Cytochrome c Oxidase Deficiency

DiMauro, Salvatore; Lombès, Anne; Nakase, Hirofumi; Mita, Shuji; Fabrizi, Gian Maria; Tritschler, Hans; Bonilla, Eduardo; Miranda, Armand F.; DeVivo, Darryl C.; Schon, Eric A.

doi:10.1203/00006450-199011000-00025

Cited by 107 publications

(46 citation statements)

References 26 publications

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“…Marked lacticacidemia has previously been described in a variety of metabolic conditions including deficiency of the pyruvate dehydrogenase complex (29), pyruvate carboxylase (30), biotinidase (3 l), holocarboxylase synthetase (32), fructose-l,6-bisphosphatase (33), glucose-6-phosphatase (34), and cytochrome c oxidase (35). None of these possibilities would explain the impaired oxidations of succinate and glutamate in the liver and muscle mitochondria using ferricyanide as an electron acceptor.…”

Section: Discussionmentioning

confidence: 99%

Fatal Lactic Acidosis in Infancy with a Defect of Complex III of the Respiratory Chain

et al. 1989

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ABSTRACT. We report our studies on the metabolic defects which caused a newborn infant to present with a severe lactic acidemia (25 mM) and to die on the 3rd d after birth despite intensive supportive measures. The mitochondrial fractions prepared from skeletal muscle and liver oxidised NAD+-linked substrates and succinate slowly. Spectrophotometric assays for complexes I, 11, and I11 of the respiratory chain demonstrate a specific defect of complex I11 in the skeletal muscle and liver mitochondrial fractions. The concentrations of cytochrome b were 75% lower in the skeletal muscle and heart mitochondria than in control preparations. The amount of non-heme iron sulphur protein of complex I11 was low in skeletal muscle, liver, and heart. This case differs from previous reports of complex I11 deficiency in three respects: the patient presented in the neonatal period, the defect was expressed in several tissues, and it was fatal. (Pediatr Res 25: 553-559, 1989)

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Section: Discussionmentioning

confidence: 99%

Fatal Lactic Acidosis in Infancy with a Defect of Complex III of the Respiratory Chain

et al. 1989

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“…The tissue-specific transcription of the genes for isoforms of subunit VIIa appears to be less strict than for subunit VIa, since co-expression of human VIIaL and VIIaH was described in skeletal muscle and myogenic cells [24, 361. The tissue-specific expression of COX subunits in the human is of relevance for studies of mitochondria1 myopathies presenting muscle-specific COX deficiencies, in particular for fatal and benign infantile myopathies [37].In the present study, we compared the steady-state levels of transcripts for all human COX subunits in fetal tissues (liver, skeletal muscle, heart and intestine) with those of the corresponding adult tissues. The data indicate a switch of isoform expression for subunit VIa (and partly VIla) in heart and skeletal muscle.…”

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confidence: 99%

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Expression of human cytochrome c, oxidase subunits during fetal development

