ACAD9

Chr 3q21.3

acyl-CoA dehydrogenase family member 9

Aliases:: NPD002, MGC14452
MANE:: ENST00000308982.12

OMIM: 611103 ↗NCBI: 28976 ↗Ensembl ↗

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Predicted protein structure

AlphaFold predicted structure

ACAD9 · Q9H845

v62025-08-01

Predicted Aligned Error matrix for ACAD9 — diagonal shows residue index, colour shows pairwise prediction confidence (lower is better) — Predicted Aligned Error

Mean pLDDT

91.9/ 100

Very high

621 residues

Confidence breakdown

Very high(≥ 90)85%
Confident(70–90)9%
Low(50–70)1%
Very low(< 50)5%

Open interactive 3D viewer

AlphaFold (Jumper et al., 2021) · CC BY 4.0

Clinical relevance (Genomics England PanelApp)

Diagnostic Grade (Green)

Acute rhabdomyolysis
BIALLELIC, autosomal or pseudoautosomal
DDG2P
BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies
BIALLELIC, autosomal or pseudoautosomal
Intellectual disability
BIALLELIC, autosomal or pseudoautosomal
Likely inborn error of metabolism
BIALLELIC, autosomal or pseudoautosomal
Mitochondrial disorder with complex I deficiency
BIALLELIC, autosomal or pseudoautosomal
Mitochondrial disorders
BIALLELIC, autosomal or pseudoautosomal
Paediatric or syndromic cardiomyopathy
BIALLELIC, autosomal or pseudoautosomal

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Disease associations (Open Targets)

acyl-CoA dehydrogenase 9 deficiency
0.85
mitochondrial complex I deficiency
0.66
neurodegenerative disease
0.52
hypertrophic cardiomyopathy
0.27
preeclampsia
0.26
lysosomal storage disease
0.22
hereditary disease
0.19
type 2 diabetes mellitus
0.16
hyperinsulinemic hypoglycemia, familial, 4
0.04
glioblastoma
0.03

Score is the Open Targets composite evidence score (0-1). Higher = stronger gene-disease association.

Protein function (UniProt)

Complex I assembly factor ACAD9, mitochondrial

Together with NDUFAF1 and ECSIT, forms part of the mitochondrial complex I (MCIA),which is required for the biogenesis of respiratory Complex I (CI) and is therefore crucial for the activation of the oxidative phosphorylation system (PubMed:20816094, PubMed:24158852, PubMed:32320651, PubMed:38086790). ECSIT binding triggers a large conformational change, switching ACAD9 from a fatty acid oxidation (FAO) enzyme to a CI assembly factor (PubMed:38086790). The function in CI assembly is independent of the fatty acid oxidation (FAO) activity of the protein (PubMed:24158852). As FAO enzyme, it catalyzes the first step in mitochondrial FAO, which consists in the proR-proR stereospecific alpha, beta-dehydrogenation of fatty acyl-CoA thioesters using the electron transfer flavoprotein (ETF) as their physiologic electron acceptor, resulting in the formation of trans-2-enoyl-CoA ((2E)-enoyl-CoA) (PubMed:12359260, PubMed:16020546, PubMed:17564966, PubMed:21237683, PubMed:24158852). Its preferred substrates are both saturated and unsaturated long-chain acyl-CoA substrates, with optimum activity toward the latter (PubMed:12359260, PubMed:16020546, PubMed:17564966, PubMed:21237683, PubMed:24158852). In addition, based on its established catalytic mechanism, and combined genetic interaction or mutant phenotype evidence, it is predicted to act also on substrates that have not been tested experimentally but are metabolized by mitochondrial FAO, including long-chain unsaturated fatty acids such as linoleate (9Z,12Z-octadecadienoate), linolenate (9Z,12Z,15Z-octadecatrienoate), and others (PubMed:26474213). Among the different mitochondrial acyl-CoA dehydrogenases, its FAO activity overlaps with that of ACADV and ACADL, but plays a primary role in tissues where it is the main long-chain ACAD expressed, such as the central nervous system (PubMed:16020546, PubMed:17564966, PubMed:24158852, PubMed:25721401, PubMed:26474213). It differs significantly from ACADVL in the use of polyunsaturated substrates in vitro, especially docosahexaenoic acid (which is not primarily used for energy but mainly beta-oxidized in the peroxisomes) (PubMed:16020546, PubMed:17564966)