Genomes and Genes
Gene Symbol: ACAD 9
Description: acyl-CoA dehydrogenase family member 9
Alias: NPD002, acyl-CoA dehydrogenase family member 9, mitochondrial, acyl-Coenzyme A dehydrogenase family, member 9, very-long-chain acyl-CoA dehydrogenase VLCAD
Products: ACAD 9
- Keeler A, Conlon T, Walter G, Zeng H, Shaffer S, Dungtao F, et al. Long-term correction of very long-chain acyl-coA dehydrogenase deficiency in mice using AAV9 gene therapy. Mol Ther. 2012;20:1131-8 pubmed publisher..These promising results suggest rAAV9 gene therapy as a potential treatment for VLCAD deficiency in humans. ..
- Takahashi Y, Sano R, Nakajima T, Kominato Y, Kubo R, Takahashi K, et al. Combination of postmortem mass spectrometry imaging and genetic analysis reveals very long-chain acyl-CoA dehydrogenase deficiency in a case of infant death with liver steatosis. Forensic Sci Int. 2014;244:e34-7 pubmed publisher..Thus, the deceased might have been vulnerable to energy crisis and sudden infant death. The present findings show that MALDI-IMS analysis as well as genetic analysis can be useful for elucidating the cause of death. ..
- Horvath R. Update on clinical aspects and treatment of selected vitamin-responsive disorders II (riboflavin and CoQ 10). J Inherit Metab Dis. 2012;35:679-87 pubmed publisher..CoQ(10) supplementation may be beneficial in both primary and secondary deficiencies and therefore the early recognition of these diseases is of utmost importance. ..
- Repp B, Mastantuono E, Alston C, Schiff M, Haack T, Rotig A, et al. Clinical, biochemical and genetic spectrum of 70 patients with ACAD9 deficiency: is riboflavin supplementation effective?. Orphanet J Rare Dis. 2018;13:120 pubmed publisher..In the patient group with disease-onset below 1 year of age, we observed a statistically-significant better survival for patients treated with riboflavin. ..
- Brown A, Crowe L, Andresen B, Anderson V, Boneh A. Neurodevelopmental profiles of children with very long chain acyl-CoA dehydrogenase deficiency diagnosed by newborn screening. Mol Genet Metab. 2014;113:278-82 pubmed publisher..VLCAD deficiency does not have a significant impact on cognitive or motor skills. Some children may be vulnerable to speech, social and behavioural issues. ..
- Tucci S, FlÃ¶gel U, Spiekerkoetter U. Sexual dimorphism of lipid metabolism in very long-chain acyl-CoA dehydrogenase deficient (VLCAD-/-) mice in response to medium-chain triglycerides (MCT). Biochim Biophys Acta. 2015;1852:1442-50 pubmed publisher..How these metabolic adaptations are finally regulated needs to be determined. More important, the relevance of these findings for humans under these dietary modifications needs to be investigated. ..
- Kang E, Kim Y, Kang M, Heo S, Kim G, Choi I, et al. Clinical and genetic characteristics of patients with fatty acid oxidation disorders identified by newborn screening. BMC Pediatr. 2018;18:103 pubmed publisher..However, severe clinical manifestations developed in some patients, indicating that careful, life-long observation is warranted in all FAODs patients. ..
- Elurbe D, Huynen M. The origin of the supernumerary subunits and assembly factors of complex I: A treasure trove of pathway evolution. Biochim Biophys Acta. 2016;1857:971-9 pubmed publisher..Complex I and its assembly can therewith be regarded as a treasure trove for pathway evolution. This article is part of a Special Issue entitled Respiratory complex I, edited by Volker Zickermann and Ulrich Brandt. ..
- Yang Y, Feng Y, Zhang X, Nakajima T, Tanaka N, Sugiyama E, et al. Activation of PPAR? by Fatty Acid Accumulation Enhances Fatty Acid Degradation and Sulfatide Synthesis. Tohoku J Exp Med. 2016;240:113-22 pubmed publisher..These results indicate that PPAR? activation plays defensive and compensative roles by reducing cellular toxicity associated with fatty acids and sulfuric acid. ..
- Bouvier D, Vianey Saban C, Ruet S, Acquaviva C. Development of a Tandem Mass Spectrometry Method for Rapid Measurement of Medium- and Very-Long-Chain Acyl-CoA Dehydrogenase Activity in Fibroblasts. JIMD Rep. 2017;35:71-78 pubmed publisher..All VLCADD patients showed less than 35% residual VLCAD activity. This technique allowed also to confirm that a novel ACADVL gene mutation (c.1400T>C) is responsible for a defective VLCAD activity (residual activity at 10%). ..
