scholarly journals Evolutionary GEM: Evolution of Cytochrome c Oxidase IV Regulation in Mammals

2017 ◽  
Vol 8 (1) ◽  
Author(s):  
Joseph Brockman ◽  
Patricia M. Gray
Keyword(s):  
Cytochrome C ◽  
Cytochrome C Oxidase ◽  
Hypoxia Inducible Factor ◽  
Aerobic Bacteria ◽  
Oxygen Species ◽  
Independent Manner ◽  
Hypoxia Inducible Factor 1 ◽  
Early Atmosphere ◽  
Responsive Element ◽  
Multicellular Organisms

Aerobic respiration, although metabolically advantageous in O2-rich environments, can be detrimental to the cell when O2 is not fully reduced resulting in cytotoxic reactive oxygen species (ROS) production. Cytochrome c oxidase subunit 4 (COX-4) is primarily responsible for fully reducing O2 during metabolism and exists as COX4-1 and COX4-2 isoforms. The former exists in normoxia, but is replaced by the latter in hypoxia. This change is brought about by two mechanisms, the first involving regulation by hypoxia inducible factor 1 (HIF-1), which directly upregulates COX4-2 and indirectly degrades COX4-1. The second mechanism involves an oxygen responsive element (ORE), which upregulates COX4-2 in a HIF-1 independent manner. The convergence of two unrelated pathways to regulate COX4-1 and COX4-2 would allow cells to optimize their metabolic profile within an environment experiencing varying O2, such as Earth’s early atmosphere in the case of primitive aerobic bacteria or in multicellular organisms where O2 levels vary between tissues such as lung tissue.

scholarly journals The NADPH Oxidase Subunit NOX4 Is a New Target Gene of the Hypoxia-inducible Factor-1

2010 ◽  
Vol 21 (12) ◽  
pp. 2087-2096 ◽  
Author(s):  
Isabel Diebold ◽  
Andreas Petry ◽  
John Hess ◽  
Agnes Görlach
Keyword(s):  
Chromatin Immunoprecipitation ◽  
Target Gene ◽  
Hypoxia Inducible Factor ◽  
Oxygen Species ◽  
Protein Levels ◽  
Hypoxia Inducible Factor 1 ◽  
Signaling Axis ◽  
Pulmonary Artery Smooth Muscle ◽  
Responsive Element

NADPH oxidases are important sources of reactive oxygen species (ROS), possibly contributing to various disorders associated with enhanced proliferation. NOX4 appears to be involved in vascular signaling and may contribute to the response to hypoxia. However, the exact mechanisms controlling NOX4 levels under hypoxia are not resolved. We found that hypoxia rapidly enhanced NOX4 mRNA and protein levels in pulmonary artery smooth-muscle cells (PASMCs) as well as in pulmonary vessels from mice exposed to hypoxia. This response was dependent on the hypoxia-inducible transcription factor HIF-1α because overexpression of HIF-1α increased NOX4 expression, whereas HIF-1α depletion prevented this response. Mutation of a putative hypoxia-responsive element in the NOX4 promoter abolished hypoxic and HIF-1α–induced activation of the NOX4 promoter. Chromatin immunoprecipitation confirmed HIF-1α binding to the NOX4 gene. Induction of NOX4 by HIF-1α contributed to maintain ROS levels after hypoxia and hypoxia-induced proliferation of PASMCs. These findings show that NOX4 is a new target gene of HIF-1α involved in the response to hypoxia. Together with our previous findings that NOX4 mediates HIF-1α induction under normoxia, these data suggest an important role of the signaling axis between NOX4 and HIF-1α in various cardiovascular disorders under hypoxic and also nonhypoxic conditions.

Nitric oxide modulates hypoxia-inducible factor-1 and poly(ADP-ribose) polymerase-1 cross talk in response to hypobaric hypoxia

2012 ◽  
Vol 112 (5) ◽  
pp. 816-823 ◽  
Author(s):  
Rubén Martínez-Romero ◽  
Ana Cañuelo ◽  
Eva Siles ◽  
F. Javier Oliver ◽  
Esther Martínez-Lara
Keyword(s):  
Nitric Oxide ◽  
Hypobaric Hypoxia ◽  
Reactive Oxygen Species Production ◽  
Transcriptional Activity ◽  
Hypoxia Inducible Factor ◽  
No Production ◽  
Oxygen Species ◽  
Hypoxia Inducible Factor 1 ◽  
Species Production ◽  
Parp 1

