Treatment of complex I deficiency with riboflavin

Bernsen, P.L.J.A.; Gabreëls, F.J.M.; Ruitenbeek, W.; Hamburger, Hans

doi:10.1016/0022-510x(93)90108-b

Cited by 85 publications

(54 citation statements)

References 15 publications

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“…Encephalopathy, cardiomyopathy, and ophthalmoplegia were not present. Reduced muscle activity for Complex I was present in 28, [4][5][6]10,23,24,27,28,34,35,39,40 C o m p l e x I I i n 3 , 3 , 1 4 , 1 7 C o m p l e x I I I i n 10, 8,11,12,19,22,26,28,31 Complex IV in 1, 6 and Complex V in 1 36 patient. Reduced muscle Complex I and IV activity, 32 Complex I, II, and III activity, 33 and Complex I, III, and IV activity 18,32,38 have also been reported.…”

Section: Discussionmentioning

confidence: 99%

Biochemical and genetic studies in a family with mitochondrial myopathy

et al. 1997

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Section: Discussionmentioning

confidence: 99%

Biochemical and genetic studies in a family with mitochondrial myopathy

et al. 1997

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“…The pathology of Wernicke-Korsakoff syndrome, resulting from decreased thiamine pyrophosphate affinity of a transketolase variant, is also avoided by adequate dietary thiamine intake (39). Patients with polymorphic variants of other flavoproteins such as the mitochondrial electron transport complex 1 (40,41), pyruvate dehydrogenase (42), electron transport flavoprotein (43), and acyl-CoA dehydrogenases (44,45) have previously been shown to respond to treatment with riboflavin, due to rescue/stabilization of inactive apoenzymes.…”

Section: Discussionmentioning

confidence: 99%

Diminished FAD Binding in the Y459H and V492E Antley-Bixler Syndrome Mutants of Human Cytochrome P450 Reductase

Marohnic

Panda

Martásek

et al. 2006

Journal of Biological Chemistry

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Numerous mutations/polymorphisms of the POR gene, encoding NADPH:cytochrome P450 oxidoreductase (CYPOR), have been described in patients with Antley-Bixler syndrome (ABS), presenting with craniofacial dysmorphogenesis, and/or disordered steroidogenesis, exhibiting ambiguous genitalia. CYPOR is the obligate electron donor to 51 microsomal cytochromes P450 that catalyze critical steroidogenic and xenobiotic reactions, and to two heme oxygenase isoforms, among other redox partners. To address the molecular basis of CYPOR dysfunction in ABS patients, the soluble catalytic domain of human CYPOR was bacterially expressed. WT enzyme was green, due to air-stable FMN semiquinone (blue) and oxidized FAD (yellow). The ABS mutant V492E was blue-gray. Flavin analysis indicated that WT had a protein:FAD:FMN ratio of ϳ1:1:1, whereas ϳ1:0.1:0.9 was observed for V492E, which retained 9% of the WT k cat /K m in NADPH:cytochrome c reductase assays. V492E was reconstituted upon addition of FAD, post-purification, as shown by flavin analysis, activity assay, and near UV-visible CD. Both Y459H and V492E were expressed as membrane anchor-containing proteins, which also exhibited FAD deficiency. CYP4A4-catalyzed -hydroxylation of prostaglandin E 1 was supported by WT CYPOR but not by either of the ABS mutants. Hydroxylation activity was rescued for both Y459H and V492E upon addition of FAD to the reaction. Based on these findings, decreased FAD-binding affinity is proposed as the basis of the observed loss of CYPOR function in the Y459H and V492E POR mutations in ABS. Antley-Bixler syndrome (ABS)3 is a disorder characterized by severe midface hypoplasia, humeroradial synostosis, bowing and fracture of femora, and other severe developmental malformations (1). The disease was initially attributed to fibroblast growth factor receptor 2 (FGFR2) mutations (2).Miller's group discovered a correlation between six allelic variants of the POR gene (encoding CYPOR, EC 1.6.2.4) and disordered steroidogenesis observed in patients with and without ABS (3). The variants were A287P, R457H, V492E, C569Y, V608F, and an intron 6 splice variant resulting in a premature stop codon. The wild-type human CYPOR cDNA and mutants, created by site-directed mutagenesis, were expressed in Escherichia coli. The resultant proteins were assayed for their respective NADPH-cytochrome c and NADPH-cytochrome P450 reductase activities. The authors concluded that deleterious POR mutations correlated well with the decreased lanosterol demethylase (CYP51) activity that had previously been observed in ABS patients, and that severe POR mutations were sufficient to cause the ABS phenotype, even in the absence of FGFR2 mutations. Retardation of somite and limb bud formation, which was observed previously in embryonic lethal CYPOR knock-out mice (4, 5), seems to substantiate this assertion. The authors also hypothesized that POR mutations were more common than the relatively low incidence of ABS suggested and that milder mutations could result in disordered steroidogenesis or incr...