- Zeng J, Deng S, Wang Y. Identification of the Catalytic Residue of Rat Acyl-CoA Dehydrogenase 9 by Site-Directed Mutagenesis. Appl Biochem Biotechnol. 2017;182:1198-1207 pubmed publisherAcyl-CoA dehydrogenase 9 (ACAD 9) is the ninth member of ACADs involved in mitochondrial fatty acid oxidation and possibly complex I assembly...
- Leipnitz G, Mohsen A, Karunanidhi A, Seminotti B, Roginskaya V, Markantone D, et al. Evaluation of mitochondrial bioenergetics, dynamics, endoplasmic reticulum-mitochondria crosstalk, and reactive oxygen species in fibroblasts from patients with complex I deficiency. Sci Rep. 2018;8:1165 pubmed publisher
- Pronicka E, Piekutowska Abramczuk D, Ciara E, Trubicka J, Rokicki D, Karkucinska Wieckowska A, et al. New perspective in diagnostics of mitochondrial disorders: two years' experience with whole-exome sequencing at a national paediatric centre. J Transl Med. 2016;14:174 pubmed publisher..There is a strong correlation between the degree of MD diagnosis by WES and MD likelihood expressed by the MDC scale. ..
- Yamamoto S, Ogasawara N, Yamamoto K, Uemura C, Takaya Y, Shiraishi T, et al. Mitochondrial proteins NIP-SNAP-1 and -2 are a target for the immunomodulatory activity of clarithromycin, which involves NF-?B-mediated cytokine production. Biochem Biophys Res Commun. 2017;483:911-916 pubmed publisher..Thus, CAM suppresses NF-?B-mediated proinflammatory cytokine production by interacting with mitochondrial proteins, NIP-SNAP-1 and -2. ..
- Uppala R, McKinney R, Brant K, Fabisiak J, Goetzman E. Nickel inhibits mitochondrial fatty acid oxidation. Biochem Biophys Res Commun. 2015;463:806-10 pubmed publisher..In conclusion, inhibition of fatty acid oxidation by nickel, concurrent with increased glucose metabolism, represents a form of metabolic reprogramming that may contribute to nickel-induced carcinogenesis. ..
- Burrage L, Miller M, Wong L, Kennedy A, Sutton V, Sun Q, et al. Elevations of C14:1 and C14:2 Plasma Acylcarnitines in Fasted Children: A Diagnostic Dilemma. J Pediatr. 2016;169:208-13.e2 pubmed publisher..Both metabolomics analysis and/or C14:1/C12:1 may distinguish C14:1 elevations from physiologic fasting-induced lipolysis vs VLCAD deficiency. ..
- Wajner M, Amaral A. Mitochondrial dysfunction in fatty acid oxidation disorders: insights from human and animal studies. Biosci Rep. 2015;36:e00281 pubmed publisher..The elucidation of the toxic mechanisms of these compounds may offer new perspectives for potential novel adjuvant therapeutic strategies in selected disorders of this group. ..
- Tucci S, Krogmann A, Herebian D, Spiekerkoetter U. Renal response to short- and long-term exercise in very-long-chain acyl-CoA dehydrogenase-deficient (VLCAD(-/-)) mice. Mol Cell Pediatr. 2014;1:5 pubmed publisher..Our data demonstrate that despite Acadvl ablation, the kidney of VLCAD(-/-) mice fully compensates for impaired fatty acid oxidation by enhanced glycogen utilization and preserves renal energy metabolism and function. ..
- Muroya Y, Ito O. Effect of clofibrate on fatty acid metabolism in the kidney of puromycin-induced nephrotic rats. Clin Exp Nephrol. 2016;20:862-870 pubmed publisher..Clofibrate is protective against renal lipotoxicity in PAN nephrosis. This study indicates that clofibrate has renoprotective effects through maintaining fatty acid metabolism in the kidney of PAN-induced nephrotic rats. ..
- Chuaijit S, Boonyatistan W, Boonchuay P, Metheetrairut C, Suthammarak W. Identification of a novel mitochondrial complex I assembly factor ACDH-12 in Caenorhabditis elegans. Mitochondrion. 2019;46:91-96 pubmed publisher..Interestingly, sequence analysis shows high homology between ACDH-12 and the human ACAD9, a protein that has initially been identified as a VLCAD, but later found to also be involved in the assembly of complex I in human. ..
