Abstract
In fatty acid oxidation defects, the majority of gene variations are of the missense type and, therefore, prone to inducing misfolding in the resulting mutant protein. The fate of the mutant protein depends on the nature of the gene variation and other genetic factors as well as cellular and environmental factors. Since it has been shown that certain fatty acid oxidation enzyme proteins, exemplified by mutant medium-chain and short-chain acyl-CoA dehydrogenases as well as electron transfer flavoprotein and electron transfer flavoprotein dehydrogenase, may accumulate during cellular stress, e.g. elevated temperature, there is speculation about how such proteins may disturb the integrity of the putative fatty acid oxidation metabolone, in which the two flavoproteins link the matrix-located acyl-CoA dehydrogenases to the respiratory chain in the mitochondrial inner membrane. However, since studies so far have not been able to define the fatty acid oxidation metabolone, it is concluded that new concepts and refined techniques are required to answer these questions and thereby contribute to the elucidation of the cellular pathophysiology and the genotype–phenotype relationship in fatty acid oxidation defects.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Andresen BS, Bross P, Udvari S et al (1997) The molecular basis of medium-chain acyl-CoA dehydrogenase (MCAD) deficiency in compound heterozygous patients: is there correlation between genotype and phenotype? Hum Mol Genet 6:695–707
Antonarakis SE, Krawczak M, Cooper DN (2001) The nature and mechanisms of human gene mutations. In: Scriver CR, Beaudet AL, Valle D (eds) The metabolic and molecular basis of inherited disease, 8th edn. McGraw-Hill, New York, pp 343–378
Benjamin ER, Flanagan JJ, Schilling A et al (2009) The pharmacological chaperone 1-deoxygalactonojirimycin increases α-galactosidase A levels in Fabry patient cell lines. J Inherit Metab Dis 32:424–440
Bross P, Andresen BS, Winter V et al (1993) Co-overexpression of bacterial GroESL chaperonins partly overcomes non-productive folding and tetramer assembly of E. coli-expressed human medium-chain acyl-CoA dehydrogenase (MCAD) carrying the prevalent disease-causing K304E mutation. Biochim Biophys Acta 1182:264–274
Bross P, Jespersen C, Jensen TG et al (1995) Effects of two mutations detected in medium chain acyl-CoA dehydrogenase (MCAD)-deficient patients on folding, oligomer assembly, and stability of MCAD enzyme. J Biol Chem 270:10284–10290
Corydon TJ, Hansen J, Bross P, Jensen TG (2005) Down-regulation of Hsp60 expression by RNAi impairs folding of medium-chain acyl-CoA dehydrogenase wild-type and disease-associated proteins. Mol Genet Metab 85:260–270
Desnick RJ (2004) Enzyme replacement and enhancement therapies for lysosomal diseases. J Inherit Metab Dis 27:385–410
Eaton S (2002) Control of mitochondrial beta-oxidation flux. Prog Lipid Res 41:197–239
Frerman FE, Goodman SI (2001) Defects in electron transfer flavoprotein and electron transfer flavoprotein-ubiquinone oxidoreductase: glutaric aciduria type II. In: Scriver CR, Beaudet AL, Valle D (eds) The metabolic and molecular basis of inherited disease, 8th edn. McGraw-Hill, New York, pp 2357-2365
Gobin-Limballe S, Djouadi F, Aubey F et al (2007) Genetic basis for correction of very-long-chain acyl-coenzyme a dehydrogenase deficiency by bezafibrate in patient fibroblasts: toward a genotype-based therapy. Am J Hum Genet 81:1133–1143
Goodman SI, Axtell KM, Bindoff LA, Beard SE, Gill RE, Frerman FE (1994) Molecular cloning and expression of a cDNA encoding human electron transfer flavoprotein-ubiquinone oxidoreductase. Eur J Biochem 219:277–286
Gregersen N (2006) Protein misfolding disorders: pathogenesis and intervention. J Inherit Metab Dis 29:456–470
Gregersen N, Winter VS, Corydon MJ et al (1998) Identification of four new mutations in the short-chain acyl-CoA dehydrogenase (SCAD) gene in two patients: one of the variant alleles, 511C-> T, is present at an unexpectedly high frequency in the general population, as was the case for 625G-> A, together conferring susceptibility to ethylmalonic aciduria. Hum Mol Genet 7:619–627
Gregersen N, Bross P, Andresen BS, Pedersen CB, Corydon TJ, Bolund L (2001) The role of chaperone-assisted folding and quality control in inborn errors of metabolism: protein folding disorders. J Inherit Metab Dis 24:189–212
Gregersen N, Bross P, Andresen BS (2004) Genetic defects in fatty acid beta-oxidation and acyl-CoA dehydrogenases. Eur J Biochem 271:470–482
Gregersen N, Bross P, Jørgensen MM (2005) Protein folding and misfolding: the role of cellular protein quality control systems in inherited disorders. In: Scriver CR, Beaudet AL, Valle D, Sly WS, Vogelstein B, Childs B, Kinzler KW (eds). McGraw-Hill, New York, p MMBID-ONLINE-URL: http://genetics.accessmedicine.com
