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Introduction to Metals in Biology 2018: Copper homeostasis and utilization in redox enzymes.
Guengerich FP
(2018) J Biol Chem 293: 4603-4605
MeSH Terms: Animals, Copper, Electron Transport Complex IV, Humans, Superoxide Dismutase
Show Abstract · Added March 14, 2018
This 11th Thematic Metals in Biology Thematic Series deals with copper, a transition metal with a prominent role in biochemistry. Copper is a very versatile element, and both deficiencies and excesses can be problematic. The five Minireviews in this series deal with several aspects of copper homeostasis in microorganisms and mammals and the role of this metal in two enzymes, copper-only superoxide dismutase and cytochrome oxidase.
© 2018 Guengerich.
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5 MeSH Terms
CtaM Is Required for Menaquinol Oxidase aa3 Function in Staphylococcus aureus.
Hammer ND, Schurig-Briccio LA, Gerdes SY, Gennis RB, Skaar EP
(2016) mBio 7:
MeSH Terms: Aerobiosis, Electron Transport Chain Complex Proteins, Electron Transport Complex IV, Heme, Oxidation-Reduction, Staphylococcus aureus
Show Abstract · Added April 8, 2017
UNLABELLED - Staphylococcus aureus is the leading cause of skin and soft tissue infections, bacteremia, osteomyelitis, and endocarditis in the developed world. The ability of S. aureus to cause substantial disease in distinct host environments is supported by a flexible metabolism that allows this pathogen to overcome challenges unique to each host organ. One feature of staphylococcal metabolic flexibility is a branched aerobic respiratory chain composed of multiple terminal oxidases. Whereas previous biochemical and spectroscopic studies reported the presence of three different respiratory oxygen reductases (o type, bd type, and aa3 type), the genome contains genes encoding only two respiratory oxygen reductases, cydAB and qoxABCD Previous investigation showed that cydAB and qoxABCD are required to colonize specific host organs, the murine heart and liver, respectively. This work seeks to clarify the relationship between the genetic studies showing the unique roles of the cydAB and qoxABCD in virulence and the respiratory reductases reported in the literature. We establish that QoxABCD is an aa3-type menaquinol oxidase but that this enzyme is promiscuous in that it can assemble as a bo3-type menaquinol oxidase. However, the bo3 form of QoxABCD restricts the carbon sources that can support the growth of S. aureus In addition, QoxABCD function is supported by a previously uncharacterized protein, which we have named CtaM, that is conserved in aerobically respiring Firmicutes In total, these studies establish the heme A biosynthesis pathway in S. aureus, determine that QoxABCD is a type aa3 menaquinol oxidase, and reveal CtaM as a new protein required for type aa3 menaquinol oxidase function in multiple bacterial genera.
IMPORTANCE - Staphylococcus aureus relies upon the function of two terminal oxidases, CydAB and QoxABCD, to aerobically respire and colonize distinct host tissues. Previous biochemical studies support the conclusion that a third terminal oxidase is also present. We establish the components of the S. aureus electron transport chain by determining the heme cofactors that interact with QoxABCD. This insight explains previous observations by revealing that QoxABCD can utilize different heme cofactors and confirms that the electron transport chain of S. aureus is comprised of two terminal menaquinol oxidases. In addition, a newly identified protein, CtaM, is found to be required for the function of QoxABCD. These results provide a more complete assessment of the molecular mechanisms that support staphylococcal respiration.
Copyright © 2016 Hammer et al.
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6 MeSH Terms
Activation of NOD2/RIPK2 pathway induces mitochondrial injury to oligodendrocyte precursor cells in vitro and CNS demyelination in vivo.
