Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:1.9.3.1 (cytochrome oxidase)
 8,822 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

This paper reports on the discovery of a protein kinase activity associated with the inner membrane of mammalian mitochondria. The enzyme does not respond to addition of cyclic AMP or cyclic GMP and has a preference for whole histone as phosphate acceptor. Some standard assay systems for the cyclic nucleotide-dependent cytosol protein kinases would be unable to pick up this activity of the orthophosphate concentration is higher than 25 mM and the pH or the assay lower than pH 6.5. The enzyme described here has an apparent pH optimum of 8.5. Activity in liver mitochondria is not evident unless the mitochondria are disrupted by either sonication or freezing and thawing. Distribution of kinase activity in centrifugal fractions of both liver and heart mitochondrial sonicates was parallel to that of the two inner membrane marker enzymes succinic dehydrogenase and cytochrome oxidase and quite different from that of the matrix enzyme malic dehydrogenase. Experiments with preparations enriched in outer or inner membranes confirmed the contention that this enzyme is located on the inner membrane. Since disruption of the inner membrane by a freeze-thaw treatment (after the outer membrane had been disrupted by swelling in phosphate) was necessary for full expression of activity by this enzyme, the tentative conclusion was reached that substrate is accepted only from the matrix side of the inner membrane.
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PMID:Protein kinase activity at the inner membrane of mammalian mitochondria. 1 32

Increases in immunocytochemically detectable type II calcium-calmodulin-dependent protein kinase (CaM II kinase) and decreases in immunocytochemically detectable glutamic acid decarboxylase (GAD) are known to occur in the visual cortex of adult monkeys following brief periods of monocular visual deprivation. In the present study, GAD and CaM II kinase gene expression was investigated under these conditions. The polymerase chain reaction (PCR) was used to generate species-specific cDNA clones that were used to make antisense RNA probes. A second form of CaM II kinase alpha, CaM II kinase alpha-33, which contains an additional phosphorylation consensus sequence, was identified. In situ hybridization in normal visual cortex revealed a complex sublaminar organization of GAD-expressing cells within layers IVC and VI and a distribution of CaM II kinase alpha-expressing cells that was greatest in layers II, III, IVB, and VI. In situ hybridization in the cortex from animals that had been monocularly deprived revealed enhanced CaM II kinase mRNA levels in deprived-eye columns of layer IVC and, associated with the deprived eye, cytochrome oxidase-stained periodicities in other layers. In layer IV, the enhancement of labeling in deprived-eye stripes was, on average, 16% greater than in normal-eye stripes. By contrast, GAD, mRNA levels appeared unchanged in all layers, suggesting a posttranscriptional regulatory mechanism.
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PMID:Differential effects of monocular deprivation on glutamic acid decarboxylase and type II calcium-calmodulin-dependent protein kinase gene expression in the adult monkey visual cortex. 184 11

The primate visual system is often divided into two channels, designated M and P, whose signals are relayed to the cerebral cortex by neurons in the magnocellular and parvicellular layers of the dorsal lateral geniculate nucleus. We have identified a third population of geniculocortical neurons in the dorsal lateral geniculate nucleus of macaques, which is immunoreactive for the alpha subunit of type II calmodulin-dependent protein kinase. This large third population occupies interlaminar regions (intercalated layers) ventral to each principal layer. Retrograde labeling of kinase-immunoreactive cells from the primary visual cortex shows that they provide the geniculocortical input to cytochrome oxidase-rich puffs in layers II and III.
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PMID:A neurochemically distinct third channel in the macaque dorsal lateral geniculate nucleus. 816 15

In vertebrate organisms, the molecular mechanisms by which extracellular signals regulate mitochondrial function and biogenesis are largely unknown. We have previously identified multiple cis-acting elements in both cytochrome c and cytochrome oxidase subunit IV (COXIV) genes that are likely targets for the regulated expression of respiratory chain components. We now demonstrate that cytochrome c but not COXIV mRNA is induced by cAMP through a mechanism involving transcriptional activation. Maximal induction occurs within 3 h and does not require de novo protein synthesis. The differential response of these genes is mediated by two distinct cAMP response elements (CREs) in the cytochrome c promoter region. Both elements function independently to drive cAMP-dependent expression from a heterologous promoter and within the proper cytochrome c promoter context. In addition, the binding properties of both elements to nuclear factors were characterized by competition DNase I footprinting, methylation interference footprinting, site-directed mutagenesis, and UV-induced DNA-protein cross-linking. The results are all consistent with the specific recognition of both CREs by CRE binding protein (CREB). A highly purified preparation of recombinant CREB formed a specific complex with each of the cytochrome c CREs identical to that formed with a crude nuclear fraction. In addition, the trans-activation of cytochrome c gene expression by recombinant CREB and protein kinase A in transfected cells was completely dependent on functional CREs within the promoter. These results establish that respiratory chain gene expression can be regulated directly by cAMP through a CREB-dependent signal transduction pathway.
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PMID:Differential regulation of respiratory chain subunits by a CREB-dependent signal transduction pathway. Role of cyclic AMP in cytochrome c and COXIV gene expression. 827 81

