Biology:Mitochondrial dicarboxylate carrier

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Short description: Mammalian protein found in Homo sapiens


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example

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][9] Mitochondrial dicarboxylate carriers are dimers, each consisting of six transmembrane domains with both the N- and C- terminus exposed to the cytoplasm.[10] 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.[11] These three tandem sequences fold into two anti-parallel transmembrane α-helices linked by hydrophilic sequences.[2]

Crystal structure of a bacterial dicarboxylate carrier
Coordinated dicarboxylate within bacterial dicarboxylate carrier

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.[12] Abundant levels of DIC are also detected in the kidneys and liver, whereas lower levels are found in the lung, spleen, heart, and brain.[8] 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] 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.[10] 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.[12][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]

Interactions

This protein has binary interactions with NOTCH2NL, KRTAP5-9, KRTAP4-2, KRTAP10-8, MDFI, and KRT40.[23][24]

See also

References

  1. ↑ "Mitochondrial tricarboxylate and dicarboxylate-tricarboxylate carriers: from animals to plants". IUBMB Life 66 (7): 462–71. September 1997. doi:10.1002/iub.1290. PMID 25045044. 
  2. ↑ 2.0 2.1 "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. doi:10.1074/jbc.273.38.24754. PMID 9733776. 
  3. ↑ "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. doi:10.1159/000015190. PMID 10072589. 
  4. ↑ 4.0 4.1 "Entrez Gene: SLC25A10 solute carrier family 25 (mitochondrial carrier; dicarboxylate transporter), member 10". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=1468. 
  5. ↑ "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. doi:10.1016/S0014-5793(96)01350-6. PMID 8985166. 
  6. ↑ "Integration of cardiac proteome biology and medicine by a specialized knowledgebase". Circulation Research 113 (9): 1043–53. Oct 2013. doi:10.1161/CIRCRESAHA.113.301151. PMID 23965338. 
  7. ↑ "SLC25A10 - Mitochondrial dicarboxylate carrier". Cardiac Organellar Protein Atlas Knowledgebase (COPaKB). https://amino.heartproteome.org/web/protein/Q9UBX3. 
  8. ↑ 8.0 8.1 "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. doi:10.1042/bj3440953. PMID 10585886. 
  9. ↑ Online Mendelian Inheritance in Man (OMIM) SLC25A10 -606794
  10. ↑ 10.0 10.1 "Predominant expression of the mitochondrial dicarboxylate carrier in white adipose tissue". The Biochemical Journal 344 (2): 313–20. December 1999. doi:10.1042/0264-6021:3440313. PMID 10567211. 
  11. ↑ "The role and structure of mitochondrial carriers". FEBS Letters 564 (3): 239–44. April 2004. doi:10.1016/S0014-5793(04)00242-X. PMID 15111103. 
  12. ↑ 12.0 12.1 "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. doi:10.1074/jbc.M503152200. PMID 16027120. 
  13. ↑ "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. doi:10.1007/s00125-010-1923-5. PMID 20949348. 
  14. ↑ "The hyperglycemia-induced inflammatory response in adipocytes: the role of reactive oxygen species". The Journal of Biological Chemistry 280 (6): 4617–26. February 2005. doi:10.1074/jbc.M411863200. PMID 15536073. 
  15. ↑ "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. doi:10.1152/ajpcell.00058.2010. PMID 20538765. 
  16. ↑ "Systems used for the transport of substrates into mitochondria". British Medical Bulletin 24 (2): 150–7. May 1968. doi:10.1093/oxfordjournals.bmb.a070618. PMID 5649935. 
  17. ↑ "Effect of sulphydryl-blocking reagents on mitochondrial anion-exchange reactions involving phosphate". FEBS Letters 8 (1): 41–44. May 1970. doi:10.1016/0014-5793(70)80220-4. PMID 11947527. 
  18. ↑ "The role of metal ions in the transport of substrates in mitochondria". FEBS Letters 38 (1): 91–5. December 1973. doi:10.1016/0014-5793(73)80521-6. PMID 4772695. 
  19. ↑ "Evolution, structure and function of mitochondrial carriers: a review with new insights". The Plant Journal 66 (1): 161–81. April 2011. doi:10.1111/j.1365-313X.2011.04516.x. PMID 21443630. 
  20. ↑ "Global transcriptome profiling identifies KLF15 and SLC25A10 as modifiers of adipocytes insulin sensitivity in obese women". PLOS ONE 12 (6): e0178485. 2017-06-01. doi:10.1371/journal.pone.0178485. PMID 28570579. Bibcode: 2017PLoSO..1278485K. 
  21. ↑ "The mitochondrial carrier SLC25A10 regulates cancer cell growth". Oncotarget 6 (11): 9271–83. April 2015. doi:10.18632/oncotarget.3375. PMID 25797253. 
  22. ↑ "Mitochondrial Glutathione in Diabetic Nephropathy". Journal of Clinical Medicine 4 (7): 1428–47. July 2015. doi:10.3390/jcm4071428. PMID 26239684. 
  23. ↑ "SLC25A3 - Mitochondrial dicarboxylate carrier - Homo sapiens (Human) - SLC25A10 gene & protein" (in en). https://www.uniprot.org/uniprot/Q9UBX3.  This article incorporates text available under the CC BY 4.0 license.
  24. ↑ "UniProt: the universal protein knowledgebase". Nucleic Acids Research 45 (D1): D158–D169. January 2017. doi:10.1093/nar/gkw1099. PMID 27899622. 

Further reading

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



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