Natarajan C, Yao SY, Zhang F, Sriram S
(2013) J Neuroimmunol 265: 51-60
MeSH Terms: Animals, Animals, Newborn, Cerebral Cortex, Corpus Callosum, Demyelinating Diseases, Disease Models, Animal, Dose-Response Relationship, Drug, Electron Transport Complex I, Electron Transport Complex IV, Gene Expression Regulation, Indazoles, Mitochondria, Neuroprotective Agents, Nitric Oxide Synthase Type I, Nod2 Signaling Adaptor Protein, Oligodendroglia, Peptidoglycan, Rats, Receptor-Interacting Protein Serine-Threonine Kinase 2, Signal Transduction, Stem Cells, Time Factors
Show Abstract · Added April 18, 2017
We examined the activation of innate immune pathway mediated by nucleotide-binding oligomerization domain-containing protein 2 (NOD2) in oligodendrocyte precursor cells (OPCs). We show that activation of NOD2 by ligand peptidoglycan (PGN) leads to the recruitment and phosphorylation of receptor-interacting serine/threonine kinase 2 (RIPK2). Phosphorylation of RIPK2 is followed by phosphorylation of neuronal nitric oxide synthase (nNOS), increase in NOS activity and subsequent accumulation of nitric oxide (NO) mediated N-tyrosinylated compounds in OPCs. The reversal of NOS activity by the nNOS inhibitor 7-nitroindazole (7-NI), but not by the iNOS inhibitor L-canavanine, supported the conclusion that the increased NOS activity was due to the selective activation of nNOS in OPCs. In addition, NO mediated injury to OPC was reflected in reduction in activity of respiratory enzymes such as complex I and IV, decrease in mitochondrial membrane potential and release of cytochrome-C from mitochondria. Furthermore, intracerebral injection of PGN into corpus callosum (CC) of rats led to the development of demyelination, which appeared as early as by day 3 post-injection, and involved the trunk of the CC by day 14. Accumulation of N-tyrosinylated proteins was seen in oligodendrocytes in regions of the CC which were in close proximity to the injection site. Taken together, these results suggest that PGN induced formation of NO, mitochondrial dysfunction and accumulation of N-tyrosinylated proteins in oligodendrocytes are likely mediators of central nervous system demyelination.
© 2013. Published by Elsevier B.V. All rights reserved.
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22 MeSH Terms
Prognostic relevance of cytochrome C oxidase in primary glioblastoma multiforme.
Griguer CE, Cantor AB, Fathallah-Shaykh HM, Gillespie GY, Gordon AS, Markert JM, Radovanovic I, Clement-Schatlo V, Shannon CN, Oliva CR
(2013) PLoS One 8: e61035
MeSH Terms: Base Sequence, Brain Neoplasms, DNA Methylation, DNA Primers, Electron Transport Complex IV, Glioblastoma, Humans, Polymerase Chain Reaction, Prognosis, Retrospective Studies, Survival Analysis
Show Abstract · Added March 20, 2014
Patients with primary glioblastoma multiforme (GBM) have one of the lowest overall survival rates among cancer patients, and reliable biomarkers are necessary to predict patient outcome. Cytochrome c oxidase (CcO) promotes the switch from glycolytic to OXPHOS metabolism, and increased CcO activity in tumors has been associated with tumor progression after chemotherapy failure. Thus, we investigated the relationship between tumor CcO activity and the survival of patients diagnosed with primary GBM. A total of 84 patients with grade IV glioma were evaluated in this retrospective cohort study. Cumulative survival was calculated by the Kaplan-Meier method and analyzed by the log-rank test, and univariate and multivariate analyses were performed with the Cox regression model. Mitochondrial CcO activity was determined by spectrophotometrically measuring the oxidation of cytochrome c. High CcO activity was detected in a subset of glioma tumors (∼30%), and was an independent prognostic factor for shorter progression-free survival and overall survival [P = 0.0087 by the log-rank test, hazard ratio = 3.57 for progression-free survival; P<0.001 by the log-rank test, hazard ratio = 10.75 for overall survival]. The median survival time for patients with low tumor CcO activity was 14.3 months, compared with 6.3 months for patients with high tumor CcO activity. High CcO activity occurs in a significant subset of high-grade glioma patients and is an independent predictor of poor outcome. Thus, CcO activity may serve as a useful molecular marker for the categorization and targeted therapy of GBMs.
