The SLC25A10 gene is located on the q arm of chromosome 17 in position 25.3 and spans 8,781 base pairs.[3] The gene has 11 exons and produces a 31.3 kDa protein composed of 287 amino acids.[5][6]Intron 1 of this gene has five short Alu sequences.[7][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.[1]
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.[12] 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.[13][13] It is also involved in reactive oxygen species (ROS) production through hyperpolarization of mitochondria and increases ROS levels when overexpressed.[14] Furthermore, dicarboxylate carriers are crucial for cellular respiration, and inhibition of DIC impairs complex I activity in mitochondria.[15]
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.[9] DIC is inhibited by some dicarboxylate analogues, such as butylmalonate, as well as bathophenanthroline and thiol reagents such as Mersalyl and p-hydroxymercuribenzoate.[16][17][18] The activity of dicarboxylate carriers has also been found to be upregulated in plants in response to stress.[19] 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.[11][20] 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.[21] 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.[22]
↑ 1.01.1Fiermonte G, Palmieri L, Dolce V, Lasorsa FM, Palmieri F, Runswick MJ, Walker JE (September 1998). "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. doi:10.1074/jbc.273.38.24754. PMID9733776.
↑Pannone E, Fiermonte G, Dolce V, Rocchi M, Palmieri F (Mar 1999). "Assignment of the human dicarboxylate carrier gene (DIC) to chromosome 17 band 17q25.3". Cytogenetics and Cell Genetics. 83 (3–4): 238–9. doi:10.1159/000015190. PMID10072589.
↑ 11.011.1Mizuarai S, Miki S, Araki H, Takahashi K, Kotani H (September 2005). "Identification of dicarboxylate carrier Slc25a10 as malate transporter in de novo fatty acid synthesis". The Journal of Biological Chemistry. 280 (37): 32434–41. doi:10.1074/jbc.M503152200. PMID16027120.
↑ 13.013.1Huypens P, Pillai R, Sheinin T, Schaefer S, Huang M, Odegaard ML, Ronnebaum SM, Wettig SD, Joseph JW (January 2011). "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. doi:10.1007/s00125-010-1923-5. PMID20949348.
↑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 (February 2005). "The hyperglycemia-induced inflammatory response in adipocytes: the role of reactive oxygen species". The Journal of Biological Chemistry. 280 (6): 4617–26. doi:10.1074/jbc.M411863200. PMID15536073.
↑Meijer AJ, Groot GS, Tager JM (May 1970). "Effect of sulphydryl-blocking reagents on mitochondrial anion-exchange reactions involving phosphate". FEBS Letters. 8 (1): 41–44. doi:10.1016/0014-5793(70)80220-4. PMID11947527.
↑Passarella S, Palmieri F, Quagliariello E (December 1973). "The role of metal ions in the transport of substrates in mitochondria". FEBS Letters. 38 (1): 91–5. doi:10.1016/0014-5793(73)80521-6. PMID4772695.
↑Palmieri F, Pierri CL, De Grassi A, Nunes-Nesi A, Fernie AR (April 2011). "Evolution, structure and function of mitochondrial carriers: a review with new insights". The Plant Journal. 66 (1): 161–81. doi:10.1111/j.1365-313X.2011.04516.x. PMID21443630.
↑Kulyté A, Ehrlund A, Arner P, Dahlman I (2017-06-01). "Global transcriptome profiling identifies KLF15 and SLC25A10 as modifiers of adipocytes insulin sensitivity in obese women". PLOS One. 12 (6): e0178485. doi:10.1371/journal.pone.0178485. PMID28570579.
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Mizuarai S, Miki S, Araki H, Takahashi K, Kotani H (September 2005). "Identification of dicarboxylate carrier Slc25a10 as malate transporter in de novo fatty acid synthesis". The Journal of Biological Chemistry. 280 (37): 32434–41. doi:10.1074/jbc.M503152200. PMID16027120.
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