Nuclear genes for cytochrome c oxidase

Grossman, Lawrence I.; Lomax, Margaret I.

doi:10.1016/s0167-4781(97)00025-0

Cited by 106 publications

(71 citation statements)

References 152 publications

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“…Because MT is not localized in myocardial mitochondria Ye et al, 2001), it is likely that MT modifies mitochondrial proteins that are encoded by nuclear DNA. CCO-Va would be such a protein (Grossman and Lomax, 1997).…”

Section: Cco-va and Metallothionein Cardioprotection 1317mentioning

confidence: 99%

“…CCO is the primary determinant of molecular oxygen consumption in the cell and is thought to play an important role in the regulation of energy production (Capaldi, 1990;Poyton and McEwen, 1996). In mammals, CCO is composed of 13 subunits (three mitochondrial-encoded subunits and 10 nuclear encoded subunits), some of which occur as tissue-specific isoforms (Grossman and Lomax, 1997). The three mitochondrial-encoded subunits compose the catalytic center of the enzyme and are essential and sufficient to carry out the catalytic function of CCO (Grossman and Lomax, 1997).…”

Section: Cco-va and Metallothionein Cardioprotection 1317mentioning

confidence: 99%

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Modulation of Cytochrome c Oxidase-Va Is Possibly Involved in Metallothionein Protection from Doxorubicin Cardiotoxicity

Merten¹,

Feng²,

Zhang³

et al. 2005

J Pharmacol Exp Ther

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Previous studies using a cardiac-specific metallothionein (MT)-overexpressing transgenic (MT-TG) mouse model have demonstrated that MT protects from doxorubicin (DOX)-induced oxidative heart injury. The molecular mechanisms that underlie this cardioprotection, however, have yet to be defined. In the present study, we tested the hypothesis that MT overexpression activates cytoprotective mechanisms, leading to cardiac protection from DOX toxicity. MT-TG mice and nontransgenic wild-type (WT) controls were treated i.p. with DOX at a single dose of 20 mg/kg and sacrificed on the third day after the treatment. An expression proteomic analysis involving twodimensional gel electrophoresis and matrix-assisted laser desorption ionization time-of-flight mass spectrometry was used to identify MT-induced changes in cytoprotection-related proteins. We identified 18 proteins that were modified by DOX treatment in the heart. These proteins included those involved in cellular antioxidant defense, enzymes of the mitochondrial electron transport chain, enzymes involved in ␤-oxidation of fatty acids and glycolysis, and proteins involved in regulation of cardiac muscle contraction. However, the most dominant modification by MT is the cytochrome c oxidase subunit Va (CCOVa). In response to DOX treatment, a specific isoform of CCO-Va was enhanced in the MT-TG but not in the WT mouse hearts. Because CCO-Va is a critical component in the mitochondrial electron transport chain, the results suggest that the cardioprotective effect of MT may be related to an increased expression or a differential modification of CCO-Va.

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Section: Cco-va and Metallothionein Cardioprotection 1317mentioning

confidence: 99%

Section: Cco-va and Metallothionein Cardioprotection 1317mentioning

confidence: 99%

Modulation of Cytochrome c Oxidase-Va Is Possibly Involved in Metallothionein Protection from Doxorubicin Cardiotoxicity

Merten¹,

Feng²,

Zhang³

et al. 2005

J Pharmacol Exp Ther

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“…COX contains skeletal muscle/heart ("heart-type") and nonskeletal muscle ("liver-type") isoforms of subunits VIa, VIIa, and VIII that have been known for the past 2 decades (reviewed in Ref. 8). We have recently discovered three additional isoforms: a lung-specific isoform of subunit IV, a third isoform of subunit VIII, and a testes-specific isoform of subunit VIb (9 -11).…”

mentioning

confidence: 99%

cAMP-dependent Tyrosine Phosphorylation of Subunit I Inhibits Cytochrome c Oxidase Activity