- Zhang Y, Bharathi S, Rardin M, Uppala R, Verdin E, Gibson B, et al. SIRT3 and SIRT5 regulate the enzyme activity and cardiolipin binding of very long-chain acyl-CoA dehydrogenase. PLoS ONE. 2015;10:e0122297 pubmed publisher..Regulation of cardiolipin binding by reversible lysine acylation is a novel mechanism that is predicted to extrapolate to other metabolic proteins that localize to the inner mitochondrial membrane. ..
- Tucci S, Behringer S, Spiekerkoetter U. DeÂ novo fatty acid biosynthesis and elongation in very long-chain acyl-CoA dehydrogenase-deficient mice supplemented with odd or even medium-chain fatty acids. FEBS J. 2015;282:4242-53 pubmed publisher..Our data raise the question of whether long-term MCFA supplementation represents the most efficient treatment in the long term. Studies on the hepatic toxicity of triheptanoin are still ongoing. ..
- Schrank B, Schoser B, Klopstock T, Schneiderat P, Horvath R, Abicht A, et al. Lifetime exercise intolerance with lactic acidosis as key manifestation of novel compound heterozygous ACAD9 mutations causing complex I deficiency. Neuromuscul Disord. 2017;27:473-476 pubmed publisher..Candidate gene sequencing revealed two novel heterozygous ACAD9 mutations. This patient report expands the mutational and phenotypic spectrum of diseases associated with mutations in ACAD9. ..
- Escudero S, Zaganjor E, Lee S, Mill C, Morgan A, Crawford E, et al. Dynamic Regulation of Long-Chain Fatty Acid Oxidation by a Noncanonical Interaction between the MCL-1 BH3 Helix and VLCAD. Mol Cell. 2018;69:729-743.e7 pubmed publisher..Thus, the MCL-1 BH3 interaction with VLCAD revealed a separable, gain-of-function role for MCL-1 in the regulation of lipid metabolism. ..
- Fragaki K, Chaussenot A, Boutron A, Bannwarth S, Rouzier C, Chabrol B, et al. Assembly defects of multiple respiratory chain complexes in a child with cardiac hypertrophy associated with a novel ACAD9 mutation. Mol Genet Metab. 2017;121:224-226 pubmed publisher..We show that ACAD9 analysis has to be performed in first intention in patients presenting with cardiac hypertrophy even in the presence of multiple assembly defects. ..
- Liu R, Wang H, Liu J, Wang J, Zheng M, Tan X, et al. Uncovering the embryonic development-related proteome and metabolome signatures in breast muscle and intramuscular fat of fast-and slow-growing chickens. BMC Genomics. 2017;18:816 pubmed publisher..Pathways related to ATP production were enriched to support the fast muscle growth in Cobb. The beta-oxidation of fatty acid is identified as the key pathway regulating chicken IMF deposition at early stages. ..
- Miller M, Burrage L, Gibson J, Strenk M, Lose E, Bick D, et al. Recurrent ACADVL molecular findings in individuals with a positive newborn screen for very long chain acyl-coA dehydrogenase (VLCAD) deficiency in the United States. Mol Genet Metab. 2015;116:139-45 pubmed publisher..Collectively, our data illustrate the molecular heterogeneity of VLCADD and provide novel insight into the outcomes of NBS for this disorder. ..
- Bar Yaacov D, Hadjivasiliou Z, Levin L, Barshad G, Zarivach R, Bouskila A, et al. Mitochondrial Involvement in Vertebrate Speciation? The Case of Mito-nuclear Genetic Divergence in Chameleons. Genome Biol Evol. 2015;7:3322-36 pubmed publisher..We conclude that our presented evidence and mathematical model underline mito-nuclear interactions as a likely role player in incipient speciation in vertebrates. ..
- Fernandez Guerra P, Lund M, Corydon T, Cornelius N, Gregersen N, Palmfeldt J, et al. Application of an Image Cytometry Protocol for Cellular and Mitochondrial Phenotyping on Fibroblasts from Patients with Inherited Disorders. JIMD Rep. 2016;27:17-26 pubmed publisher..Our results establish the capacity of our protocol for fast analysis of cellular and mitochondrial parameters by image cytometry in HDFs from patients with inherited metabolic diseases. ..
