Mitochondrial dicarboxylate carrier

The SLC25A10 gene is located on the q arm of chromosome 17 in position 25.3 and spans 8,781 base pairs.[7] The gene has 11 exons and produces a 31.3 kDa protein composed of 287 amino acids.[9][10] Intron 1 of this gene has five short Alu sequences.[11][12] Mitochondrial dicarboxylate carriers are dimers, each consisting of six transmembrane domains with both the N- and C- terminus exposed to the cytoplasm.[13] 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.[14] These three tandem sequences fold into two anti-parallel transmembrane α-helices linked by hydrophilic sequences.[5]

Crystal structure of a bacterial dicarboxylate carrier

Coordinated 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 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.[15] Abundant levels of DIC are also detected in the kidneys and liver, whereas lower levels are found in the lung, spleen, heart, and brain.[11] 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.[16] It is also involved in reactive oxygen species (ROS) production through hyperpolarization of mitochondria and increases ROS levels when overexpressed.[17] Furthermore, dicarboxylate carriers are crucial for cellular respiration, and inhibition of DIC impairs complex I activity in mitochondria.[18]

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.[13] DIC is inhibited by some dicarboxylate analogues, such as butylmalonate, as well as bathophenanthroline and thiol reagents such as Mersalyl and p-hydroxymercuribenzoate.[19][20][21] The activity of dicarboxylate carriers has also been found to be upregulated in plants in response to stress.[22] 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.

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.[15][23] 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.[24] 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.[25]

This protein has binary interactions with NOTCH2NL, KRTAP5-9, KRTAP4-2, KRTAP10-8, MDFI, and KRT40.[26][27]

• Solute carrier family

This article incorporates text from the United States National Library of Medicine, which is in the public domain.