The physiological response to hypobaric hypoxia represents a complex network of biochemical pathways in which the nitrergic system plays an important role. Previous studies have provided evidence for an interplay between the hypoxia-inducible factor-1 (HIF-1) and poly(ADP-ribose) polymerase-1 (PARP-1) under hypoxia. Here, we evaluate the potential involvement of nitric oxide (NO) in the cross talk between these two proteins. With this aim, we studied comparatively the effect of pharmacological inhibitors of NO production or PARP activity in the response of the mouse cerebral cortex to 4 h of exposure to a simulated altitude of 31,000 ft. Particularly, we analyzed the NO and reactive oxygen species production, the expression of NO synthase (NOS) isoforms, PARP-1 activity, HIF-1α expression and HIF-1 transcriptional activity, the protein level of the factor inhibiting HIF, and, finally, beclin-1 and fractin expression, as markers of cellular damage. Our results demonstrate that the reduction of NO level did not affect reactive oxygen species production but significantly 1) dampened the posthypoxic increase in neuronal NOS and inducible NOS expression without altering endothelial NOS protein level; 2) prevented PARP activation; 3) decreased HIF-1α response to hypoxia; 4) achieved a higher long-term HIF-1 transcriptional activity by reducing factor inhibiting HIF expression; and 5) reduced hypoxic damage. The pharmacological inhibition of PARP reproduced the NOS expression pattern and the HIF-1α response observed in NOS-inhibited mice, supporting its involvement in the NO-dependent regulation of hypoxia. As a whole, these results provide new data about the molecular mechanism underlying the beneficial effects of controlling NO production under hypobaric hypoxic conditions.

scholarly journals Neuroglobin Regulates Hypoxic Response of Neuronal Cells through Hif-1α- and Nrf2-mediated Mechanism

2012 ◽  
Vol 32 (6) ◽  
pp. 1046-1060 ◽  
Author(s):  
Kalpana B Hota ◽  
Sunil K Hota ◽  
Ravi B Srivastava ◽  
Shashi B Singh
Keyword(s):  
Cytochrome C ◽  
Acute Hypoxia ◽  
Neuronal Cells ◽  
Hypoxia Inducible Factor ◽  
Redox Status ◽  
Related Factor ◽  
Cytochrome C Release ◽  
Hypoxia Inducible Factor 1 ◽  
Hypoxic Conditions ◽  
Cellular Antioxidants

Oxygen sensing in hypoxic neurons has been classically attributed to cytochrome c oxidase and prolyl-4-hydroxylases and involves stabilization of transcription factors, hypoxia-inducible factor-1 α (Hif-1 α) and nuclear factor erythroid 2-related factor 2 (Nrf2) that mediate survival responses. On the contrary, release of cytochrome c into the cytosol during hypoxic stress triggers apoptosis in neuronal cells. We, here advocate that the redox state of neuroglobin (Ngb) could regulate both Hif-1 α and Nrf2 stabilization and cytochrome c release during hypoxia. The hippocampal regions showing higher expression of Ngb were less susceptible to global hypoxia-mediated neurodegeneration. During normoxia, Ngb maintained cytochrome c in the reduced state and prevented its release from mitochondria by using cellular antioxidants. Greater turnover of oxidized cytochrome c and increased utilization of cellular antioxidants during acute hypoxia altered cellular redox status and stabilized Hif-1 α and Nrf2 through Ngb-mediated mechanism. Chronic hypoxia, however, resulted in oxidation and degradation of Ngb, accumulation of ferric ions and release of cytochrome c that triggered apoptosis. Administration of N-acetyl-cysteine during hypoxic conditions improved neuronal survival by preventing Ngb oxidation and degradation. Taken together, these results establish a role for Ngb in regulating both the survival and apoptotic mechanisms associated with hypoxia.

scholarly journals Reactive Oxygen Species and Nrf2: Functional and Transcriptional Regulators of Hematopoiesis

2019 ◽  
Vol 2019 ◽  
pp. 1-11 ◽  
Author(s):  
Linping Hu ◽  
Yawen Zhang ◽  
Weimin Miao ◽  
Tao Cheng
Keyword(s):  
Reactive Oxygen Species ◽  
Oxygen Sensor ◽  
Hypoxia Inducible Factor ◽  
Reactive Oxygen ◽  
Ambient Air ◽  
Oxygen Species ◽  
Human Cord Blood ◽  
Hematopoietic Stem ◽  
Hypoxia Inducible Factor 1 ◽  
Cellular Oxygen

