Glutathione metabolism links FOXRED1 to NADH:ubiquinone oxidoreductase (complex I) deficiency: A hypothesis

Lemire, Bernard D.

doi:10.1016/j.mito.2015.07.009

Cited by 7 publications

(6 citation statements)

References 66 publications

(108 reference statements)

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“…Studies in different mammalian species have shown that FOXRED1 expression increases rapidly during embryonic development (17), and proinflammatory conditions during pregnancy, such as IUGR and preeclampsia, can dramatically increase ROS production, placing even higher demands on the oxidative stress defense systems (18). Accordingly, in 2015, one researcher hypothesized that, as a sarcosine oxidase, the catalytic activity of FOXRED1 protects the developing fetus from oxidative stress during pregnancy (19), a notion that is consistent with our investigations. However, more evidence must be elucidated.…”

Section: Discussionsupporting

confidence: 87%

Clinical and Genetic Characteristics of Mitochondrial Encephalopathy Due to FOXRED1 Mutations: Two Chinese Case Reports and a Review of the Literature

Shen

et al. 2021

Front. Neurol.

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Background: As one of the assembly factors of complex I in the mitochondrial respiratory chain, FOXRED1 plays an important role in mitochondrial function. However, only a few patients with mitochondrial encephalopathy due to FOXRED1 defects have been reported.Methods: Two Chinese patients with mitochondrial encephalopathy due to mutations in FOXRED1 were identified through trio whole-exome sequencing. The clinical presentation, laboratory data, brain imaging findings, and genetic results were collected and reviewed. All previously reported cases with FOXRED1-related mitochondrial encephalopathy were collected using a PubMed search, and their data were reviewed.Results: Two patients presented with severe neurodevelopmental delay, epilepsy, high lactic acid levels, and remarkable diffuse brain atrophy and polycystic encephalomalacia during early infancy. Trio whole-exome sequencing revealed compound heterozygous variants in both patients: one case harbored a c.606_607delAG frameshift variant and a c.1054C>T (p.R352W) variant. At the same time, the other carried a novel c.352C>T (p.Q118X) variant and a reported c.1054C>T (p.R352W) variant. To date, nine patients have been reported with FOXRED1 defects, including our two cases. The most common presentations were neurodevelopment delay (100%), epilepsy (80%), poor feeding (30%), and vision loss (20%). Multisystem involvement comprised cardiovascular dysfunction (30%), abnormal liver function (20%), and hypoglycemia (10%). The neuroimaging results ranged from normal to severe cerebral atrophy and polycystic encephalomalacia in early infancy. Eleven pathogenic variants in FOXRED1 have been reported, comprising six missense variants, two non-sense variants, two frameshift variants, and one splice variant; among these the c.1054C>T (p.R352W) and c.612_615dupAGTG (p.A206SfsX15) variants are more common.Conclusion:FOXRED1-related mitochondrial disorders have high clinical and genetic heterogeneity. Our study expanded the clinical and genetic spectrum of FOXRED1 defects. Early infantile onset and progressive encephalopathy are the most common clinical presentations, while the variants c.1054C>T (p.R352W) and c.612_615dupAGTG (p.A206SfsX15) may be critical founder mutations.

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Section: Discussionsupporting

confidence: 87%

Clinical and Genetic Characteristics of Mitochondrial Encephalopathy Due to FOXRED1 Mutations: Two Chinese Case Reports and a Review of the Literature

Shen

et al. 2021

Front. Neurol.

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“…Among these components, disease-causing mutations in 14 nuclear-encoded structural subunits of CI (NDUFS1, NDUFS2, NDUFS3, NDUFS4, NDUFS7, NDUFS8, NDUFV2, NDUFS6, NDUFV1, NDUFA1, NDUFA2, NDUFA9, NDUFA10, NDUFA12), four assembly factor defects (NDUFAF2, NDUFAF5, NDUFAF6, FOXRED1) and 6 mtDNA subunits have previously been linked with Leigh syndrome (Ogilvie et al 2005;Mimaki et al 2012;Lemire 2015;Lake et al 2015). Mutations in four CI subunits (NDUFV1, NDUFS1, NDUFS4 and NDUFS6), all located in the matrix arm (N-module) of CI, lead to CI subassembly complexes of about 830 kDa on BN-PAGE analysis that appear to have lost the matrix arm of CI (Mimaki et al 2012;Ogilvie et al 2005;Tuppen et al 2010;Leong et al 2012).…”

