ACAD9 explained

Acyl-CoA dehydrogenase family member 9, mitochondrial is an enzyme that in humans is encoded by the ACAD9 gene.^{[1] [2]} Mitochondrial Complex I Deficiency with varying clinical manifestations has been associated with mutations in ACAD9.^[3]

Structure

The ACAD9 gene contains an open reading frame of 1866 base pairs; this gene encodes a protein with 621 amino acid residues. Alignment of the ACAD9 protein sequence with that of other human ACAD proteins showed that ACAD-9 protein displays 46–27% identity, and 56–38% similarity with the eight members of the ACAD family, including ACADVL, ACADS, ACADM, ACADL, IVD, GCD, ACADSB, and ACD8. The calculated molecular weight of the ACAD9 is 68.8 kDa.

Function

The ACAD9 enzyme catalyzes a crucial step in fatty acid beta-oxidation by forming a C2-C3 trans-double bond in the fatty acid. LVCAD is specific to very long-chain fatty acids, typically C16-acylCoA and longer.^[4] It has been observed that ACAD9 can catalyze acyl-CoAs with very long chains. The specific activity of ACAD9 towards palmitoyl-CoA (C16:0) is three times higher than that towards stearoyl-CoA (C18:0). ACAD-9 has little activity on n-octanoyl-CoA (C8:0), n-butyryl-CoA (C4:0) or isovaleryl-CoA (C5:0).

In contrast with ACADVL, ACAD9 is also involved in assembly of the oxidative phosphorylation complex I. ACAD9 binds complex I assembly factors NDUFAF1 and Ecsit and is specifically required for the assembly of complex I. Furthermore, ACAD9 mutations result in complex I deficiency and not in disturbed long-chain fatty acid oxidation.^[5]

Clinical significance

Mutations in the ACAD9 gene are associated with mitochondrial complex I deficiency type 20, which is autosomal recessive. This deficiency is the most common enzymatic defect of the oxidative phosphorylation disorders.^{[6] [7]} Mitochondrial complex I deficiency shows extreme genetic heterogeneity and can be caused by mutation in nuclear-encoded genes or in mitochondrial-encoded genes. There are no obvious genotype–phenotype correlations, and inference of the underlying basis from the clinical or biochemical presentation is difficult, if not impossible.^[8] However, the majority of cases are caused by mutations in nuclear-encoded genes.^{[9] [10]} It causes a wide range of clinical disorders, ranging from lethal neonatal disease to adult-onset neurodegenerative disorders. Phenotypes include macrocephaly with progressive leukodystrophy, nonspecific encephalopathy, hypertrophic cardiomyopathy, myopathy, liver disease, Leigh syndrome, Leber hereditary optic neuropathy, and some forms of Parkinson disease.^[11]

A few cases specific to ACAD9 have been reported. Some cases presented with episodic liver dysfunction during otherwise mild illnesses or cardiomyopathy, along with chronic neurologic dysfunction. Brain findings were notable for generalized edema with diffuse ventricular compression, acute left tonsillar herniation, and diffuse multifocal acute damage in the hippocampus. In addition, some abnormalities consistent with nonacute changes were seen, including a subacute right cerebellar hemispheric infarct and reduction in the number of neurons in several areas.^[12] In one patient, whose clinical manifestations of hypotonia, cardiomyopathy, and lactic acidosis, a vigorous treatment with riboflavin allowed the individual to have normal psychomotor development and no cognitive impairment at 5 years of age.^[13] Exercise-induced rhabdomyolysis, mitochondrial encephalomyopathy, and hyperplasia in liver, cardiac myocytes, skeletal muscle, and renal tubules have also been observed in patients with ACAD9 mutations.^{[14] [15]}

Interactions

ACAD9 is part of the mitochondrial complex I assembly (MCIA) complex. The complex comprises at least TMEM126B, NDUFAF1, ECSIT, and ACAD9, which interacts directly with NDUFAF1 and ECSIT.^[5]

