Infantile presentation of the mitochondrial A8344G mutation

Scalais, Emmanuel; Nuttin, C.; Seneca, Sara; Smet, Joél; Paepe, Boél De; Martin, J. J.; Stevens, R. W. C.; Pierart, F.; Battisti, Oreste; Lissens, Willy; Meırleır, Linda De; Coster, Rudy Van

doi:10.1111/j.1468-1331.2007.01926.x

Cited by 7 publications

(4 citation statements)

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“…As already pointed out, complex V is [15] The mammalian enzyme is composed of 16 different subunits. Only two subunits (a and A6L) are encoded by genes located on the mtDNA (MT-ATP6 and MT-ATP8 respectively).…”

Section: Discussionmentioning

confidence: 98%

Subcomplexes of mitochondrial complex V reveal mutations in mitochondrial DNA

et al. 2009

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Complex V, site of the final step in oxidative phosphorylation, uses the proton gradient across the inner mitochondrial membrane for the production of ATP. It is a multi-subunit complex composed of a catalytic domain (F(1)) and a membrane domain (F(0)) linked by two stalks. Subcomplexes of complex V containing the F(1) domain have previously been reported in small series of patients. We report the results in tissue samples and/or cultured skin fibroblasts studied by blue native PAGE followed by activity staining in the gel. Catalytically active subcomplexes of complex V were detected in 66 tissues originating from 53 patients. In 29 of the latter (55%), a mitochondrial DNA (mtDNA) defect was identified. Twelve patients had a pathogenic point mutation in a mitochondrial tRNA, one a large mtDNA deletion, 12 showed mtDNA depletion and four had a mutation in the MT-ATP6 gene. We conclude that the presence of subcomplexes of complex V is a valuable indicator in the detection of mtDNA defects.

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Section: Discussionmentioning

confidence: 98%

Subcomplexes of mitochondrial complex V reveal mutations in mitochondrial DNA

et al. 2009

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“…De Paepe et al Table 3 (17)(18)(19)(20)(21)(22)(23). Diagnostic workup of the cultured skin fibroblasts consisted of spectrophotometric analysis of the activities of complex II (24), III (25), and IV (26) and activity staining of all complexes after separation by blue native-polyacrylamide gel electrophoresis (27) and immunocytochemical staining (28) ( Table 4).…”

Section: Articlesmentioning

confidence: 99%

Fluorescence imaging of mitochondria in cultured skin fibroblasts: a useful method for the detection of oxidative phosphorylation defects

et al. 2012

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Background: Protons are pumped from the mitochondrial matrix via oxidative phosphorylation (OXPhOs) into the intermembrane space, creating an electric membrane potential (ΔΨ) that is used for adenosine triphosphate (aTP) production. Defects in one or more of the OXPhOs complexes are associated with a variety of clinical symptoms, often making it difficult to pinpoint the causal mutation. Methods: In this article, a microscopic method for the quantitative evaluation of ΔΨ in cultured skin fibroblasts is described. The method using 5,5′,6,6′-tetraethylbenzimidazolyl-carbocyanine iodide (Jc-1) fluorescence staining was tested in a selection of OXPhOs-deficient cell lines. results: a significant reduction of ΔΨ was found in the cell lines of patients with either an isolated defect in complex I, II, or IV or a combined defect (complex I + complex IV). ΔΨ was not reduced in the fibroblasts of two patients with severe complex V deficiency. addition of the complex I inhibitor rotenone induced a significant reduction of ΔΨ and perinuclear relocalization of the mitochondria. In cells with a heteroplasmic mitochondrial DNa (mtDNa) defect, a more heterogeneous reduction of ΔΨ was detected. conclusion: Our data show that imaging of ΔΨ in cultured skin fibroblasts is a useful method for the evaluation of OXPhOs functioning in cultured cell lines.t he majority of cellular adenosine triphosphate (ATP) is supplied in the mitochondria through oxidative phosphorylation (OXPHOS). The OXPHOS system consists of five multiprotein complexes embedded within the inner mitochondrial membrane: complex I (reduced nicotinamide adenine dinucleotide: ubiquinone oxidoreductase), complex II (succinate: ubiquinone oxidoreductase), complex III (ubiquinol: cytochrome c oxidoreductase), complex IV (cytochrome c oxidase), and complex V (ATP synthase). Complexes I, III, and IV pump protons, donated by reduced nicotinamide adenine dinucleotide, ubiquinone, and cytochrome c, respectively, into the mitochondrial intermembrane space. The proton gradient that develops between the mitochondrial matrix and the intermembrane space generates an electrochemical membrane potential (ΔΨ), which is the driving force for the conversion of ADP and inorganic phosphate into ATP (1).The estimated incidence of OXPHOS defects in humans is ~1 in 5,000 live births. Isolated complex I deficiency (2) and the mitochondrial DNA (mtDNA) depletion syndromes (3) are the most commonly recognized mitochondrial disorders. Defects in OXPHOS are associated with a broad spectrum of symptoms and syndromes, ranging from mild myopathy to severe multisystem disorders. OXPHOS defects are complex due to the dual origin of genes involved and the specific nature of the mitochondrial genome. The mtDNA encodes 13 structural proteins of the complexes I, III, IV, and V; two rRNAs; and 22 transfer RNAs (tRNAs) necessary for intramitochondrial protein translation. The mitochondrial genome is polyploid, with multiple copies of mtDNA present within each individual mitochondrion. Two different populatio...

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“…Severe involvement of the basal ganglia and brainstem suggestive for Leigh syndrome was seen on cerebral MRI. He died before the age of 1 year 5. P3 and P4 carried the mtDNA tRNA Leu A3251G mutation and had classical MELAS.…”

Section: Methodsmentioning

confidence: 99%