This study deals with two kinds of activity-dependent phenomena in the somatosensory cortex of adult monkeys, both of which may be related: (1) mutability of representational maps, as defined electrophysiologically; (2) alterations in expression of genes important in the inhibitory and excitatory neurotransmitter systems. Area 3b of the cerebral cortex was mapped physiologically and mRNA levels or numbers of immunocytochemically stained neurons quantified after disrupting afferent input peripherally by section of peripheral nerves, or centrally by making lesions of increasing size in the somatosensory thalamus. Survival times ranged from a few weeks to many months. Mapping studies after peripheral nerve lesions replicated results of previous studies in showing the contraction of representations deprived of sensory input and expansion of adjacent representations. However, these changes in representational maps were in most cases unaccompanied by significant alterations in gene expression for calcium calmodulin-dependent protein kinase isoforms, for glutamic acid decarboxylase, GABA(A) receptor subunits, GABA(B) receptors, alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) or N-methyl-D-aspartate (NMDA) receptor subunits. Mapping studies after lesions in the ventral posterior lateral nucleus (VPL) of the thalamus revealed no changes in cortical representations of the hand or fingers until >15% of the thalamic representation was destroyed, and only slight changes until approximately 45% of the representation was destroyed, at which point the cortical representation of the finger at the center of a lesion began to shrink. Lesions destroying >60% of VPL resulted in silencing of the hand representation. Although all lesions were associated with a loss of parvalbumin-immunoreactive thalamocortical fiber terminations, and of cytochrome oxidase staining in a focal zone of area 3b, no changes in gene expression could be detected in the affected zone until >40-50% of VPL was destroyed, and even after that changes in mRNA levels or in numbers of GABA-immunoreactive neurons in the affected zone were remarkably small. The results of these studies differ markedly from the robust changes in gene expression detectable in the visual cortex of monkeys deprived of vision in one eye. The results confirm the view that divergence of the afferent somatosensory pathways from periphery to cerebral cortex is sufficiently great that many fibers can be lost before neuronal activity is totally silenced in area 3b. This divergence is capable of maintaining a high degree of cortical function in the face of diminishing inputs from the periphery and is probably an important element in promoting representational plasticity in response to altered patterns of afferent input.
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PMID:Adaptive responses of monkey somatosensory cortex to peripheral and central deafferentation. 1203 4

We have previously shown that mitochondrial activity increases in response to insulin in differentiating muscle cells. Moreover, the protein kinase kinase/extracellular-signal-regulated kinase (MAPKK/ERK-MEK) inhibitor PD98059 accelerates insulin-mediated myogenesis, whereas the phosphatidylinositol 3-kinase (PI3-K) inhibitor LY294002 or blockade of mitochondrial respiration abrogates insulin-mediated myogenesis. Our present study focuses on the mitochondrial transmembrane protein, hyperplasia suppressor gene/mitofusin2 (HSG/Mfn2), which regulates both mitochondrial fusion (as demonstrated by perinuclear mitochondria clustering) and insulin-dependent myogenesis in vitro. Increased mitochondrial length and interconnectivity are not observed after the inhibition of PI3-K activity with LY294002. Insulin induces Mfn2 and subunits I and IV of cytochrome-c oxidase (MTCOI and NCOIV) in L6 myoblasts. Inhibition of the MEK-dependent signalling pathway elevates the Mfn-2 protein level. The molecular mechanism of this phenomenon is unknown, although immunoprecipitation studies indicate that, during insulin-mediated myogenesis, Ras protein (an upstream activator of the MAPK/ERK1/2 cascade) interacts with HSG/Mfn2 in muscle cells. Interaction of Ras with Mfn2 continues unless insulin is present and is reduced after PD98059 co-treatment indicating that insulin-mediated myogenesis is increased by the inhibition of MEK, most probably by the lack of mitogenic signals opposing muscle differentiation. We conclude that insulin-mediated myogenesis depends on PI3-K activity, which stimulates mitochondrial activity and the extensive fusion of mitochondria. We further suggest that insulin stimulates the expression of Mfn2 protein, which in turn binds to Ras and inhibits the MEK-dependent signalling pathway. At the same time, the PI3-K-dependent signalling pathway is boosted, mitochondrial respiration increases and the rate of myogenesis is accelerated.
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PMID:Mitofusin 2 (Mfn2): a key player in insulin-dependent myogenesis in vitro. 1709 23