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11 MeSH Terms
nNOS mediated mitochondrial injury in LPS stimulated oligodendrocytes.
Yao SY, Natarajan C, Sriram S
(2012) Mitochondrion 12: 336-44
MeSH Terms: Animals, Apoptosis, Cell Survival, Cells, Cultured, Cytochromes c, Electron Transport Complex I, Electron Transport Complex IV, Lipopolysaccharides, Membrane Potential, Mitochondrial, Mitochondria, Nitric Oxide Synthase, Oligodendroglia, Rats, Rats, Sprague-Dawley
Show Abstract · Added April 18, 2017
Products of inflammation and the activation of nitric oxide synthase have been proposed as a mechanism of oligodendrocyte injury in CNS inflammation. There are currently three well described and known isoforms of NOS. Of these, neuronal NOS (nNOS) was initially discovered in neurons, endothelial NOS (eNOS) in vascular endothelium, while the inducible form of NOS (iNOS) is known to be activated in oligodendrocytes, astrocytes and microglia. We examined the activation of nNOS and the down stream effects of NO production in oligodendrocyte precursor cells (OPC) and MO3.13 cell line following culture with LPS. Our studies show that both MO3.13 cells and OPC are susceptible to the cellular injury resulting from LPS mediated activation and NO production. Activation of the TLR4 receptor with LPS led to decrease in cell viability that was associated with loss of mitochondrial membrane potential and impaired enzymatic activity of complex I and complex IV protein of the respiratory chain. 7-NI, a known inhibitor of nNOS was able to rescue of cells from LPS mediated mitochondrial damage. Loss of mitochondrial function was associated with translocation of cytochrome C and apoptosis inducing factor to the cytosol, setting the stage for apoptosis. Phosphorylation of PI3K and Akt was required for optimal activation of NOS. These studies provide a biochemical basis for nNOS mediated oligodendrocyte injury and suggest similar mechanisms may play a role in diseases characterized by oligodendrocyte loss and demyelination.
Copyright © 2012 Elsevier B.V. and Mitochondria Research Society. All rights reserved. All rights reserved.
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14 MeSH Terms
Molecular analysis of tumor margins by MALDI mass spectrometry in renal carcinoma.
Oppenheimer SR, Mi D, Sanders ME, Caprioli RM
(2010) J Proteome Res 9: 2182-90
MeSH Terms: Algorithms, Artificial Intelligence, Carcinoma, Renal Cell, Diagnostic Imaging, Electron Transport Complex IV, Histocytochemistry, Humans, Image Interpretation, Computer-Assisted, Kidney Neoplasms, Molecular Diagnostic Techniques, Neoplasm Invasiveness, Protein Array Analysis, Proteome, Proteomics, Reproducibility of Results, Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
Show Abstract · Added March 5, 2014
The rate of tumor recurrence post resection suggests that there are underlying molecular changes in nearby histologically normal tissue that go undetected by conventional diagnostic methods that utilize contrast agents and immunohistochemistry. MALDI MS is a molecular technology that has the specificity and sensitivity to monitor and identify molecular species indicative of these changes. The current study utilizes this technology to assess molecular distributions within a tumor and adjacent normal tissue in clear cell renal cell carcinoma biopsies. Results indicate that the histologically normal tissue adjacent to the tumor expresses many of the molecular characteristics of the tumor. Proteins of the mitochondrial electron transport system are examples of such distributions. This work demonstrates the utility of MALDI MS for the analysis of tumor tissue in the elucidation of aberrant molecular changes in the tumor microenvironment.
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16 MeSH Terms
Mitochondrial content and distribution changes specific to mouse diaphragm after chronic normobaric hypoxia.