Bonne

Seibel²,

Possekel

et al. 1993

European Journal of Biochemistry

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Expression of human cytochrome c oxidase (COX) subunits was examined at fetal (20-28 weeks) and adult state by Northern blot hybridization with mRNA from liver, heart, skeletal muscle, and intestine. The data were related to COX and citrate synthase activities and to immunodetected COX subunits (II/III, IV, VIIaH). In liver little changes of COX transcripts are observed from fetal to adult state. In contrast, in heart and skeletal muscle all transcripts of COX subunits increase between 2-20-fold, when related to the amount of 28s rRNA. In fetal heart and skeletal muscle the relative amounts of the liver-type transcripts of subunit VIa were 30% and 25% from total VIa transcripts (VIaL + VIaH), respectively, but decrease to only 2-5% at adult state. The liver-type transcripts of subunit VIIa occur to 50% in fetal heart and skeletal muscle, which remained unchanged in adult heart and decrease to 5 8 % in adult skeletal muscle. The results clearly indicate a switch of gene expression in heart and skeletal muscle during development, from the liver type to the headmuscle type of subunit VIa (and partly VIIa).Cytochrome c oxidase (COX) is the terminal enzyme complex of the respiratory chain, coupling the transfer of electrons from cytochrome c to molecular oxygen with the concomitant production of a proton electrochemical gradient across the inner mitochondrial membrane [l]. In mammals, the enzyme consists of 13 dissimilar polypeptides [ 2 ] . The three largest subunits (1-111) are encoded by the mitochondrial genome and constitute the catalytic core of the enzyme [3, 41. The ten smaller nuclear gene products [S] have been suggested to play a keyrole in the regulation of the enzyme [6, 71. Recently it was demonstrated [8, 91 that the activity and energy transduction of COX from heart and skeletal muscle is tissue-specific and regulated by nucleotides via interaction with subunit VIaH (heart/muscle type).The mammalian COX occurs in tissue-specific isoforms differing in the isotype of subunits VIa, VIIa and/or VIII (liver type or heart/muscle type). This has been demonstrated by immunological, electrophoretic and amino acid sequence differences between corresponding nuclear-coded subunits of COX from different mammalian tissues and species [2, 5, 101. These findings have been confirmed by cloning and sequencing of cDNAs coding for the different subunits of tissue-specific isoforms for subunit VIa of rat [ I l l , VIIa [lo,12, 161 and VIII [lo, 131 occur as liver (L) and heart (H) isoforms. In rat only the L form of subunit VIIa was found [17, 181, but both isoforms of subunits VIa [ l l ] and VIII [19]. In human, subunit VIII is present only in the L form [20, 211, whereas both isoforms occur for subunits VIa [22, Most of the other nuclearcoded subunits have been cloned and sequenced from rat, beef and human (for review see [28, 291).A co-ordinate expression of the mitochondrial-coded subunit 111 and the nuclear-coded subunit VIc has been demonstrated in rat tissues under steady-state conditions [30-321. Under non-s...

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“…Usually these disorders present with multiple respiratory chain enzyme deficiencies including COX deficiency (11)(12)(13). Several types of isolated COX deficiency have been described including Leigh disease and a fatal infantile form presenting as a myopathy or cardiomyopathy (14,15).…”

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A Pathogenic 15-Base Pair Deletion in Mitochondrial DNA-encoded Cytochrome c Oxidase Subunit III Results in the Absence of Functional Cytochrome c Oxidase

Hoffbuhr¹,

Davidson²,

Filiano³

et al. 2000

Journal of Biological Chemistry

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A 15-base pair, in-frame, deletion (9480del15) in the mitochondrial DNA (mtDNA)-encoded cytochrome c oxidase subunit III (COX III) gene was identified previously in a patient with recurrent episodes of myoglobinuria and an isolated COX deficiency. Transmitochondrial cell lines harboring 0, 97, and 100% of the 9480del15 deletion were created by fusing human cells lacking mtDNA ( 0 cells) with platelet and lymphocyte fractions isolated from the patient. The COX III gene mutation resulted in a severe respiratory chain defect in all mutant cell lines. Cells homoplasmic for the mutation had no detectable COX activity or respiratory ATP synthesis, and required uridine and pyruvate supplementation for growth, a phenotype similar to 0 cells. The cells with 97% mutated mtDNA exhibited severe reductions in both COX activity (6% of wild-type levels) and rates of ATP synthesis (9% of wild-type). The COX III polypeptide in the mutant cells, although translated at rates similar to wild-type, had reduced stability. There was no evidence for assembly of COX

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Cytochrome c Oxidase Deficiency

Cited by 107 publications

References 26 publications

Fatal Lactic Acidosis in Infancy with a Defect of Complex III of the Respiratory Chain

Fatal Lactic Acidosis in Infancy with a Defect of Complex III of the Respiratory Chain

Expression of human cytochrome c, oxidase subunits during fetal development

A Pathogenic 15-Base Pair Deletion in Mitochondrial DNA-encoded Cytochrome c Oxidase Subunit III Results in the Absence of Functional Cytochrome c Oxidase

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