TheSLC25A10 gene is located on the q arm ofchromosome 17 in position 25.3 and spans 8,781 base pairs.[8] The gene has 11exons and produces a 31.3 kDa protein composed of 287amino acids.[10][11]Intron 1 of this gene has five shortAlu sequences.[12][13] Mitochondrial dicarboxylate carriers aredimers, each consisting of sixtransmembrane domains with both theN- andC- terminus exposed to thecytoplasm.[14] Like all mitochondrial carriers, dicarboxylate carriers features a tripartite structure with three repeats of about 100amino acid residues, each of which contains a conserved sequence motif.[15] These three tandem sequences fold into two anti-parallel transmembraneα-helices linked byhydrophilic sequences.[6]
Crystal structure of a bacterial dicarboxylate carrierCoordinated dicarboxylate within bacterial dicarboxylate carrier
A crucial function of dicarboxylate carriers is to export malate from the mitochondria in exchange for inorganic phosphate. Dicarboxylate carriers are highly abundant in theadipose tissue and play a central role in supplying cytosolic malate for the citrate transporter, which then exchanges cytosolic malate for mitochondrialcitrate to beginfatty acid synthesis.[16] Abundant levels of DIC are also detected in thekidneys andliver, whereas lower levels are found in thelung,spleen,heart, andbrain.[12] Dicarboxylate carriers are involved in glucose-stimulatedinsulin secretion throughpyruvate cycling, which mediatesNADPH production, and by providing cytosolic malate as a counter-substrate for citrate export.[17] It is also involved inreactive oxygen species (ROS) production throughhyperpolarization ofmitochondria and increases ROS levels when overexpressed.[18] Furthermore, dicarboxylate carriers are crucial for cellular respiration, and inhibition of DIC impairscomplex I activity in mitochondria.[19]
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.[14] DIC is inhibited by some dicarboxylate analogues, such as butylmalonate, as well as bathophenanthroline and thiol reagents such asMersalyl andp-hydroxymercuribenzoate.[20][21][22] The activity of dicarboxylate carriers has also been found to be upregulated in plants in response to stress.[23] The rate of malonate uptake is inhibited by2-oxoglutarate and unaffected by citrate, whereas the rates of succinate and malate uptake are inhibited by both 2-oxoglutarate and citrate.
Suppression ofSLC25A10 down-regulated fatty acid synthesis in mice, resulting in decreased lipid accumulation inadipocytes. Additionally, knockout ofSLC25A10 inhibited insulin-stimulatedlipogenesis in adipocytes. These findings presents a possible target for anti-obesity treatments.[16][24] It is also upregulated in tumors, which is likely because it regulatesenergy metabolism andredox homeostasis, both of which are frequently altered in tumor cells. Innon-small cell lung cancer (NSCLC) cells, inhibition ofSLC25A10 was found to increase the sensitivity to traditional anticancer drugs, and thus may present a potential target for anti-cancer strategies.[25] 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.[26]
^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.S2CID38031823.
^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.S2CID28153182.
^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.hdl:11586/79017.PMID21443630.
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