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GeneE
25 sources retrieved Β· Most recent: April 2026 Β· Index updated 14 days ago
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HADHA
hydroxyacyl-CoA dehydrogenase trifunctional multienzyme complex subunit alpha
Chromosome 2 Β· 2p23.3
NCBI Gene: 3030Ensembl: ENSG00000084754.13HGNC: HGNC:4801UniProt: E9KL44
333PubMed Papers
23Diseases
0Drugs
238Pathogenic Variants
RESEARCH IMPACT
Highly StudiedTrendingVariant-Rich
CLINICAL
OMIM Disease Gene
DATA QUALITY
βœ“ Experimental GO Evidenceβœ“ Swiss-Prot Reviewed
protein bindingmitochondrionlong-chain fatty acyl-CoA hydrolase activitymitochondrial inner membranelong chain 3-hydroxyacyl-CoA dehydrogenase deficiencymitochondrial trifunctional protein deficiencymitochondrial trifunctional protein deficiency 1genetic disorder
✦AI Summary

HADHA (hydroxyacyl-CoA dehydrogenase trifunctional multienzyme complex subunit alpha) is a mitochondrial enzyme catalyzing the final three reactions of beta-oxidation, the major pathway for long-chain fatty acid breakdown into acetyl-CoA 1. As the alpha subunit of the heterotetrameric trifunctional enzyme complex, HADHA exhibits 2,3-enoyl-CoA hydratase and 3-hydroxyacyl-CoA dehydrogenase activities 1. Beyond beta-oxidation, HADHA possesses cardiolipin acyltransferase activity, participating in cardiolipin remodelingβ€”a critical mitochondrial phospholipid function 2. HADHA regulates cellular energy metabolism at multiple levels. It couples fatty acid oxidation to oxidative phosphorylation (OXPHOS), with HADHA expression increased under metabolic stress (galactose supplementation, high-fat diet) 3. HADHA-deficient cells show impaired respiratory complex assembly and OXPHOS dysfunction 3. The enzyme promotes ketone body (Ξ²-hydroxybutyrate) production, which suppresses hepatic gluconeogenesis by inhibiting HDAC7 activity 4. Disease relevance is substantial: mutations cause mitochondrial trifunctional protein deficiency and long-chain 3-hydroxyl-CoA dehydrogenase deficiency. HADHA dysregulation contributes to osteoarthritis through excessive fatty acid oxidation-driven SOX9 degradation 5 and intrahepatic cholangiocarcinoma chemoresistance via post-translational modifications affecting enzyme stability 6. HADHA regulation is also critical for effector T regulatory cell differentiation and immune tolerance 7.

Sources cited
1
HADHA catalyzes the last three of four beta-oxidation reactions and is part of the trifunctional enzyme complex
PMID: 29915090
2
HADHA exhibits cardiolipin acyltransferase activity for cardiolipin remodeling
PMID: 31604922
3
HADHA couples fatty acid oxidation to OXPHOS and regulates respiratory complex assembly
PMID: 39488787
4
HADHA promotes ketone body production which inhibits hepatic gluconeogenesis via HDAC7
PMID: 35046401
5
Elevated HADHA activity in chondrocytes promotes osteoarthritis via SOX9 degradation and epigenetic changes
PMID: 40425566
6
HADHA SUMOylation status regulates fatty acid oxidation and affects intrahepatic cholangiocarcinoma chemotherapy sensitivity
PMID: 40320039
7
HADHA-mediated fatty acid oxidation is required for effector T regulatory cell differentiation and immune tolerance
PMID: 37843279
Disease Associationsβ“˜23
long chain 3-hydroxyacyl-CoA dehydrogenase deficiencyOpen Targets
0.84Strong
mitochondrial trifunctional protein deficiencyOpen Targets
0.76Strong
mitochondrial trifunctional protein deficiency 1Open Targets
0.75Strong
genetic disorderOpen Targets
0.47Moderate
neurodegenerative diseaseOpen Targets
0.39Weak
hypertrophic cardiomyopathyOpen Targets
0.37Weak
cervical carcinomaOpen Targets
0.36Weak
metabolic diseaseOpen Targets
0.34Weak
Seckel syndrome 6Open Targets
0.12Weak
hepatocellular carcinomaOpen Targets
0.10Suggestive
non-alcoholic fatty liver diseaseOpen Targets
0.09Suggestive
ovarian cancerOpen Targets
0.09Suggestive
breast cancerOpen Targets
0.07Suggestive
colorectal carcinomaOpen Targets
0.06Suggestive
glioblastoma multiformeOpen Targets
0.06Suggestive
head and neck squamous cell carcinomaOpen Targets
0.06Suggestive
AnxietyOpen Targets
0.06Suggestive
glycogen storage disease VIOpen Targets
0.06Suggestive
neonatal intrahepatic cholestasis due to citrin deficiencyOpen Targets