Gregersen N, Bross P, Vang S, Christensen JH (2006) Protein misfolding and human disease. Annu Rev Genomics Hum Genet 7:103–124
Gregersen N, Andresen BS, Pedersen CB, Olsen RK, Corydon TJ, Bross P (2008) Mitochondrial fatty acid oxidation defects—remaining challenges. J Inherit Metab Dis 31:643–657
Henriques BJ, Rodrigues JV, Olsen RK, Bross P, Gomes CM (2008) Role of flavinylation in a mild variant of multiple acyl-CoA dehydrogenation deficiency: a molecular rationale for the effects of riboflavin supplementation. J Biol Chem 13:4222–4229
Ikeda Y, Keese SM, Tanaka K (1986) Biosynthesis of electron transfer flavoprotein in a cell-free system and in cultured human fibroblasts: defect in the alpha subunit synthesis is a primary lesion in glutaric aciduria type II. J Clin Invest 78:997–1002
Loehr JP, Goodman SI, Frerman FE (1990) Glutaric acidemia type II: heterogeneity of clinical and biochemical phenotypes. Pediatr Res 27:311–315
Magen D, Georgopoulos C, Bross P et al (2008) Mitochondrial hsp60 chaperonopathy causes an autosomal-recessive neurodegenerative disorder linked to brain hypomyelination and leukodystrophy. Am J Hum Genet 83:30–42
Nada MA, Rhead WJ, Sprecher H, Schulz H, Roe CR (1995) Evidence for intermediate channeling in mitochondrial beta-oxidation. J Biol Chem 270:530–535
Olsen RK, Andresen BS, Christensen E, Bross P, Skovby F, Gregersen N (2003) Clear relationship between ETF/ETFDH genotype and phenotype in patients with multiple acyl-CoA dehydrogenation deficiency. Hum Mutat 22:12–23
Olsen RK, Olpin SE, Andresen BS et al (2007) ETFDH mutations as a major cause of riboflavin-responsive multiple acyl-CoA dehydrogenation deficiency. Brain 130:2045–2054
Pagliarini DJ, Calvo SE, Chang B et al (2008) A mitochondrial protein compendium elucidates complex I disease biology. Cell 134:112–123
Parker A, Engel PC (2000) Preliminary evidence for the existence of specific functional assemblies between enzymes of the beta-oxidation pathway and the respiratory chain. Biochem J 345(Pt 3):429–435
Pedersen CB, Bross P, Winter VS et al (2003) Misfolding, degradation, and aggregation of variant proteins. The molecular pathogenesis of short chain acyl-CoA dehydrogenase (SCAD) deficiency. J Biol Chem 278:47449–47458
Pedersen CB, Kolvraa S, Kolvraa A et al (2008) The ACADS gene variation spectrum in 114 patients with short-chain acyl-CoA dehydrogenase (SCAD) deficiency is dominated by missense variations leading to protein misfolding at the cellular level. Hum Genet 124:43–56
Purevjav E, Kimura M, Takusa Y et al (2002) Molecular study of electron transfer flavoprotein alpha-subunit deficiency in two Japanese children with different phenotypes of glutaric acidemia type II. Eur J Clin Invest 32:707–712
Reifschneider NH, Goto S, Nakamoto H et al (2006) Defining the mitochondrial proteomes from five rat organs in a physiologically significant context using 2D blue-native/SDS-PAGE. J Proteome Res 5:1117–1132
Salazar D, Zhang LN, Degala GD, Frerman FE (1997) Expression and characterization of two pathogenic mutations in human electron transfer flavoprotein. J Biol Chem 272:26425–26433
Schiff M, Froissart R, Olsen RK, Acquaviva C, Vianey-Saban C (2006) Electron transfer flavoprotein deficiency: functional and molecular aspects. Mol Genet Metab 88:153–158
Stanley KK, Tubbs PK (1975) The role of intermediates in mitochondrial fatty acid oxidation. Biochem J 150:77–88
Toogood HS, Leys D, Scrutton NS (2007) Dynamics driving function: new insights from electron transferring flavoproteins and partner complexes. FEBS J 274:5481–5504
Yotsumoto Y, Hasegawa Y, Fukuda S et al (2008) Clinical and molecular investigations of Japanese cases of glutaric acidemia type 2. Mol Genet Metab 94:61–67
Acknowledgement
The investigations done at the Research Unit for Molecular Medicine have over the years been supported by The Danish Medical Research Council; Danish Human Genome Centre; Karen Elise Jensen Foundation; Lundbeck Foundation; The March of Dimes Foundation; Aarhus County Research Initiative; Institute of Experimental Clinical Research, Aarhus University; Institute of Human Genetics, Aarhus University, and Aarhus University Hospital. We thank employees at the research unit as well as national and international friends for ongoing discussions concerning genotype–phenotype relationships in FAO defects.
Author information
Authors and Affiliations
Corresponding author
Additional information
Communicated by: Ertan Mayatepek
Competing interest: None declared.
Rights and permissions
About this article
Cite this article
Gregersen, N., Olsen, R.K.J. Disease mechanisms and protein structures in fatty acid oxidation defects. J Inherit Metab Dis 33, 547–553 (2010). https://doi.org/10.1007/s10545-010-9046-1
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10545-010-9046-1