- Zurita RendÃ³n O, Antonicka H, Horvath R, Shoubridge E. A Mutation in the Flavin Adenine Dinucleotide-Dependent Oxidoreductase FOXRED1 Results in Cell-Type-Specific Assembly Defects in Oxidative Phosphorylation Complexes I and II. Mol Cell Biol. 2016;36:2132-40 pubmed publisher..Although we could not identify subassemblies of complex II, our results establish that FOXRED1 function is both broader than expected, involving the assembly of two flavoprotein-containing OXPHOS complexes, and cell type specific. ..
- Lagoutte Renosi J, Ségalas Milazzo I, Crahes M, Renosi F, Menu Bouaouiche L, Torre S, et al. Lethal Neonatal Progression of Fetal Cardiomegaly Associated to ACAD9 Deficiency. JIMD Rep. 2015;: pubmed..1030-1G>T mutation generating a non-degraded truncated protein and the p.Arg417Cys, creating an aberrant dimer. Our results underscore the crucial role of ACAD9 protein for cardiac function. ..
- Tucci S. Very long-chain acyl-CoA dehydrogenase (VLCAD-) deficiency-studies on treatment effects and long-term outcomes in mouse models. J Inherit Metab Dis. 2017;40:317-323 pubmed publisher..While long term use of MCT oil in mice has adverse effects, no such effects have been demonstrated in humans, likely reflecting the differences in long chain fatty acid oxidation between the two species. ..
- StÄ™pieÅ„ K, Roberts M, Hendriksz C. Very-Long-Chain Acyl-CoA Dehydrogenase Deficiency--diagnostic difficulties and own experience in multidisciplinary management. Dev Period Med. 2015;19:450-3 pubmed..Hence, the liaison between neurologists, rheumatologists and metabolic physicians is essential in early diagnosis and the management of patients with conditions causing myopathy. ..
- Delgado Goñi T, Miniotis M, Wantuch S, Parkes H, Marais R, Workman P, et al. The BRAF Inhibitor Vemurafenib Activates Mitochondrial Metabolism and Inhibits Hyperpolarized Pyruvate-Lactate Exchange in BRAF-Mutant Human Melanoma Cells. Mol Cancer Ther. 2016;15:2987-2999 pubmed..Mol Cancer Ther; 15(12); 2987-99. Â©2016 AACR. ..
- He M, Rutledge S, Kelly D, Palmer C, Murdoch G, Majumder N, et al. A new genetic disorder in mitochondrial fatty acid beta-oxidation: ACAD9 deficiency. Am J Hum Genet. 2007;81:87-103 pubmed
- Oey N, den Boer M, Ruiter J, Wanders R, Duran M, Waterham H, et al. High activity of fatty acid oxidation enzymes in human placenta: implications for fetal-maternal disease. J Inherit Metab Dis. 2003;26:385-92 pubmed
- Nouws J, te Brinke H, Nijtmans L, Houten S. ACAD9, a complex I assembly factor with a moonlighting function in fatty acid oxidation deficiencies. Hum Mol Genet. 2014;23:1311-9 pubmed publisher..Our results underscore the importance of the ACAD9 protein in complex I assembly and suggest that the enzymatic activity is a rudiment of the duplication event. ..
- Dewulf J, Barrea C, Vincent M, De Laet C, Van Coster R, Seneca S, et al. Evidence of a wide spectrum of cardiac involvement due to ACAD9 mutations: Report on nine patients. Mol Genet Metab. 2016;118:185-9 pubmed publisher..It is yet unknown whether these cardiac manifestations were related to ACAD9 mutation. In conclusion, this disorder should be suspected in the presence of lactic acidosis, complex I deficiency, and any cardiac involvement, even mild. ..
- Gerards M, van den Bosch B, Danhauser K, Serre V, van Weeghel M, Wanders R, et al. Riboflavin-responsive oxidative phosphorylation complex I deficiency caused by defective ACAD9: new function for an old gene. Brain. 2011;134:210-9 pubmed publisher..Our data support a new function for ACAD9 in complex I function, making this gene an important new candidate for patients with complex I deficiency, which could be improved by riboflavin treatment. ..
- Pena L, van Calcar S, Hansen J, Edick M, Walsh Vockley C, Leslie N, et al. Outcomes and genotype-phenotype correlations in 52 individuals with VLCAD deficiency diagnosed by NBS and enrolled in the IBEM-IS database. Mol Genet Metab. 2016;118:272-81 pubmed publisher..Functional testing, including fibroblast acylcarnitine profiling and white blood cell or fibroblast enzyme assay, is a useful diagnostic adjunct if uncharacterized mutations are identified. ..
