Sequence of a cDNA specifying subunit VIa of human cytochrome<i>c</i>oxidase

Koga, Yasotoshi; Fabrizi, Gian Maria; Mita, Shuji; Arnaudo, Enrica; Lomax, Margaret I.; Aqua, Mfon S.; Grossman, Lawrence I.; Schon, Eric A.

doi:10.1093/nar/17.15.6409

Cited by 33 publications

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“…The CG17280 gene is an ortholog of the human COX subunit VIa precursor (Fabrizi et al 1989). Sequencing of CG17280 DNA in the levy 1 mutant revealed a G-to-A transition occurring at the 39-splice junction of the single intron ( Figure 2A).…”

Section: Resultsmentioning

confidence: 99%

Mutations in Cytochrome c Oxidase Subunit VIa Cause Neurodegeneration and Motor Dysfunction in Drosophila

et al. 2007

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Mitochondrial dysfunction is involved in many neurodegenerative disorders in humans. Here we report mutations in a gene (designated levy) that codes for subunit VIa of cytochrome c oxidase (COX). The mutations were identified by the phenotype of temperature-induced paralysis and showed the additional phenotypes of decreased COX activity, age-dependent bang-induced paralysis, progressive neurodegeneration, and reduced life span. Germ-line transformation using the levy 1 gene rescued the mutant flies from all phenotypes including neurodegeneration. The data from levy mutants reveal a COX-mediated pathway in Drosophila, disruption of which leads to mitochondrial encephalomyopathic effects including neurodegeneration, motor dysfunction, and premature death. The data present the first case of a mutation in a nuclear-encoded structural subunit of COX that causes mitochondrial encephalomyopathy rather than lethality, whereas several previous attempts to identify such mutations have not been successful. The levy mutants provide a genetic model to understand the mechanisms underlying COXmediated mitochondrial encephalomyopathies and to explore possible therapeutic interventions.

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Section: Resultsmentioning

confidence: 99%

Mutations in Cytochrome c Oxidase Subunit VIa Cause Neurodegeneration and Motor Dysfunction in Drosophila

et al. 2007

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“…For analysis of nuclear transcripts, human cDNA probes for the following subunits of COX were used: IV [38], Va [39], Vb [40], liver type of VIa (VIaL) [22] and of VIIa (VIIaL) [26], heart type of VIa (VIaH) [23] and VIIc [41], all kindly provided by Dr E. A. Schon. A bovine cDNA probe was used to analyse transcripts of subunit VIIb [42] (a kind gift of Dr R. A. Capaldi).…”

Section: Probesmentioning

confidence: 99%

“…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).…”

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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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“…Va, human Va, rat (Droste et ai., 1989) Vlb, human (Taanman et ai., 1989) Vlb, beef (Lightowlers & Capaldi, 1989) IV, human (Zeviani et al, 1987) IV, rat (Gopdan et al, 1989) IV, beef (Lomax et ai., 1984) Vla, human L (Fabrizi et al, 1989) Vla, rat H Vlc, human (Otsuka et al, 1988) Vlc, rat (Suske et al, 1987) Vllb, beef (Lightowlers et al, 1989) VIII, human (Rizzuto et al, 1989) VIII, beef L (Lightowlers et al, 1990) VIII sequences shown in capital letters and mature sequences given in lower case letters.…”

Section: Mlgaalrrcavattradrrgllhsartpgpavaiqsvrcy-mlaaalrrct--taaaaarmentioning

confidence: 99%

Topology of subunits of the mammalian cytochrome c oxidase: relationship to the assembly of the enzyme complex

Zhang¹,

Ewart²,

Capaldi³

1991

Biochemistry

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The arrangement of three subunits of beef heart cytochrome c oxidase, subunits Va, VIa, and VIII, has been explored by chemical labeling and protease digestion studies. Subunit Va is an extrinsic protein located on the C side of the mitochondrial inner membrane. This subunit was found to label with N-(4-azido-2-nitrophenyl)-2-aminoethane[35S]sulfonate and sodium methyl 4-[3H]formylphenyl phosphate in reconstituted vesicles in which 90% of cytochrome c oxidase complexes were oriented with the C domain outermost. Subunit VIa was cleaved by trypsin both in these reconstituted vesicles and in submitochondrial particles, indicating a transmembrane orientation. The epitope for a monoclonal antibody (mAb) to subunit VIa was lost or destroyed when cleavage occurred in reconstituted vesicles. This epitope was localized to the C-terminal part of the subunit by antibody binding to a fusion protein consisting of glutathione S-transferase (G-ST) and the C-terminal amino acids 55-85 of subunit VIa. No antibody binding was obtained with a fusion protein containing G-ST and the N-terminal amino acids 1-55. The mAb reaction orients subunit VIa with its C-terminus in the C domain. Subunit VIII was cleaved by trypsin in submitochondrial particles but not in reconstituted vesicles. N-Terminal sequencing of the subunit VIII cleavage product from submitochondrial particles gave the same sequence as the untreated subunit, i.e., ITA, indicating that it is the C-terminus which is cleaved from the M side. Subunits Va and VIII each contain N-terminal extensions or leader sequences in the precursor polypeptides; subunit VIa is made without an N-terminal extension.

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Sequence of a cDNA specifying subunit VIa of human cytochromecoxidase

Cited by 33 publications

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Mutations in Cytochrome c Oxidase Subunit VIa Cause Neurodegeneration and Motor Dysfunction in Drosophila

Mutations in Cytochrome c Oxidase Subunit VIa Cause Neurodegeneration and Motor Dysfunction in Drosophila

Expression of human cytochrome c, oxidase subunits during fetal development

Topology of subunits of the mammalian cytochrome c oxidase: relationship to the assembly of the enzyme complex

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