Complex I assembly function and fatty acid oxidation enzyme activity of ACAD9 both contribute to disease severity in ACAD9 deficiency

Schiff, Manuel; Haberberger, Birgit; Xia, Chuanwu; Mohsen, Al‐Walid; Goetzman, Eric S.; Wang, Yudong; Uppala, Radha; Zhang, Yuxun; Karunanidhi, Anuradha; Prabhu, Dolly; Alharbi, Hana; Prochownik, Edward V.; Haack, Tobias B.; Häberle, Johannes; Münnich, Arnold; Rötig, Agnès; Taylor, Robert W.; Nicholls, Robert D.; Kim, Jung-Ja; Prokisch, Holger; Vockley, Jerry

doi:10.1093/hmg/ddv074

Cited by 56 publications

(67 citation statements)

References 55 publications

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“…This L-shaped structure is composed of a hydrophilic arm and a hydrophobic arm and is highly conserved from bacteria to eukaryotes [138][139][140]. The proper assembly of mature CI involves the coordinated assembly of 45 structural subunits, the majority of which are encoded by the nDNA and must be transported into the mitochondria via membrane bound transport systems [55,141,142]. Furthermore, a group of proteins termed 'assembly factors' are required to form the final, mature holocomplex [143].…”

Section: Fao Proteins and Oxphos Complex I Assemblymentioning

confidence: 99%

Combined defects in oxidative phosphorylation and fatty acid β-oxidation in mitochondrial disease

2016

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SynopsisMitochondria provide the main source of energy to eukaryotic cells, oxidizing fats and sugars to generate ATP . Mitochondrial fatty acid β-oxidation (FAO) and oxidative phosphorylation (OXPHOS) are two metabolic pathways which are central to this process. Defects in these pathways can result in diseases of the brain, skeletal muscle, heart and liver, affecting approximately 1 in 5000 live births. There are no effective therapies for these disorders, with quality of life severely reduced for most patients. The pathology underlying many aspects of these diseases is not well understood; for example, it is not clear why some patients with primary FAO deficiencies exhibit secondary OXPHOS defects. However, recent findings suggest that physical interactions exist between FAO and OXPHOS proteins, and that these interactions are critical for both FAO and OXPHOS function. Here, we review our current understanding of the interactions between FAO and OXPHOS proteins and how defects in these two metabolic pathways contribute to mitochondrial disease pathogenesis.Key words: disease, mitochondria, protein complex assembly, protein interactions, supercomplex. MITOCHONDRIAL METABOLISMMitochondria occupy almost all human cell types and are involved in essential metabolic and cellular processes, including calcium and iron homoeostasis, apoptosis, innate immunity and haeme biosynthesis [1]. However, the primary function of mitochondria is the production of energy in the form of ATP [2][3][4]. ATP is the body's energy currency, playing vital roles in cell differentiation, growth and reproduction, thermogenesis and powering the contraction of muscles for movement [1]. In humans, ATP is produced by two different processes; through the breakdown of glucose or other sugars in Abbreviations: ACAD9, acyl-CoA dehydrogenase 9; BN-PAGE, blue native polyacrylamide gel electrophoresis; CACT, carnitine acylcarnitine translocase; CI, oxidative phosphorylation complex I (NADH: ubiquinone oxidoreductase, EC 1.6.5.3); CII, oxidative phosphorylation complex II (succinate: ubiquinone oxidoreductase, EC 1.3.5.1); CIII, oxidative phosphorylation complex III (ubiquinol: ferricytochrome c oxidoreductase, EC 1.10.2.2); CIV, oxidative phosphorylation complex IV (cytochrome c oxidase, EC 1.9.3.1); COPP , complex one phylogenetic profile; CPT1, carnitine O-palmitoyltransferase 1; CPT2, carnitine O-palmitoyltransferase 2; CV, OXPHOS complex V (FoF 1 -ATP synthetase, EC; 3.6.3.14); ECHS1, enoyl-CoA hydratase, short chain 1, mitochondrial; ECI1, enoyl-CoA delta isomerase, 1; ETF, electron transfer flavoprotein; ETFA, electron transfer flavoprotein alpha subunit; ETFB, electron transfer flavoprotein beta subunit; ETF-QO, electron transfer flavoprotein: ubiquinone oxidoreductase; FAD, flavin adenine dinucleotide; FADH 2 , reduced flavin adenine dinucleotide; FAO, fatty acid β-oxidation; H 2 O, water; HADH, hydroxyacyl-CoA dehydrogenase; KAT, 3-ketoacyl-CoA thiolase, mitochondrial; LCAD, long chain acyl-CoA dehydrogenase; LCEH, long chain enoyl-CoA hydra...

