Biology:MECR

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Mitochondrial trans-2-enoyl-CoA reductase (MECR) is an enzyme that in humans is encoded by the MECR gene.[1] It belongs to the enzyme class of oxidoreductases and catalyzes the last step of mitochondrial fatty acid synthesis (mtFAS).[2] In doing so, MECR makes the fatty acyl chain bound to mitochondrial acyl carrier protein (mtACP) available again for elongation.[3] MECR thereby contributes to mitochondrial respiration and oxidative phosphorylation.[4] Beyond its mitochondrial role, a cytosolic and nuclear isoform (cMECR) has been linked to PPARα-dependent transcription.[5] Pathogenic variants in the MECR gene cause MEPAN syndrome.[4]

Structure

The MECR gene is located on chromosome 1 at locus p35.3 and contains 18 exons.[2] Through alternative splicing, it produces nine protein-coding mRNA transcripts, which encode five isoforms of mitochondrial trans-2-enoyl-CoA reductase (MECR).[2] The cMECR isoform lacks the N-terminal mitochondrial targeting sequence and localizes to the cytosol and nucleus.[5]

MECR forms a dimer with a bent substrate-binding cavity between the two monomers that accommodates acyl substrates with carbon chain lengths from C4 to C16.[6][7]

Reaction

The reaction catalyzed by MECR can be summarized as follows:

trans-2-enoyl-mtACP + NADPH + H+ → acyl-mtACP + NADP+

Function

MECR catalyzes the last step of the mitochondrial fatty acid synthesis pathway. By using NADPH to reduce trans-2-enoyl-mtACP to saturated acyl-mtACP, MECR prepares the acyl chain for another round of elongation.

The MECR gene encodes mitochondrial trans-2-enoyl-CoA reductase, which catalyzes the last step of mitochondrial fatty acid synthesis (mtFAS).[4] Condensation in mtFAS produces an unsaturated fatty acyl chain bound to mtACP.[3] It must undergo reduction and dehydration reactions to become saturated, making it available again for the next elongation cycle.[3] MECR completes this process by reducing the trans double bond between carbon atoms 2 and 3, yielding a saturated acyl-mtACP species.[8] NADPH, whose availability in mitochondria depends on NADK2, provides the required reducing power.[9] Through repeated elongation cycles, mitochondrial fatty acid synthesis generates acyl-mtACP species with chain lengths from C2 to C16.[10] Octanoyl-mtACP (C8) serves as the precursor for lipoic acid biosynthesis and subsequent protein lipoylation, which is essential for several mitochondrial enzyme complexes, including the pyruvate dehydrogenase complex, the 2-oxoglutarate dehydrogenase complex, the branched-chain alpha-keto acid dehydrogenase complex, the 2-oxoadipate dehydrogenase complex, and the glycine cleavage system.[11] Longer-chain acyl-mtACP species interact with LYRM proteins that are required for iron–sulfur cluster biogenesis and respiratory-chain assembly.[11] In addition, mtFAS has been linked to mitochondrial translation and to levels of polyamines, including spermidine and spermine, as well as bioactive lipids such as lysophospholipids and sphingolipids.[9][6]

MECR has also been reported to bind transcription factors of the PPAR family and activate transcription, suggesting a possible link between nuclear gene regulation and mtFAS.[4]

Clinical significance

Pathogenic variants in the MECR gene cause MEPAN syndrome, a rare autosomal recessive mitochondrial metabolic disorder characterized by childhood-onset dystonia, optic atrophy, and basal ganglia signal abnormalities on MRI.[12] A later-onset phenotype with LHON-like optic neuropathy but without movement disorder or basal ganglia signal abnormalities has also been reported.[13][14][15]