0.05Suggestive
phosphoenolpyruvate carboxykinase deficiency, mitochondrialOpen Targets
0.05Suggestive
Long-chain 3-hydroxyl-CoA dehydrogenase deficiencyUniProt
Maternal acute fatty liver of pregnancyUniProt
Mitochondrial trifunctional protein deficiency 1UniProt
Pathogenic Variants238
NM_000182.5(HADHA):c.1528G>C (p.Glu510Gln)Pathogenic
Mitochondrial trifunctional protein deficiency|LCHAD deficiency with maternal acute fatty liver of pregnancy|Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency|not provided|Inborn genetic diseases|Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency;Mitochondrial trifunctional protein deficiency|HADHA-related disorder|Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency;Mitochondrial trifunctional protein deficiency 1|Metabolic disease
β˜…β˜…β˜†β˜†2026β†’ Residue 510
NM_000182.5(HADHA):c.919-2A>GPathogenic
Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency|not provided|Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency;Mitochondrial trifunctional protein deficiency|Mitochondrial trifunctional protein deficiency 1;Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency
β˜…β˜…β˜†β˜†2026
NM_000182.5(HADHA):c.1678C>T (p.Arg560Ter)Pathogenic
Mitochondrial trifunctional protein deficiency|Mitochondrial trifunctional protein deficiency;Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency|Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency|Mitochondrial trifunctional protein deficiency 1|Mitochondrial trifunctional protein deficiency 1;Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency|not provided
β˜…β˜…β˜†β˜†2026β†’ Residue 560
NM_000182.5(HADHA):c.1793_1794del (p.His598fs)Pathogenic
Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency|Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency;Mitochondrial trifunctional protein deficiency|Mitochondrial trifunctional protein deficiency|not provided|Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency;Mitochondrial trifunctional protein deficiency 1|Mitochondrial trifunctional protein deficiency 1
β˜…β˜…β˜†β˜†2025β†’ Residue 598
NM_000182.5(HADHA):c.180+3A>GPathogenic
not provided|Mitochondrial trifunctional protein deficiency;Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency|Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency|Mitochondrial trifunctional protein deficiency 1|Mitochondrial trifunctional protein deficiency 1;Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency
β˜…β˜…β˜†β˜†2025
NM_000182.5(HADHA):c.2026C>T (p.Arg676Cys)Pathogenic
Mitochondrial trifunctional protein deficiency;Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency|Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency|Mitochondrial trifunctional protein deficiency 1
β˜…β˜…β˜†β˜†2025β†’ Residue 676
NM_000182.5(HADHA):c.1086-3_1092delPathogenic
Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency|Mitochondrial trifunctional protein deficiency;Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency
β˜…β˜…β˜†β˜†2025
NM_000182.5(HADHA):c.314+1G>CLikely pathogenic
Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency|Mitochondrial trifunctional protein deficiency;Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency
β˜…β˜…β˜†β˜†2025
NM_000182.5(HADHA):c.1195C>T (p.Arg399Ter)Pathogenic
not provided|Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency|Mitochondrial trifunctional protein deficiency|Mitochondrial trifunctional protein deficiency;Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency
β˜…β˜…β˜†β˜†2025β†’ Residue 399
NM_000182.5(HADHA):c.2027G>A (p.Arg676His)Pathogenic
Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency;Mitochondrial trifunctional protein deficiency|not provided|Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency|Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency;Mitochondrial trifunctional protein deficiency 1
β˜…β˜…β˜†β˜†2025β†’ Residue 676
NM_000182.5(HADHA):c.1690-2A>GPathogenic
Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency|not provided|Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency;Mitochondrial trifunctional protein deficiency
β˜…β˜…β˜†β˜†2025
NM_000182.5(HADHA):c.1811del (p.Gly604fs)Pathogenic
Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency|not provided|Mitochondrial trifunctional protein deficiency|Mitochondrial trifunctional protein deficiency;Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency
β˜…β˜…β˜†β˜†2025β†’ Residue 604
NM_000182.5(HADHA):c.1432del (p.Ala478fs)Pathogenic
Mitochondrial trifunctional protein deficiency;Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency|Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency
β˜…β˜…β˜†β˜†2025β†’ Residue 478
NM_000182.5(HADHA):c.914T>A (p.Ile305Asn)Pathogenic
not provided|Mitochondrial trifunctional protein deficiency;Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency|Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency|Mitochondrial trifunctional protein deficiency 1|Mitochondrial trifunctional protein deficiency 1;Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency
β˜…β˜…β˜†β˜†2025β†’ Residue 305
NM_000182.5(HADHA):c.314+2T>GLikely pathogenic
Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency;Mitochondrial trifunctional protein deficiency|not provided|Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency
β˜…β˜…β˜†β˜†2025
NM_000182.5(HADHA):c.180+1G>APathogenic
Mitochondrial trifunctional protein deficiency|Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency|Mitochondrial trifunctional protein deficiency;Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency|Mitochondrial trifunctional protein deficiency 1
β˜…β˜…β˜†β˜†2025
NM_000182.5(HADHA):c.2225_2228dup (p.Phe744fs)Pathogenic
Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency|Mitochondrial trifunctional protein deficiency;Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency|Mitochondrial trifunctional protein deficiency
β˜…β˜…β˜†β˜†2025β†’ Residue 744
NM_000182.5(HADHA):c.1814_1815del (p.Lys605fs)Pathogenic
not provided|Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency|Mitochondrial trifunctional protein deficiency;Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency
β˜…β˜…β˜†β˜†2025β†’ Residue 605
NM_000182.5(HADHA):c.1916_1919dup (p.Glu641fs)Pathogenic
not provided|See cases|Mitochondrial trifunctional protein deficiency;Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency|Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency|Mitochondrial trifunctional protein deficiency 1;Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency
β˜…β˜…β˜†β˜†2025β†’ Residue 641
NM_000182.5(HADHA):c.676+2T>CPathogenic
Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency|Mitochondrial trifunctional protein deficiency;Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency
β˜…β˜…β˜†β˜†2025
View on ClinVar β†—
Related Genes
SLC25A20Protein interaction99%CPT1AProtein interaction99%CPT2Protein interaction99%ETFAProtein interaction99%ACSL1Protein interaction99%HSD17B4Protein interaction99%
Tissue Expression6 tissues
Heart
100%
Liver
59%
Brain
44%
Lung
41%
Ovary
34%
Bone Marrow
26%
Gene Interaction Network
Click a node to explore
HADHASLC25A20CPT1ACPT2ETFAACSL1HSD17B4
PROTEIN STRUCTURE
Preparing viewer…
PDB6DV2 Β· 3.60 Γ… Β· X-ray
View on RCSB β†—
Constraintβ“˜
LOEUFβ“˜
0.76LoF Tolerant
pLIβ“˜
0.00Tolerant
Observed/Expected LoF0.53 [0.37–0.76]
RankingsWhere HADHA stands among ~20K protein-coding genes
  • #976of 20,598
    Most Researched333 Β· top 5%
  • #266of 5,498
    Most Pathogenic Variants238 Β· top 5%
  • #6,092of 17,882
    Most Constrained (LOEUF)0.76
Genes detectedHADHA
Sources retrieved25 papers
Response timeβ€”
πŸ“„ Sources
25β–Ό
1
Regulation of energy metabolism by long-chain fatty acids.
PMID: 24362249
Prog Lipid Res Β· 2014
1.00
2
The mitochondrial Ξ²-oxidation enzyme HADHA restrains hepatic glucagon response by promoting Ξ²-hydroxybutyrate production.
PMID: 35046401
Nat Commun Β· 2022
0.90
3
A 20-year Clinical and Genetic Neuromuscular Cohort Analysis in Lebanon: An International Effort.
PMID: 34602496
J Neuromuscul Dis Β· 2022
0.80
4
Mitochondrial bioenergetics and cardiolipin remodeling abnormalities in mitochondrial trifunctional protein deficiency.
PMID: 39088276
JCI Insight Β· 2024
0.72
5
Chondrocyte fatty acid oxidation drives osteoarthritis via SOX9 degradation and epigenetic regulation.
PMID: 40425566
Nat Commun Β· 2025
0.70