Gamboa JL, Andrade FH
(2010) Am J Physiol Regul Integr Comp Physiol 298: R575-83
MeSH Terms: Animals, Atmospheric Pressure, Autophagy, Blotting, Western, Chronic Disease, Diaphragm, Electron Transport Complex IV, Hypoxia, Male, Membrane Proteins, Mice, Mice, Inbred C57BL, Microscopy, Electron, Mitochondria, Mitochondrial Proteins, Muscle, Skeletal, Oxygen, PPAR gamma, Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha, RNA, Messenger, Trans-Activators, Transcription Factors
Show Abstract · Added April 25, 2016
Chronic hypoxia reduces aerobic capacity (mitochondrial content) in limb skeletal muscles, and one of the causes seems to be decreased physical activity. Diaphragm and other respiratory muscles, however, may have a different pattern of adaptation as hypoxia increases the work of breathing. Thus, we hypothesized that chronic hypoxia would not reduce mitochondrial content in mouse diaphragm. Adult male C57BL/6J mice were kept in normoxia (Fi(O(2)) = 21%, control) or normobaric hypoxia (Fi(O(2)) = 10%, hypoxia) for 1, 2, and 4 wk. Mice were then killed, and the diaphragm and gastrocnemius muscles collected for analysis. In the diaphragm, cytochrome c oxidase histochemistry showed less intense staining in the hypoxia group. The total content of subunits from the electron transport chain, pyruvate dehydrogenase kinase 1 (PDK1), and voltage-dependent anion channel 1 (VDAC1) was evaluated by Western blot. These proteins decreased by 25-30% after 4 wk of hypoxia (P < 0.05 vs. control for all comparisons), matching a comparable decrease in diaphragmatic mitochondrial volume density (control 33.6 +/- 5.5% vs. hypoxia 26.8 +/- 6.7%, P = 0.013). Mitochondrial volume density or protein content did not change in gastrocnemius after hypoxia. Hypoxia decreased the content of peroxisome proliferator-activated receptor gamma (PPARgamma) and PPARgamma cofactor 1-alpha (PGC-1alpha) in diaphragm but not in gastrocnemius. PGC-1alpha mRNA levels in diaphragm were also reduced with hypoxia. BCL2/adenovirus E1B interacting protein 3 (BNIP-3) mRNA levels were upregulated after 1 and 2 wk of hypoxia in diaphragm and gastrocnemius, respectively; BNIP-3 protein content increased only in the diaphragm after 4 wk of hypoxia. Contrary to our hypothesis, these results show that chronic hypoxia decreases mitochondrial content in mouse diaphragm, despite the increase in workload. A combination of reduced mitochondrial biogenesis and increased mitophagy seems to be responsible for the decrease in mitochondrial content in the mouse diaphragm after hypoxia.
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22 MeSH Terms
A novel homozygous SCO2 mutation, p.G193S, causing fatal infantile cardioencephalomyopathy.
Mobley BC, Enns GM, Wong LJ, Vogel H
(2009) Clin Neuropathol 28: 143-9
MeSH Terms: Alkyl and Aryl Transferases, Base Sequence, Cardiomyopathies, Carrier Proteins, Consanguinity, Electron Transport, Electron Transport Complex IV, Fatal Outcome, Female, Humans, Infant, Newborn, Male, Membrane Proteins, Mitochondrial Encephalomyopathies, Mitochondrial Proteins, Molecular Chaperones, Molecular Sequence Data, Muscle, Skeletal, Mutation, Pedigree, Sequence Homology, Nucleic Acid
Show Abstract · Added August 14, 2014
Cytochrome c oxidase (COX) deficiency is a frequent cause of mitochondrial disease in infants. Mutations in the COX assembly gene SCO2 cause fatal infantile cardioencephalomyopathy. All patients reported to date with SCO2 deficiency share a common p.E140K mutation in at least 1 allele. In order to further the understanding of the genotype-phenotype spectrum associated with fatal infantile cardioencephalomyopathy, we describe a novel homozygous SCO2 mutation p.G193S in a patient with fatal infantile cardioencephalomyopathy born to consanguineous parents of Indian ancestry.