Hematopoietic stem cells (HSCs) are characterized by self-renewal and multilineage differentiation potentials. Although they play a central role in hematopoietic homeostasis and bone marrow (BM) transplantation, they are affected by multiple environmental factors in the BM. Here, we review the effects of reactive oxygen species (ROS) and Nrf2 on HSC function and BM transplantation. HSCs reside in the hypoxic microenvironment of BM, and ROS play an important role in HSPC regulation. Recently, an extraphysiologic oxygen shock/stress phenomenon was identified in human cord blood HSCs collected under ambient air conditions. Moreover, Nrf2 has been recently recognized as a master transcriptional factor that regulates multiple antioxidant enzymes. Since several years, the role of Nrf2 in hematopoiesis has been extensively studied, which has functional similarities of cellular oxygen sensor hypoxia-inducible factor-1 as transcriptional factors. Increasing evidence has revealed that abnormally elevated ROS production due to factors such as genetic defects, aging, and ionizing radiation unexceptionally resulted in lethal impairment of HSC function and hematopoiesis. Both experimental and clinical studies have identified elevated ROS levels as a major culprit of ineffective BM transplantation. Lastly, we discuss the possibility of using small molecule antioxidants, such as N-acetyl cysteine, resveratrol, and curcumin, to augment HSC function and improve the therapeutic efficacy of BM transplantation. Further research on the function of ROS levels and improving the efficacy of BM transplantation may have a great potential for broad clinical applications of HSCs.

scholarly journals Hypoxia-inducible Factor-1 Activation in Nonhypoxic Conditions: The Essential Role of Mitochondrial-derived Reactive Oxygen Species

2010 ◽  
Vol 21 (18) ◽  
pp. 3247-3257 ◽  
Author(s):  
David A. Patten ◽  
Véronique N. Lafleur ◽  
Geneviève A. Robitaille ◽  
Denise A. Chan ◽  
Amato J. Giaccia ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Nadph Oxidase ◽  
Hypoxia Inducible Factor ◽  
Reactive Oxygen ◽  
Protein Stabilization ◽  
Complex Iii ◽  
Oxygen Species ◽  
Ang Ii ◽  
Hypoxia Inducible Factor 1

Hypoxia-inducible factor-1 (HIF-1) is a key transcription factor for responses to low oxygen. Different nonhypoxic stimuli, including hormones and growth factors, are also important HIF-1 activators in the vasculature. Angiotensin II (Ang II), the main effecter hormone in the renin-angiotensin system, is a potent HIF-1 activator in vascular smooth muscle cells (VSMCs). HIF-1 activation by Ang II involves intricate mechanisms of HIF-1α transcription, translation, and protein stabilization. Additionally, the generation of reactive oxygen species (ROS) is essential for HIF-1 activation during Ang II treatment. However, the role of the different VSMC ROS generators in HIF-1 activation by Ang II remains unclear. This work aims at elucidating this question. Surprisingly, repression of NADPH oxidase-generated ROS, using Vas2870, a specific inhibitor or a p22phox siRNA had no significant effect on HIF-1 accumulation by Ang II. In contrast, repression of mitochondrial-generated ROS, by complex III inhibition, by Rieske Fe-S protein siRNA, or by the mitochondrial-targeted antioxidant SkQ1, strikingly blocked HIF-1 accumulation. Furthermore, inhibition of mitochondrial-generated ROS abolished HIF-1α protein stability, HIF-1–dependent transcription and VSMC migration by Ang II. A large number of studies implicate NADPH oxidase–generated ROS in Ang II–mediated signaling pathways in VSMCs. However, our work points to mitochondrial-generated ROS as essential intermediates for HIF-1 activation in nonhypoxic conditions.

scholarly journals Mitochondrial glycerol phosphate oxidation is modulated by adenylates through allosteric regulation of cytochrome c oxidase activity in mosquito flight muscle

2019 ◽  
Author(s):  
Alessandro Gaviraghi ◽  
Juliana B.R. Correa Soares ◽  
Julio A. Mignaco ◽  
Carlos Frederico L. Fontes ◽  
Marcus F. Oliveira
Keyword(s):  
Cytochrome C ◽  
Cytochrome C Oxidase ◽  
Energy Demand ◽  
Flight Muscle ◽  
Allosteric Regulation ◽  
High Energy ◽  
Protonmotive Force ◽  
Independent Manner ◽  
Oxidoreductase Activity ◽  
Regulatory Effects