Further reading

• Fragaki K, Chaussenot A, Boutron A, Bannwarth S, Cochaud C, Richelme C, Sacconi S, Paquis-Flucklinger V . Severe defect in mitochondrial complex I assembly with mitochondrial DNA deletions in ACAD9-deficient mild myopathy . Muscle & Nerve . 55 . 6 . 919–922 . June 2017 . 27438479 . 10.1002/mus.25262 . 5530200 .
• Szafranski K, Schindler S, Taudien S, Hiller M, Huse K, Jahn N, Schreiber S, Backofen R, Platzer M . Violating the splicing rules: TG dinucleotides function as alternative 3' splice sites in U2-dependent introns . Genome Biology . 8 . 8 . R154 . 2008 . 17672918 . 2374985 . 10.1186/gb-2007-8-8-r154 . free .
• He M, Rutledge SL, Kelly DR, Palmer CA, Murdoch G, Majumder N, Nicholls RD, Pei Z, Watkins PA, Vockley J . A new genetic disorder in mitochondrial fatty acid beta-oxidation: ACAD9 deficiency . American Journal of Human Genetics . 81 . 1 . 87–103 . July 2007 . 17564966 . 1950923 . 10.1086/519219 .
• Oey NA, Ruiter JP, Ijlst L, Attie-Bitach T, Vekemans M, Wanders RJ, Wijburg FA . Acyl-CoA dehydrogenase 9 (ACAD 9) is the long-chain acyl-CoA dehydrogenase in human embryonic and fetal brain . Biochemical and Biophysical Research Communications . 346 . 1 . 33–7 . July 2006 . 16750164 . 10.1016/j.bbrc.2006.05.088 .
• Ensenauer R, He M, Willard JM, Goetzman ES, Corydon TJ, Vandahl BB, Mohsen AW, Isaya G, Vockley J . Human acyl-CoA dehydrogenase-9 plays a novel role in the mitochondrial beta-oxidation of unsaturated fatty acids . The Journal of Biological Chemistry . 280 . 37 . 32309–16 . September 2005 . 16020546 . 10.1074/jbc.M504460200 . free .
• Oey NA, den Boer ME, Ruiter JP, Wanders RJ, Duran M, Waterham HR, Boer K, van der Post JA, Wijburg FA . High activity of fatty acid oxidation enzymes in human placenta: implications for fetal-maternal disease . Journal of Inherited Metabolic Disease . 26 . 4 . 385–92 . 2004 . 12971426 . 10.1023/A:1025163204165 . 12128475 .