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Section: Fao Proteins and Oxphos Complex I Assemblymentioning

confidence: 99%

Combined defects in oxidative phosphorylation and fatty acid β-oxidation in mitochondrial disease

2016

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“…The expression profiles of 16 other mutations have been studied by Schiff et al 2015 [30]. In this study, it was determined that mutations with little or no impact on ACAD9 activity and stability/folding were located after the C-terminal domain, while those which were inactivating were found in the catalytic portion of the molecule, which is conserved in all mitochondrial matrix ACADs (Fig.…”

Section: Discussionmentioning

confidence: 93%

“…Locations of V59F and L166W mutations (red arrows) and mutations reported by Schiff et al 2015 (black arrows) with stability of the recombinant purified ACAD9 proteins after trypsin digest, an indicator of protein stability/folding (labeled “Stability”) and percentage of the activity of wild type recombinant ACAD9 (labeled “Activity %”) [30]. These are displayed on a polypeptide model of the three ACAD domains: N-terminal α-helical domain, middle β-sheet domain, and a C-terminal α-helical domain.…”

Section: Figmentioning

confidence: 98%

An atypical presentation of ACAD9 deficiency: Diagnosis by whole exome sequencing broadens the phenotypic spectrum and alters treatment approach

Aintablian

Narayanan

Belnap

et al. 2017

Molecular Genetics and Metabolism Reports

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Acyl-CoA dehydrogenase 9 (ACAD9), linked to chromosome 3q21.3, is one of a family of multimeric mitochondrial flavoenzymes that catalyze the degradation of fatty acyl-CoA from the carnitine shuttle via β-oxidation (He et al. 2007). ACAD9, specifically, is implicated in the processing of palmitoyl-CoA and long-chain unsaturated substrates, but unlike other acyl-CoA dehydrogenases (ACADs), it has a significant role in mitochondrial complex I assembly (Nouws et al. 2010 & 2014). Mutations in this enzyme typically cause mitochondrial complex I deficiency, as well as a mild defect in long chain fatty acid metabolism (Haack et al. 2010, Kirby et al. 2004, Mcfarland et al. 2003, Nouws et al. 2010 & 2014). The clinical phenotype of ACAD9 deficiency and the associated mitochondrial complex I deficiency reflect this unique duality, and symptoms are variable in severity and onset. Patients classically present with cardiac dysfunction due to hypertrophic cardiomyopathy. Other common features include Leigh syndrome, macrocephaly, and liver disease (Robinson et al. 1998).We report the case of an 11-month old girl presenting with microcephaly, dystonia, and lactic acidosis, concerning for a mitochondrial disorder, but atypical for ACAD9 deficiency. Muscle biopsy showed mitochondrial proliferation, but normal mitochondrial complex I activity. The diagnosis of ACAD9 deficiency was not initially considered, due both to these findings and to her atypical presentation. Biochemical assay for ACAD9 deficiency is not clinically available. Family trio-based whole exome sequencing (WES) identified 2 compound heterozygous mutations in the ACAD9 gene. This discovery led to optimized treatment of her mitochondrial dysfunction, and supplementation with riboflavin, resulting in clinical improvement.There have been fewer than 25 reported cases of ACAD9 deficiency in the literature to date. We review these and compare them to the unique features of our patient. ACAD9 deficiency should be considered in the differential diagnosis of patients with lactic acidosis, seizures, and other symptoms of mitochondrial disease, including those with normal mitochondrial enzyme activities. This case demonstrates the utility of WES, in conjunction with biochemical testing, for the appropriate diagnosis and treatment of disorders of energy metabolism.

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“…If the pivotal role of ACAD9 in complex I assembly has been demonstrated, the physiological function of ACAD9 in b-oxidation still remains controversial. Nouws et al concluded that ACAD9 seems not necessary for fatty acid oxidation (Nouws et al 2014a, b), while it has been, recently, demonstrated in cultured cells that ACAD9 plays a physiological role in fatty acid oxidation (Schiff et al 2015).…”

Section: Discussionmentioning

confidence: 99%

Lethal Neonatal Progression of Fetal Cardiomegaly Associated to ACAD9 Deficiency

Lagoutte-Renosi¹,

Ségalas-Milazzo²,

Crahès³

et al. 2015

JIMD Reports

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ACAD9 (acyl-CoA dehydrogenase 9) is an essential factor for the mitochondrial respiratory chain complex I assembly. ACAD9, a member of acyl-CoA dehydrogenase family, has high homology with VLCAD (very long-chain acyl-CoA dehydrogenase) and harbors a homodimer structure. Recently, patients with ACAD9 deficiency have been described with a wide clinical spectrum ranging from severe lethal form to moderate form with exercise intolerance.We report here a prenatal presentation with intrauterine growth retardation and cardiomegaly, with a fatal outcome shortly after birth. Compound heterozygous mutations, a splice-site mutation -c.1030-1G>T and a missense mutation -c.1249C>T; p.Arg417Cys, were identified in the ACAD9 gene. Their effect on protein structure and expression level was investigated. Protein modeling suggested a functional effect of the c.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.

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Complex I assembly function and fatty acid oxidation enzyme activity of ACAD9 both contribute to disease severity in ACAD9 deficiency

Cited by 56 publications

References 55 publications

Combined defects in oxidative phosphorylation and fatty acid β-oxidation in mitochondrial disease

Combined defects in oxidative phosphorylation and fatty acid β-oxidation in mitochondrial disease

An atypical presentation of ACAD9 deficiency: Diagnosis by whole exome sequencing broadens the phenotypic spectrum and alters treatment approach

Lethal Neonatal Progression of Fetal Cardiomegaly Associated to ACAD9 Deficiency

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