Hydrogen sulfide (H2S) is a naturally occurring gas that is also associated with several industries. The potential for widespread human inhalation exposure to this toxic gas is a public health concern. The nasal epithelium is especially susceptible to H2S-induced pathology. Injury to and regeneration of the nasal respiratory mucosa occurred in animals with ongoing H2S exposure, suggesting that the regenerated respiratory epithelium under-goes an adaptive response and becomes resistant to further injury. To better understand this response, ten-week-old male Sprague-Dawley rats were exposed nose-only to either air or 200 ppm H2S for three hours per day for one day or five consecutive days. Nasal respiratory epithelial cells at the site of injury and regeneration were laser capture microdissected, and gene expression profiles were generated at three, six, and twenty-four hours after the initial three-hour exposure and at twenty-four hours after the fifth exposure using the Affymetrix Rat Genome 230 2.0 microarray. Gene ontology enrichment analysis showed that H2S exposure altered gene expression associated with a variety of biological processes, including cell cycle regulation, protein kinase regulation, and cytoskeletal organization and biogenesis. Surprisingly, our results did not show a significant change in cytochrome oxidase gene expression or bioenergetics.
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PMID:Gene expression changes following acute hydrogen sulfide (H2S)-induced nasal respiratory epithelial injury. 1846 78

Aging is associated with an increase in insulin resistance in skeletal muscle, yet the underlying mechanism is not well established. We hypothesize that with aging, a chronic increase in stress kinase activation, coupled with a decrease in oxidative capacity, leads to insulin resistance in skeletal muscle. In aged (24 mo old) and young (3 mo old) Fischer 344 rats, 2-deoxyglucose uptake and insulin signaling [as measured by phosphorylation of insulin receptor substrate-1 (IRS-1), Akt (protein kinase B), and Akt substrate of 160 kDa (AS160)] decreased significantly with age. Activation of, c-Jun NH(2)-terminal kinase (JNK), glycogen serine kinase-3beta (GSK-3beta), and degradation of IkappaBalpha by the upstream inhibitor of kappa B kinase (IKKbeta), as measured by Western blot analysis, were increased with age in both soleus and epitrochlearis (Epi) muscles. However, much higher activation of these kinases in Epi muscles from young rats compared with soleus results in a greater effect of these kinases on insulin signaling in fast-twitch muscle with age. Heat shock protein (HSP) 72 expression and phosphorylation of HSP25 were higher in soleus compared with Epi muscles, and both parameters decreased with age. Age and fiber type differences in cytochrome oxidase activity are consistent with observed changes in HSP expression and activation. Our results demonstrate a significant difference in the ability of slow-twitch and fast-twitch muscles to respond to insulin and regulate glucose with age. A greater constitutive HSP expression and lower stress kinase activation may account for the ability of slow-twitch muscles to preserve the capacity to respond to insulin and maintain glucose homeostasis with age.
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PMID:Age-related differences in skeletal muscle insulin signaling: the role of stress kinases and heat shock proteins. 1859 80

Mitochondrial dysfunction is a major contributor in heart failure (HF). We investigated whether the decrease in respirasome organization reported by us previously in cardiac mitochondria in HF is due to changes in the phospholipids of the mitochondrial inner membrane or modifications of the subunits of the electron transport chain (ETC) complexes. The contents of the main phospholipid species, including cardiolipin, as well as the molecular species of cardiolipin were unchanged in cardiac mitochondria in HF. Oxidized cardiolipin molecular species were not observed. In heart mitochondria isolated from HF, complex IV not incorporated into respirasomes exhibits increased threonine phosphorylation. Since HF is associated with increased adrenergic drive to cardiomyocytes, this increased protein phosphorylation might be explained by the involvement of cAMP-activated protein kinase. Does the preservation of cAMP-induced phosphorylation changes of mitochondrial proteins or the addition of exogenous cAMP have similar effects on oxidative phosphorylation? The usage of phosphatase inhibitors revealed a specific decrease in complex I-supported respiration with glutamate. In saponin-permeabilized cardiac fibers, pre-incubation with cAMP decreases oxidative phosphorylation due to a defect localized at complex IV of the ETC inter alia. We propose that phosphorylation of specific complex IV subunits decreases oxidative phosphorylation either by limiting the incorporation of complex IV in supercomplexes or by decreasing supercomplex stability.
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PMID:Cardiac mitochondria in heart failure: normal cardiolipin profile and increased threonine phosphorylation of complex IV. 2132 Apr 65

Rapid regulation of oxidative phosphorylation is crucial for mitochondrial adaptation to swift changes in fuels availability and energy demands. An intramitochondrial signaling pathway regulates cytochrome oxidase (COX), the terminal enzyme of the respiratory chain, through reversible phosphorylation. We find that PKA-mediated phosphorylation of a COX subunit dictates mammalian mitochondrial energy fluxes and identify the specific residue (S58) of COX subunit IV-1 (COXIV-1) that is involved in this mechanism of metabolic regulation. Using protein mutagenesis, molecular dynamics simulations, and induced fit docking, we show that mitochondrial energy metabolism regulation by phosphorylation of COXIV-1 is coupled with prevention of COX allosteric inhibition by ATP. This regulatory mechanism is essential for efficient oxidative metabolism and cell survival. We propose that S58 COXIV-1 phosphorylation has evolved as a metabolic switch that allows mammalian mitochondria to rapidly toggle between energy utilization and energy storage.
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PMID:Protein phosphorylation and prevention of cytochrome oxidase inhibition by ATP: coupled mechanisms of energy metabolism regulation. 2164 52


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