Notes and References

1. Zhang J, Zhang W, Zou D, Chen G, Wan T, Zhang M, Cao X . Cloning and functional characterization of ACAD-9, a novel member of human acyl-CoA dehydrogenase family . Biochemical and Biophysical Research Communications . 297 . 4 . 1033–42 . October 2002 . 12359260 . 10.1016/S0006-291X(02)02336-7 .
2. Web site: Entrez Gene: ACAD9 acyl-Coenzyme A dehydrogenase family, member 9.
3. Leslie N, Wang X, Peng Y, Valencia CA, Khuchua Z, Hata J, Witte D, Huang T, Bove KE . Neonatal multiorgan failure due to ACAD9 mutation and complex I deficiency with mitochondrial hyperplasia in liver, cardiac myocytes, skeletal muscle, and renal tubules . Human Pathology . 49 . 27–32 . March 2016 . 26826406 . 10.1016/j.humpath.2015.09.039 .
4. Aoyama T, Souri M, Ushikubo S, Kamijo T, Yamaguchi S, Kelley RI, Rhead WJ, Uetake K, Tanaka K, Hashimoto T . Purification of human very-long-chain acyl-coenzyme A dehydrogenase and characterization of its deficiency in seven patients . The Journal of Clinical Investigation . 95 . 6 . 2465–73 . June 1995 . 7769092 . 295925 . 10.1172/JCI117947 .
5. Nouws J, Nijtmans L, Houten SM, van den Brand M, Huynen M, Venselaar H, Hoefs S, Gloerich J, Kronick J, Hutchin T, Willems P, Rodenburg R, Wanders R, van den Heuvel L, Smeitink J, Vogel RO . Acyl-CoA dehydrogenase 9 is required for the biogenesis of oxidative phosphorylation complex I . Cell Metabolism . 12 . 3 . 283–94 . September 2010 . 20816094 . 10.1016/j.cmet.2010.08.002 . free .
6. Kirby DM, Salemi R, Sugiana C, Ohtake A, Parry L, Bell KM, Kirk EP, Boneh A, Taylor RW, Dahl HH, Ryan MT, Thorburn DR . NDUFS6 mutations are a novel cause of lethal neonatal mitochondrial complex I deficiency . The Journal of Clinical Investigation . 114 . 6 . 837–45 . September 2004 . 15372108 . 516258 . 10.1172/JCI20683 .
7. McFarland R, Kirby DM, Fowler KJ, Ohtake A, Ryan MT, Amor DJ, Fletcher JM, Dixon JW, Collins FA, Turnbull DM, Taylor RW, Thorburn DR . De novo mutations in the mitochondrial ND3 gene as a cause of infantile mitochondrial encephalopathy and complex I deficiency . Annals of Neurology . 55 . 1 . 58–64 . January 2004 . 14705112 . 10.1002/ana.10787 . 21076359 .
8. Haack TB, Haberberger B, Frisch EM, Wieland T, Iuso A, Gorza M, Strecker V, Graf E, Mayr JA, Herberg U, Hennermann JB, Klopstock T, Kuhn KA, Ahting U, Sperl W, Wilichowski E, Hoffmann GF, Tesarova M, Hansikova H, Zeman J, Plecko B, Zeviani M, Wittig I, Strom TM, Schuelke M, Freisinger P, Meitinger T, Prokisch H . Molecular diagnosis in mitochondrial complex I deficiency using exome sequencing . Journal of Medical Genetics . 49 . 4 . 277–83 . April 2012 . 22499348 . 10.1136/jmedgenet-2012-100846 . 3177674 .
9. Loeffen JL, Smeitink JA, Trijbels JM, Janssen AJ, Triepels RH, Sengers RC, van den Heuvel LP . Isolated complex I deficiency in children: clinical, biochemical and genetic aspects . Human Mutation . 15 . 2 . 123–34 . 2000 . 10649489 . 10.1002/(SICI)1098-1004(200002)15:2<123::AID-HUMU1>3.0.CO;2-P . 35579133 . free .
10. Triepels RH, Van Den Heuvel LP, Trijbels JM, Smeitink JA . Respiratory chain complex I deficiency . American Journal of Medical Genetics . 106 . 1 . 37–45 . 2001 . 11579423 . 10.1002/ajmg.1397 .
11. Robinson BH . Human complex I deficiency: clinical spectrum and involvement of oxygen free radicals in the pathogenicity of the defect . Biochimica et Biophysica Acta (BBA) - Bioenergetics . 1364 . 2 . 271–86 . May 1998 . 9593934 . 10.1016/s0005-2728(98)00033-4 . free .
12. He M, Rutledge SL, Kelly DR, Palmer CA, Murdoch G, Majumder N, Nicholls RD, Pei Z, Watkins PA, Vockley J . A new genetic disorder in mitochondrial fatty acid beta-oxidation: ACAD9 deficiency . American Journal of Human Genetics . 81 . 1 . 87–103 . July 2007 . 17564966 . 1950923 . 10.1086/519219 .
13. Haack TB, Danhauser K, Haberberger B, Hoser J, Strecker V, Boehm D, Uziel G, Lamantea E, Invernizzi F, Poulton J, Rolinski B, Iuso A, Biskup S, Schmidt T, Mewes HW, Wittig I, Meitinger T, Zeviani M, Prokisch H . Exome sequencing identifies ACAD9 mutations as a cause of complex I deficiency . Nature Genetics . 42 . 12 . 1131–4 . December 2010 . 21057504 . 10.1038/ng.706 . 12953553 .
14. Garone C, Donati MA, Sacchini M, Garcia-Diaz B, Bruno C, Calvo S, Mootha VK, Dimauro S . Mitochondrial encephalomyopathy due to a novel mutation in ACAD9 . JAMA Neurology . 70 . 9 . 1177–9 . September 2013 . 23836383 . 3891824 . 10.1001/jamaneurol.2013.3197 .
15. Daniel R, Singh M, O'Rourke K . Another "Complex" Case: Complex I Deficiency Secondary to Acyl-CoA Dehydrogenase 9 Mutation . The American Journal of the Medical Sciences . 350 . 5 . 423–4 . November 2015 . 26445304 . 10.1097/MAJ.0000000000000570 .