Lee

Salomon

Ficarro

et al. 2005

Journal of Biological Chemistry

188

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Signaling pathways targeting mitochondria are poorly understood. We here examine phosphorylation by the cAMP-dependent pathway of subunits of cytochrome c oxidase (COX), the terminal enzyme of the electron transport chain. Using anti-phospho antibodies, we show that cow liver COX subunit I is tyrosinephosphorylated in the presence of theophylline, a phosphodiesterase inhibitor that creates high cAMP levels, but not in its absence. The site of phosphorylation, identified by mass spectrometry, is tyrosine 304 of COX catalytic subunit I. Subunit I phosphorylation leads to a decrease of V max and an increase of K m for cytochrome c and shifts the reaction kinetics from hyperbolic to sigmoidal such that COX is fully or strongly inhibited up to 10 M cytochrome c substrate concentrations, even in the presence of allosteric activator ADP. To assess our findings with the isolated enzyme in a physiological context, we tested the starvation signal glucagon on human HepG2 cells and cow liver tissue. Glucagon leads to COX inactivation, an effect also observed after incubation with adenylyl cyclase activator forskolin. Thus, the glucagon receptor/G-protein/cAMP pathway regulates COX activity. At therapeutic concentrations used for asthma relief, theophylline causes lung COX inhibition and decreases cellular ATP levels, suggesting a mechanism for its clinical action.Cytochrome c oxidase (COX), 1 the terminal enzyme of the mitochondrial respiratory chain, reduces oxygen to water and pumps protons across the inner mitochondrial membrane. COX contains 13 subunits per monomer, three of which are encoded by the mitochondrial genome. COX has been shown to be the rate-limiting enzyme of oxidative metabolism under physiological conditions in a variety of human cell types (1) and in a mouse cell line with a mutation in COX subunit I (2). The functional mammalian enzyme has been crystallized as a dimer (3) and shows three features, described below, that are found in key metabolic enzymes: allosteric regulation, isoforms, and phosphorylation. COX activity is regulated by small molecules such as ATP and ADP (4 -6), and the thyroid hormone T2 (7). COX contains skeletal muscle/heart ("heart-type") and nonskeletal muscle ("liver-type") isoforms of subunits VIa, VIIa, and VIII that have been known for the past 2 decades (reviewed in Ref. 8). We have recently discovered three additional isoforms: a lung-specific isoform of subunit IV, a third isoform of subunit VIII, and a testes-specific isoform of subunit VIb (9 -11). Although it is clear that protein kinases and phosphatases are crucial in cellular signaling, little is known about their role in the regulation of the respiratory chain complexes.There have been three studies of COX phosphorylation: Steenaart and Shore (12) examined mitochondrial proteins phosphorylated by endogenous kinases in the presence of [␥-32 P]ATP and identified COX subunit IV; Miyazaki et al. (13) showed that COX subunit II can be phosphorylated by nonreceptor tyrosine kinase c-Src in osteoblasts and found a positive ...

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“…There are strong similarities in the primary, secondary, and tertiary structures of these subunits, as evidenced by the x-ray crystallographic models of cytochrome c oxidases from Paracoccus denitrificans and bovine mitochondria (2,3). In addition, a variable set of nuclearencoded subunits that exhibit either no transmembrane stretch or a single transmembrane stretch are synthesized in the cytoplasm and imported into mitochondria (4).…”

mentioning

confidence: 99%

Unusual Location of a Mitochondrial Gene

Pérez-Martı́nez

Vázquez-Acevedo

Tolkunova

et al. 2000

Journal of Biological Chemistry

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The algae of the family Chlamydomonadaceae lack the gene cox3 that encodes subunit III of cytochrome c oxidase in their mitochondrial genomes. This observation has raised the question of whether this subunit is present in cytochrome c oxidase or whether the corresponding gene is located in the nucleus. Cytochrome c oxidase was isolated from the colorless chlamydomonad Polytomella spp., and the existence of subunit III was established by immunoblotting analysis with an antibody directed against Saccharomyces cerevisiae subunit III. Based partly upon the N-terminal sequence of this subunit, oligodeoxynucleotides were designed and used for polymerase chain reaction amplification, and the resulting product was used to screen a cDNA library of Chlamydomonas reinhardtii. The complete sequences of the cox3 cDNAs from Polytomella spp. and C. reinhardtii are reported. Evidence is provided that the genes for cox3 are encoded by nuclear DNA, and the predicted polypeptides exhibit diminished physical constraints for import as compared with mitochondrial-DNA encoded homologs. This indicates that transfer of this gene to the nucleus occurred before Polytomella diverged from the photosynthetic Chlamydomonas lineage and that this transfer may have occurred in all chlamydomonad algae.

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Nuclear genes for cytochrome c oxidase

Cited by 106 publications

References 152 publications

Modulation of Cytochrome c Oxidase-Va Is Possibly Involved in Metallothionein Protection from Doxorubicin Cardiotoxicity

Modulation of Cytochrome c Oxidase-Va Is Possibly Involved in Metallothionein Protection from Doxorubicin Cardiotoxicity

cAMP-dependent Tyrosine Phosphorylation of Subunit I Inhibits Cytochrome c Oxidase Activity

Unusual Location of a Mitochondrial Gene

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