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21 MeSH Terms
Lower respiratory capacity in extraocular muscle mitochondria: evidence for intrinsic differences in mitochondrial composition and function.
Patel SP, Gamboa JL, McMullen CA, Rabchevsky A, Andrade FH
(2009) Invest Ophthalmol Vis Sci 50: 180-6
MeSH Terms: Abdominal Muscles, Animals, Blotting, Western, Electron Transport, Electron Transport Complex I, Electron Transport Complex II, Electron Transport Complex III, Electron Transport Complex IV, Energy Metabolism, Male, Membrane Potential, Mitochondrial, Mitochondria, Muscle, Mitochondrial Membranes, Oculomotor Muscles, Oxygen Consumption, Rats, Rats, Sprague-Dawley
Show Abstract · Added April 25, 2016
PURPOSE - The constant activity of the extraocular muscles is supported by abundant mitochondria. These organelles may enhance energy production by increasing the content of respiratory complexes. The authors tested the hypothesis that extraocular muscle mitochondria respire faster than do mitochondria from limb muscles because of the higher content of respiratory complexes.
METHODS - Inner mitochondrial membrane density was determined by stereological analysis of triceps surae (a limb muscle) and extraocular muscles of adult male Sprague-Dawley rats. The authors measured respiration rates of isolated mitochondria using a Clark-type electrode. The activity of respiratory complexes I, II, and IV was determined by spectrophotometry. The content of respiratory complexes was estimated by Western blot.
RESULTS - States 3, 4, and 5 respiration rates in extraocular muscle mitochondria were 40% to 60% lower than in limb muscle mitochondria. Extraocular muscle inner mitochondrial membrane density was similar to that of other skeletal muscles. Activity of complexes I and IV was lower in extraocular muscle mitochondria (approximately 50% the activity in triceps), but their content was approximately 15% to 30% higher. There was no difference in complex II content or activity or complex III content. Finally, complex V was less abundant in extraocular muscle mitochondria.
CONCLUSIONS - The results demonstrate that extraocular muscle mitochondria respire at slower rates than mitochondria from limb muscles, despite similar mitochondrial ultrastructure. Instead, differences were found in the activity (I, IV) and content (I, IV, V) of electron transport chain complexes. The discrepancy between activity and content of some complexes is suggestive of alternative subunit isoform expression in the extraocular muscles compared with limb muscles.
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17 MeSH Terms
Normal levels of wild-type mitochondrial DNA maintain cytochrome c oxidase activity for two pathogenic mitochondrial DNA mutations but not for m.3243A-->G.
Durham SE, Samuels DC, Cree LM, Chinnery PF
(2007) Am J Hum Genet 81: 189-95
MeSH Terms: Adult, DNA, Mitochondrial, Electron Transport Complex IV, Female, Humans, Male, Mitochondrial Diseases, Muscle Fibers, Skeletal, Muscle, Skeletal, Point Mutation
Show Abstract · Added December 12, 2013
Mitochondrial DNA (mtDNA) mutations are a common cause of human disease and accumulate as part of normal ageing and in common neurodegenerative disorders. Cells express a biochemical defect only when the proportion of mutated mtDNA exceeds a critical threshold, but it is not clear whether the actual cause of this defect is a loss of wild-type mtDNA, an excess of mutated mtDNA, or a combination of the two. Here, we show that segments of human skeletal muscle fibers harboring two pathogenic mtDNA mutations retain normal cytochrome c oxidase (COX) activity by maintaining a minimum amount of wild-type mtDNA. For these mutations, direct measurements of mutated and wild-type mtDNA molecules within the same skeletal muscle fiber are consistent with the "maintenance of wild type" hypothesis, which predicts that there is nonselective proliferation of mutated and wild-type mtDNA in response to the molecular defect. However, for the m.3243A-->G mutation, a superabundance of wild-type mtDNA was found in many muscle-fiber sections with negligible COX activity, indicating that the pathogenic mechanism for this particular mutation involves interference with the function of the wild-type mtDNA or wild-type gene products.
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10 MeSH Terms