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. 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. It is also involved in reactive oxygen species (ROS) production through hyperpolarization of mitochondria and increases ROS levels when overexpressed. Furthermore, dicarboxylate carriers are crucial for cellular respiration, and inhibition of DIC impairs complex I activity in mitochondria.
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. The activity of dicarboxylate carriers has also been found to be upregulated in plants in response to stress. 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. 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. 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.
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