Section: Discussionmentioning

confidence: 99%

Whole Exome Sequencing Identifies the Genetic Basis of Late-Onset Leigh Syndrome in a Patient with MRI but Little Biochemical Evidence of a Mitochondrial Disorder

et al. 2016

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Leigh syndrome is a subacute necrotising encephalomyopathy proven by post-mortem analysis of brain tissue showing spongiform lesions with vacuolation of the neuropil followed by demyelination, gliosis and capillary proliferation caused by mutations in one of over 75 different genes, including nuclear-and mitochondrialencoded genes, most of which are associated with mitochondrial respiratory chain function. In this study, we report a patient with suspected Leigh syndrome presenting with seizures, ptosis, scoliosis, dystonia, symmetrical putaminal abnormalities and a lactate peak on brain MRS, but showing normal MRC enzymology in muscle and liver, thereby complicating the diagnosis. Whole exome sequencing uncovered compound heterozygous mutations in NADH dehydrogenase (ubiquinone) flavoprotein 1 gene (NDUFV1), c.1162+4A>C (NM_007103.3), resulting in skipping of exon 8, and c.640G>A, causing the amino acid substitution p.Glu214Lys, both of which have previously been reported in a patient with complex I deficiency. Patient fibroblasts showed a significant reduction in NDUFV1 protein expression, decreased complex CI and complex IV assembly and consequential reductions in the enzymatic activities of both complexes by 38% and 67%, respectively. The pathogenic effect of these variations was further confirmed by immunoblot analysis of subunits for MRC enzyme complexes in patient muscle, liver and fibroblast where we observed 90%, 60% and 95% reduction in complex CI, respectively. Together these studies highlight the importance of a comprehensive, multipronged approach to the laboratory evaluation of patients with suspected Leigh syndrome.

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“…FOXRED1 has been proposed to be a dual function protein. It plays a key role as an assembly factor for Complex I biogenesis, and, secondly, due to its oxidoreductase activity, it is hypothesized to participate in glycine metabolism which modulates glutathione biosynthesis, an antioxidant protecting the cells from ROS [53][54][55] . Co-immunoprecipitation experiments suggest that FOXRED1 facilitates Complex I assembly by associating with the 370-kDa subcomplex and two other FAD-dependent Complex I assembly factors, ACAD9 and probably AIFM1 [55] .…”

Section: Fad-dependent Oxidoreductase Deficiency (Foxred1) (Omim #618mentioning

confidence: 99%

Riboflavin metabolism: role in mitochondrial function

Balasubramaniam¹,

Yaplito‐Lee²

2020

jtgg

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Riboflavin, known as vitamin B2, a water-soluble vitamin, is an essential nutrient in vertebrates, hence adequate dietary intake is imperative. Riboflavin plays a role in a variety of metabolic pathways, serving primarily as an integral component of its crucial biologically active forms, the flavocoenzymes flavin adenine dinucleotide and flavin mononucleotide. These flavocoenzymes ensure the functionality of numerous flavoproteins including dehydrogenases, oxidases, monooxygenases, and reductases, which play pivotal roles in mitochondrial electron transport chain, β-oxidation of fatty acids, redox homeostasis, citric acid cycle, branched-chain amino acid catabolism, chromatin remodeling, DNA repair, protein folding, and apoptosis. Unsurprisingly, impairment of flavin homeostasis in humans has been linked to various diseases including neuromuscular and neurological disorders, abnormal fetal development, and cardiovascular diseases. This review presents an overview of riboflavin metabolism, its role in mitochondrial function, primary and secondary flavocoenzyme defects associated with mitochondrial dysfunction, and the role of riboflavin supplementation in these conditions.

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Glutathione metabolism links FOXRED1 to NADH:ubiquinone oxidoreductase (complex I) deficiency: A hypothesis

Cited by 7 publications

References 66 publications

Clinical and Genetic Characteristics of Mitochondrial Encephalopathy Due to FOXRED1 Mutations: Two Chinese Case Reports and a Review of the Literature

Clinical and Genetic Characteristics of Mitochondrial Encephalopathy Due to FOXRED1 Mutations: Two Chinese Case Reports and a Review of the Literature

Whole Exome Sequencing Identifies the Genetic Basis of Late-Onset Leigh Syndrome in a Patient with MRI but Little Biochemical Evidence of a Mitochondrial Disorder

Riboflavin metabolism: role in mitochondrial function

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