See also

References

  1. ↑ "Gene symbol report | HUGO Gene Nomenclature Committee". https://www.genenames.org/data/gene-symbol-report/#!/hgnc_id/HGNC:19691. 
  2. ↑ 2.0 2.1 2.2 "MECR mitochondrial trans-2-enoyl-CoA reductase [Homo sapiens (human) - Gene - NCBI"]. https://www.ncbi.nlm.nih.gov/gene/51102. 
  3. ↑ 3.0 3.1 3.2 Nowinski, Sara M; Solmonson, Ashley; Rusin, Scott F; Maschek, J Alan; Bensard, Claire L; Fogarty, Sarah; Jeong, Mi-Young; Lettlova, Sandra et al. (2020-08-17). "Mitochondrial fatty acid synthesis coordinates oxidative metabolism in mammalian mitochondria" (in en). eLife 9. doi:10.7554/eLife.58041. ISSN 2050-084X. PMID 32804083. 
  4. ↑ 4.0 4.1 4.2 4.3 Murdock, Deborah G.; Janssen, Kevin A.; Keller, Kierstin; Mitchell, Katherine L.; Beauplan, Maina; O'Brien, William T.; D'Alessandro, Lia; Haltom, Jeffrey A. et al. (2025-10-07). "A mouse model of MEPAN demonstrates a role for mitochondrial fatty acid synthesis in iron–sulfur cluster and supercomplex formation" (in en). Proceedings of the National Academy of Sciences 122 (40). doi:10.1073/pnas.2506761122. ISSN 0027-8424. PMID 41021813. PMC 12519216. https://pnas.org/doi/10.1073/pnas.2506761122. 
  5. ↑ 5.0 5.1 Kim, Dong-Gyu; Yoo, Jae Cheal; Kim, Eunju; Lee, Young-Sun; Yarishkin, Oleg V.; Lee, Da Yong; Lee, Kun Ho; Hong, Seong-Geun et al. (2014). "A Novel Cytosolic Isoform of Mitochondrial Trans-2-Enoyl-CoA Reductase Enhances Peroxisome Proliferator-Activated Receptor α Activity" (in en). Endocrinology and Metabolism 29 (2): 185. doi:10.3803/EnM.2014.29.2.185. ISSN 2093-596X. PMID 25031892. 
  6. ↑ 6.0 6.1 Clay, Hayley B.; Parl, Angelika K.; Mitchell, Sabrina L.; Singh, Larry; Bell, Lauren N.; Murdock, Deborah G. (2016-03-10). Peterson, Jonathan. ed. "Altering the Mitochondrial Fatty Acid Synthesis (mtFASII) Pathway Modulates Cellular Metabolic States and Bioactive Lipid Profiles as Revealed by Metabolomic Profiling" (in en). PLOS ONE 11 (3). doi:10.1371/journal.pone.0151171. ISSN 1932-6203. PMID 26963735. 
  7. ↑ Rahman, M. Tanvir; Koski, M. Kristian; Panecka-Hofman, Joanna; Schmitz, Werner; Kastaniotis, Alexander J.; Wade, Rebecca C.; Wierenga, Rik K.; Hiltunen, J. Kalervo et al. (2023-02-04). "An engineered variant of MECR reductase reveals indispensability of long-chain acyl-ACPs for mitochondrial respiration" (in en). Nature Communications 14 (1). doi:10.1038/s41467-023-36358-7. ISSN 2041-1723. PMID 36739436. 
  8. ↑ Wedan, Riley J.; Longenecker, Jacob Z.; Nowinski, Sara M. (January 2024). "Mitochondrial fatty acid synthesis is an emergent central regulator of mammalian oxidative metabolism" (in en). Cell Metabolism 36 (1): 36–47. doi:10.1016/j.cmet.2023.11.017. PMID 38128528. 
  9. ↑ 9.0 9.1 Wedan, Riley J.; Nowinski, Sara M. (July 2025). "Powering the powerhouse: Mitochondrial NADPH propels oxidative metabolism" (in en). Cell Chemical Biology 32 (7): 902–904. doi:10.1016/j.chembiol.2025.06.006. PMID 40680726. 
  10. ↑ Kim, Dohun; Kesavan, Rushendhiran; Ryu, Kevin; Dey, Trishna; Marckx, Austin; Menezes, Cameron; Praharaj, Prakash P.; Morley, Stewart et al. (May 2025). "Mitochondrial NADPH fuels mitochondrial fatty acid synthesis and lipoylation to power oxidative metabolism" (in en). Nature Cell Biology 27 (5): 790–800. doi:10.1038/s41556-025-01655-4. ISSN 1465-7392. PMID 40258949. 
  11. ↑ 11.0 11.1 Wedan, Riley J.; Longenecker, Jacob Z.; Nowinski, Sara M. (January 2024). "Mitochondrial fatty acid synthesis is an emergent central regulator of mammalian oxidative metabolism" (in en). Cell Metabolism 36 (1): 36–47. doi:10.1016/j.cmet.2023.11.017. PMID 38128528. 
  12. ↑ "MECR Mutations Cause Childhood-Onset Dystonia and Optic Atrophy, a Mitochondrial Fatty Acid Synthesis Disorder". American Journal of Human Genetics 99 (6): 1229–1244. December 2016. doi:10.1016/j.ajhg.2016.09.021. PMID 27817865. 
  13. ↑ Zhang, Shuangxi; Liu, Ruichen; Liu, Quanyu; Liu, Jiankang; Long, Jiangang; Shi, Le (January 2026). "Mitochondrial fatty acid synthesis: The physiopathological role in cellular processes and human diseases" (in en). Genes & Diseases. doi:10.1016/j.gendis.2026.102034. ISSN 2352-3042. 
  14. ↑ Jia, Nan; Yu, Shuiqing; Zhang, Geng; Li, Lin; Wang, Jiawei; Lai, Chuntao (April 2024). "Recurrent MECR R258W causes adult-onset optic atrophy: A case report" (in en). European Journal of Medical Genetics 68. doi:10.1016/j.ejmg.2024.104917. ISSN 1769-7212. 
  15. ↑ Fiorini, Claudio; Degiorgi, Andrea; Cascavilla, Maria Lucia; Tropeano, Concetta Valentina; La Morgia, Chiara; Battista, Marco; Ormanbekova, Danara; Palombo, Flavia et al. (January 2024). "Recessive MECR pathogenic variants cause an LHON-like optic neuropathy" (in en). Journal of Medical Genetics 61 (1): 93–101. doi:10.1136/jmg-2023-109340. ISSN 0022-2593. PMID 37734847. 

Further reading



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