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Trifunctional enzyme subunit alpha, mitochondrial also known as hydroxyacyl-CoA dehydrogenase/3-ketoacyl-CoA thiolase/enoyl-CoA hydratase (trifunctional protein), alpha subunit is a protein that in humans is encoded by the HADHA gene. Mutations in HADHA have been associated with trifunctional protein deficiency or long-chain 3-hydroxyacyl-coenzyme A dehydrogenase deficiency.[1]


HADHA is an 82.9 kDa protein composed of 763 amino acids.[2][3]

The mitochondrial membrane-bound heterocomplex is composed of four alpha and four beta subunits, with the alpha subunit catalyzing the 3-hydroxyacyl-CoA dehydrogenase and enoyl-CoA hydratase activities. The genes of the alpha and beta subunits of the mitochondrial trifunctional protein are located adjacent to each other in the human genome in a head-to-head orientation.[1]


This gene encodes the alpha subunit of the mitochondrial trifunctional protein, which catalyzes the last three steps of mitochondrial beta-oxidation of long chain fatty acids.[1] The enzyme converts medium- and long-chain 2-enoyl-CoA compounds into the following 3-ketoacyl-CoA when NAD is solely present, and acetyl-CoA when NAD and CoASH are present.[4] The alpha subunit catalyzes this reaction, and is attached to HADHB, which catalyzes the last step of the reaction.[5]

Clinical significance

Mutations in this gene result in trifunctional protein deficiency or long-chain 3-hydroxyacyl-coenzyme A dehydrogenase deficiency.[1]

The most common form of the mutation is G1528C, in which the guanine at the 1528th position is changed to a cytosine. The gene mutation creates a protein deficiency that is associated with impaired oxidation of long-chain fatty acids that can lead to sudden infant death.[6] Clinical manifestations of this deficiency can include myopathy, cardiomyopathy, episodes of coma, and hypoglycemia.[7] Long-chain L-3-hydroxyacyl-coenzyme A dehydrogenase deficiency is associated with some pregnancy-specific disorders, including preeclampsia, HELLP syndrome (hemolysis, elevated liver enzymes, low platelets), hyperemesis gravidarum, acute fatty liver of pregnancy, and maternal floor infarct of the placenta.[8][9] Additionally, it has been correlated with Acute fatty liver of pregnancy (AFLP) disease.[10]

From a clinical perspective, HADHA might also be a useful marker to predict resistance to certain types of chemotherapy in patients with lung cancer.[11]


HADHA has been shown to have 142 binary protein-protein interactions including 117 co-complex interactions. HADHA appears to interact with GABARAP, MAP1LC3B, TRAF6, GABARAPL2, GABARAPL1, GAST, BCAR3, EPB41, TNFRSF1A, HLA-B, NFKB2, MAP3K1, IKBKE, PRKAB1, RIPK3, CD74, NR4A1, cdsA, mtaD, ATXN2L, ABCF2, and MAPK3.[12]


  1. 1.0 1.1 1.2 1.3 "Entrez Gene: Hydroxyacyl-CoA dehydrogenase/3-ketoacyl-CoA thiolase/enoyl-CoA hydratase (trifunctional protein), alpha subunit".
  2. Zong NC, Li H, Li H, Lam MP, Jimenez RC, Kim CS, Deng N, Kim AK, Choi JH, Zelaya I, Liem D, Meyer D, Odeberg J, Fang C, Lu HJ, Xu T, Weiss J, Duan H, Uhlen M, Yates JR, Apweiler R, Ge J, Hermjakob H, Ping P (Oct 2013). "Integration of cardiac proteome biology and medicine by a specialized knowledgebase". Circulation Research. 113 (9): 1043–53. doi:10.1161/CIRCRESAHA.113.301151. PMC 4076475. PMID 23965338.
  3. "hydroxyacyl-CoA dehydrogenase/3-ketoacyl-CoA thiolase/enoyl-CoA hydratase (trifunctional protein), alpha subunit". Cardiac Organellar Protein Atlas Knowledgebase (COPaKB).
  4. Carpenter K, Pollitt RJ, Middleton B (Mar 1992). "Human liver long-chain 3-hydroxyacyl-coenzyme A dehydrogenase is a multifunctional membrane-bound beta-oxidation enzyme of mitochondria". Biochemical and Biophysical Research Communications. 183 (2): 443–8. doi:10.1016/0006-291x(92)90501-b. PMID 1550553.
  5. Voet DJ, Voet JG, Pratt CW (2010). "Chapter 18, Mitochondrial ATP synthesis". Principles of Biochemistry (4th ed.). Wiley. p. 669. ISBN 978-0-470-23396-2.
  6. IJlst L, Ruiter JP, Hoovers JM, Jakobs ME, Wanders RJ (August 1996). "Common missense mutation G1528C in long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency. Characterization and expression of the mutant protein, mutation analysis on genomic DNA and chromosomal localization of the mitochondrial trifunctional protein alpha subunit gene". The Journal of Clinical Investigation. 98 (4): 1028–33. doi:10.1172/jci118863. PMC 507519. PMID 8770876.
  7. Rocchiccioli F, Wanders RJ, Aubourg P, Vianey-Liaud C, Ijlst L, Fabre M, Cartier N, Bougneres PF (December 1990). "Deficiency of long-chain 3-hydroxyacyl-CoA dehydrogenase: a cause of lethal myopathy and cardiomyopathy in early childhood". Pediatric Research. 28 (6): 657–62. doi:10.1203/00006450-199012000-00023. PMID 2284166.
  8. Rakheja D, Bennett MJ, Rogers BB (July 2002). "Long-chain L-3-hydroxyacyl-coenzyme a dehydrogenase deficiency: a molecular and biochemical review". Laboratory Investigation; A Journal of Technical Methods and Pathology. 82 (7): 815–24. doi:10.1097/01.lab.0000021175.50201.46. PMID 12118083.
  9. Griffin AC, Strauss AW, Bennett MJ, Ernst LM (September–October 2012). "Mutations in long-chain 3-hydroxyacyl coenzyme a dehydrogenase are associated with placental maternal floor infarction/massive perivillous fibrin deposition". Pediatric and Developmental Pathology. 15 (5): 368–74. doi:10.2350/12-05-1198-oa.1. PMID 22746996.
  10. Ibdah JA, Yang Z, Bennett MJ (September–October 2000). "Liver disease in pregnancy and fetal fatty acid oxidation defects". Molecular Genetics and Metabolism. 71 (1–2): 182–9. doi:10.1006/mgme.2000.3065. PMID 11001809.
  11. Kageyama T, Nagashio R, Ryuge S, Matsumoto T, Iyoda A, Satoh Y, Masuda N, Jiang SX, Saegusa M, Sato Y (2011). "HADHA is a potential predictor of response to platinum-based chemotherapy for lung cancer". Asian Pacific Journal of Cancer Prevention. 12 (12): 3457–63. PMID 22471497.
  12. "142 binary interactions found for search term HADHA". IntAct Molecular Interaction Database. EMBL-EBI. Retrieved 2018-08-25.

Further reading

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