- Collet M, Assouline Z, Bonnet D, Rio M, Iserin F, Sidi D, et al. High incidence and variable clinical outcome of cardiac hypertrophy due to ACAD9 mutations in childhood. Eur J Hum Genet. 2016;24:1112-6 pubmed publisher..Heart transplantation in children surviving neonatal period should be considered with caution, as delayed-onset muscle and brain involvement of various severity may occur, even if absent prior to transplantation. ..
- Zhang J, Zhang W, Zou D, Chen G, Wan T, Zhang M, et al. Cloning and functional characterization of ACAD-9, a novel member of human acyl-CoA dehydrogenase family. Biochem Biophys Res Commun. 2002;297:1033-42 pubmed..Enzymatic assay proved that the recombinant ACAD-9 protein has the dehydrogenase activity on palmitoyl-coenzyme A (C16:0) and stearoyl-coenzyme A (C18:0). Our results indicate that ACAD-9 is a novel member of ACADs. ..
- Calvo S, Compton A, Hershman S, Lim S, Lieber D, Tucker E, et al. Molecular diagnosis of infantile mitochondrial disease with targeted next-generation sequencing. Sci Transl Med. 2012;4:118ra10 pubmed publisher..The pathogenicity of two such genes, NDUFB3 and AGK, was supported by complementation studies and evidence from multiple patients, respectively. The results underscore the potential and challenges of deploying NGS in clinical settings. ..
- Ensenauer R, He M, Willard J, Goetzman E, Corydon T, Vandahl B, et al. Human acyl-CoA dehydrogenase-9 plays a novel role in the mitochondrial beta-oxidation of unsaturated fatty acids. J Biol Chem. 2005;280:32309-16 pubmed..Because of the substrate specificity and abundance of ACAD-9 in brain, we speculate that it may play a role in the turnover of lipid membrane unsaturated fatty acids that are essential for membrane integrity and structure. ..
- Oey N, Ruiter J, Ijlst L, Attie Bitach T, Vekemans M, Wanders R, et al. Acyl-CoA dehydrogenase 9 (ACAD 9) is the long-chain acyl-CoA dehydrogenase in human embryonic and fetal brain. Biochem Biophys Res Commun. 2006;346:33-7 pubmed..In this study, using in situ hybridization as well as enzymatic studies, we identified acyl-CoA dehydrogenase 9 (ACAD 9) as the long-chain ACAD in human embryonic and fetal central nervous tissue...
- Obaid A, Nashabat M, Alfadhel M, Alasmari A, Al Mutairi F, Alswaid A, et al. Clinical, Biochemical, and Molecular Features in 37 Saudi Patients with Very Long Chain Acyl CoA Dehydrogenase Deficiency. JIMD Rep. 2018;40:47-53 pubmed publisher..Despite early diagnosis and treatment, the outcome of VLCAD deficiency in this Saudi Arabian population remains poor. Preventive measures, such as prenatal diagnosis, could be implemented. ..
- Leslie N, Wang X, Peng Y, Valencia C, Khuchua Z, Hata J, et al. Neonatal multiorgan failure due to ACAD9 mutation and complex I deficiency with mitochondrial hyperplasia in liver, cardiac myocytes, skeletal muscle, and renal tubules. Hum Pathol. 2016;49:27-32 pubmed publisher..Autopsy-derived fibroblasts had reduced complex I activity (53% of control) with normal activity in complexes II to IV, similar to reported cases of ACAD9 deficiency. ..
- Schiff M, Haberberger B, Xia C, Mohsen A, Goetzman E, Wang Y, et al. Complex I assembly function and fatty acid oxidation enzyme activity of ACAD9 both contribute to disease severity in ACAD9 deficiency. Hum Mol Genet. 2015;24:3238-47 pubmed publisher..Accordingly, treatment of ACAD9 patients should aim at counteracting both CI and fatty acid oxidation dysfunctions. ..
- Haack T, Danhauser K, Haberberger B, Hoser J, Strecker V, Boehm D, et al. Exome sequencing identifies ACAD9 mutations as a cause of complex I deficiency. Nat Genet. 2010;42:1131-4 pubmed publisher..ACAD9 screening of 120 additional complex I-defective index cases led us to identify two additional unrelated cases and a total of five pathogenic ACAD9 alleles. ..