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“…Pharmacological doses of riboflavin are said to have helped several patients with myopathy due to complex I deficiency (68). Similarly, large doses of menadione and ascorbate caused functional improvement in a girl with a complex III-deficient myopathy: these vitamins can, in theory, pass electrons from ubiquinone to cytochrome c, bypassing complex I11 (69).…”

Section: Management Treatmentmentioning

confidence: 99%

Mitochondrial respiratory chain disorders and the liver

Morris

1999

Liver

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Mitochondrial respiratory chain disorders are an established cause of liver failure in early childhood but they are probably under-diagnosed, partly due to under-recognition and partly due to the difficulty of investigation. It is particularly important to look for mitochondrial disorders if the liver disease presents with hypoglycaemia and lactic acidaemia or if it is accompanied by neurological, muscle or renal tubular abnormalities. Respiratory chain defects have been demonstrated in a number of patients who die of liver failure following severe epilepsy; this includes at least some cases of Alpers syndrome or 'progressive neuronal degeneration of childhood'. In mitochondrial liver disease, histology usually shows steatosis, often accompanied by fibrosis, cholestasis and loss of hepatocytes. Unless the clinical picture suggests a particular syndrome, such as Pearson syndrome, biochemical assays and histochemistry should be the initial investigations. Ideally, investigations should be carried out on liver as well as more standard tissues, such as muscle, since defects can be tissue-specific. Nuclear defects and nitDNA point mutations are probably responsible for many cases of mitochondrial liver disease but, as yet, the only identified molecular abnormalities are mtDNA rearrangements and mtDNA depletion. Treatment of mitochondrial liver disease is unsatisfactory. If the disease is confined to the liver, transplantation may be appropriate but in several patients transplantation has been followed by the appearance of disease in other organs, particularly the I brain.Mitochondria are subcellular organelles whose primary role is the oxidation of fuels to produce energy. This process is accomplished by a series of enzymes known as the mitochondrial respiratory chain. Mitochondria are the site of many other metabolic pathways but the term 'mitochondrial disease' is generally used to refer to those conditions associated with respiratory chain defects. Since the oxidation of fuels is important for almost all cells, defects of the mitochondrial respiratory chain can cause disease in any organ of the body. Liver disease is a relatively common problem in respiratory chain disorders that present during infancy. These genetic disorders are the sub,ject of the current review. Secondary defects of tlhe respiratory chain caused, for example, by drugs or toxins, can also lead to liver disease but these disorders are only considered briefly in the section on pathogenesis, where key references are giiven. Mitochondrial biochemistryMany oxidative reactions occur within mitochondria, including the D-oxidation pathway for fatty acids, the oxidative decarboxylation of pyruvate by the pyruvate dehydrogenase complex and the oxidation of acetyl-CoA by the tricarboxylic acid cycle. These reactions all generate reduced cofactors, such as the reduced forms of flavin adenine dinucleotide (FADH2) and nicotinamide adenine dinucleotide (NADH). The mitochondrial respiratory chain couples the reoxidation of these cofactors to the for...

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Treatment of complex I deficiency with riboflavin

Cited by 85 publications

References 15 publications

Biochemical and genetic studies in a family with mitochondrial myopathy

Biochemical and genetic studies in a family with mitochondrial myopathy

Diminished FAD Binding in the Y459H and V492E Antley-Bixler Syndrome Mutants of Human Cytochrome P450 Reductase

Mitochondrial respiratory chain disorders and the liver

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