
5. Palmieri L, Palmieri F, Runswick MJ, Walker JE . Identification by bacterial expression and functional reconstitution of the yeast genomic sequence encoding the mitochondrial dicarboxylate carrier protein . FEBS Letters . 399 . 3 . 299–302 . December 1996 . 8985166 . 10.1016/S0014-5793(96)01350-6 . 42731082 . free .
6. Zong NC, Li H, Li H, Lam MP, Jimenez RC, Kim CS, Deng N, Kim AK, Choi JH, Zelaya I, Liem D, Meyer D, Odeberg J, Fang C, Lu HJ, Xu T, Weiss J, Duan H, Uhlen M, Yates JR, Apweiler R, Ge J, Hermjakob H, Ping P . Integration of cardiac proteome biology and medicine by a specialized knowledgebase . Circulation Research . 113 . 9 . 1043–53 . Oct 2013 . 23965338 . 4076475 . 10.1161/CIRCRESAHA.113.301151 .
7. Web site: SLC25A10 - Mitochondrial dicarboxylate carrier . Cardiac Organellar Protein Atlas Knowledgebase (COPaKB) .
8. Fiermonte G, Dolce V, Arrigoni R, Runswick MJ, Walker JE, Palmieri F . Organization and sequence of the gene for the human mitochondrial dicarboxylate carrier: evolution of the carrier family . The Biochemical Journal . 344 . 953–60 . December 1999 . 10585886 . 1220721 . 10.1042/bj3440953 . 3.
9. Das K, Lewis RY, Combatsiaris TP, Lin Y, Shapiro L, Charron MJ, Scherer PE . Predominant expression of the mitochondrial dicarboxylate carrier in white adipose tissue . The Biochemical Journal . 344 . 2 . 313–20 . December 1999 . 10567211 . 1220646 . 10.1042/0264-6021:3440313.
10. Kunji ER . The role and structure of mitochondrial carriers . FEBS Letters . 564 . 3 . 239–44 . April 2004 . 15111103 . 10.1016/S0014-5793(04)00242-X . 34604794 .
11. Mizuarai S, Miki S, Araki H, Takahashi K, Kotani H . Identification of dicarboxylate carrier Slc25a10 as malate transporter in de novo fatty acid synthesis . The Journal of Biological Chemistry . 280 . 37 . 32434–41 . September 2005 . 16027120 . 10.1074/jbc.M503152200 . free .
12. Huypens P, Pillai R, Sheinin T, Schaefer S, Huang M, Odegaard ML, Ronnebaum SM, Wettig SD, Joseph JW . The dicarboxylate carrier plays a role in mitochondrial malate transport and in the regulation of glucose-stimulated insulin secretion from rat pancreatic beta cells . Diabetologia . 54 . 1 . 135–45 . January 2011 . 20949348 . 10.1007/s00125-010-1923-5 . free .
13. Lin Y, Berg AH, Iyengar P, Lam TK, Giacca A, Combs TP, Rajala MW, Du X, Rollman B, Li W, Hawkins M, Barzilai N, Rhodes CJ, Fantus IG, Brownlee M, Scherer PE . The hyperglycemia-induced inflammatory response in adipocytes: the role of reactive oxygen species . The Journal of Biological Chemistry . 280 . 6 . 4617–26 . February 2005 . 15536073 . 10.1074/jbc.M411863200 . free .
14. Kamga CK, Zhang SX, Wang Y . Dicarboxylate carrier-mediated glutathione transport is essential for reactive oxygen species homeostasis and normal respiration in rat brain mitochondria . American Journal of Physiology. Cell Physiology . 299 . 2 . C497-505 . August 2010 . 20538765 . 2928630 . 10.1152/ajpcell.00058.2010 .
15. Chappell JB . Systems used for the transport of substrates into mitochondria . British Medical Bulletin . 24 . 2 . 150–7 . May 1968 . 5649935 . 10.1093/oxfordjournals.bmb.a070618 .
16. Meijer AJ, Groot GS, Tager JM . Effect of sulphydryl-blocking reagents on mitochondrial anion-exchange reactions involving phosphate . FEBS Letters . 8 . 1 . 41–44 . May 1970 . 11947527 . 10.1016/0014-5793(70)80220-4 . 28153182 .
17. Passarella S, Palmieri F, Quagliariello E . The role of metal ions in the transport of substrates in mitochondria . FEBS Letters . 38 . 1 . 91–5 . December 1973 . 4772695 . 10.1016/0014-5793(73)80521-6 . 27910976 .
18. Palmieri F, Pierri CL, De Grassi A, Nunes-Nesi A, Fernie AR . Evolution, structure and function of mitochondrial carriers: a review with new insights . The Plant Journal . 66 . 1 . 161–81 . April 2011 . 21443630 . 10.1111/j.1365-313X.2011.04516.x . 11586/79017 .
19. Kulyté A, Ehrlund A, Arner P, Dahlman I . Global transcriptome profiling identifies KLF15 and SLC25A10 as modifiers of adipocytes insulin sensitivity in obese women . PLOS ONE . 12 . 6 . e0178485 . 2017-06-01 . 28570579 . 10.1371/journal.pone.0178485 . 5453532. 2017PLoSO..1278485K . free .
20. Zhou X, Paredes JA, Krishnan S, Curbo S, Karlsson A . The mitochondrial carrier SLC25A10 regulates cancer cell growth . Oncotarget . 6 . 11 . 9271–83 . April 2015 . 25797253 . 4496216 . 10.18632/oncotarget.3375 .
21. Lash LH . Mitochondrial Glutathione in Diabetic Nephropathy . Journal of Clinical Medicine . 4 . 7 . 1428–47 . July 2015 . 26239684 . 4519798 . 10.3390/jcm4071428 . free .
22. Web site: SLC25A3 - Mitochondrial dicarboxylate carrier - Homo sapiens (Human) - SLC25A10 gene & protein. www.uniprot.org. en. 2018-08-21.
23. January 2017. UniProt: the universal protein knowledgebase. Nucleic Acids Research. 45. D1. D158–D169. 10.1093/nar/gkw1099. 5210571. 27899622.