AbstractThe huge energy demand posed by insect flight activity is met by an efficient oxidative phosphorylation process that takes place within flight muscle mitochondria. In the major arbovirus vector Aedes aegypti, mitochondrial oxidation of pyruvate, proline and glycerol 3 phosphate (G3P) represent the major energy sources of ATP to sustain flight muscle energy demand. Although adenylates exert critical regulatory effects on several mitochondrial enzyme activities, the potential consequences of altered adenylate levels to G3P oxidation remains to be determined. Here, we report that mitochondrial G3P oxidation is controlled by adenylates through allosteric regulation of cytochrome c oxidase (COX) activity in A. aegypti flight muscle. We observed that ADP significantly activated respiratory rates linked to G3P oxidation, in a protonmotive force-independent manner. Kinetic analyses revealed that ADP activates respiration through a slightly cooperative mechanism. Despite adenylates caused no effects on G3P-cytochrome c oxidoreductase activity, COX activity was allosterically activated by ADP. Conversely, ATP exerted powerful inhibitory effects on respiratory rates linked to G3P oxidation and on COX activity. We also observed that high energy phosphate recycling mechanisms did not contribute to the regulatory effects of adenylates on COX activity or G3P oxidation. We conclude that mitochondrial G3P oxidation by A. aegypti flight muscle is regulated by adenylates essentially through the allosteric modulation of COX activity, underscoring the bioenergetic relevance of this novel mechanism and the potential consequences for mosquito dispersal.

scholarly journals Tumor necrosis factor receptor-associated protein 1 regulates hypoxia-induced apoptosis through a mitochondria-dependent pathway mediated by cytochrome c oxidase subunit II

2019 ◽  
Vol 7 ◽  
Author(s):  
Fei Xiang ◽  
Si-yuan Ma ◽  
Yan-ling Lv ◽  
Dong-xia Zhang ◽  
Hua-pei Song ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Tumor Necrosis Factor ◽  
Cytochrome C ◽  
Cytochrome C Oxidase ◽  
Tumor Necrosis ◽  
Tumor Necrosis Factor Receptor ◽  
Cardiomyocyte Apoptosis ◽  
Oxygen Species ◽  
Receptor Associated Protein ◽  
Necrosis Factor

Abstract Background Tumor necrosis factor receptor-associated protein 1 (TRAP1) plays a protective effect in hypoxic cardiomyocytes, but the precise mechanisms are not well clarified. The study is aimed to identify the mechanism of TRAP1 on hypoxic damage in cardiomyocytes. Methods In this study, the effects of TRAP1 and cytochrome c oxidase subunit II (COXII) on apoptosis in hypoxia-induced cardiomyocytes were explored using overexpression and knockdown methods separately. Results Hypoxia induced cardiomyocyte apoptosis, and TRAP1 overexpression notably inhibited apoptosis induced by hypoxia. Conversely, TRAP1 silencing promoted apoptosis in hypoxic cardiomyocytes. Further investigation revealed that the proapoptotic effects caused by the silencing of TRAP1 were prevented by COXII overexpression, whereas COXII knockdown reduced the antiapoptotic function induced by TRAP1 overexpression. Additionally, changes in the release of cytochrome c from mitochondria into the cytosol and the caspase-3 activity in the cytoplasm, as well as reactive oxygen species production, were found to be correlated with the changes in apoptosis. Conclusions The current study uncovered that TRAP1 regulates hypoxia-induced cardiomyocyte apoptosis through a mitochondria-dependent apoptotic pathway mediated by COXII, in which reactive oxygen species presents as an important component.

Bioenergetic remodeling during cellular differentiation: changes in cytochrome c oxidase regulation do not affect the metabolic phenotype

2004 ◽  
Vol 82 (3) ◽  
pp. 391-399 ◽  
Author(s):  
Carrie N Lyons ◽  
Scot C Leary ◽  
Christopher D Moyes
Keyword(s):  
Nitric Oxide ◽  
Reactive Oxygen Species ◽  
Cytochrome C ◽  
Oxidative Phosphorylation ◽  
Cytochrome C Oxidase ◽  
Oxidative Metabolism ◽  
Specific Activity ◽  
Reactive Oxygen ◽  
Metabolic Phenotype ◽  
Oxygen Species

Myogenesis induces mitochondrial proliferation, a decrease in reactive oxygen species (ROS) production, and an increased reliance upon oxidative phosphorylation. While muscles typically possess 20%–40% excess capacity of cytochrome c oxidase (COX), undifferentiated myoblasts have only 5%–20% of the mitochondrial content of myotubes and muscles. We used two muscle lines (C2C12, Sol8) and 3T3-L1 pre-adipocytes to examine if changes in COX regulation or activity with differentiation cause a shift in metabolic phenotype (i.e., more oxidative, less glycolytic, less ROS). COX activity in vivo can be suppressed by its inhibitor, nitric oxide, or sub-optimal substrate (cytochrome c) concentrations. Inhibition of nitric oxide synthase via L-NAME had no effect on the respiration of adherent undifferentiated cells, although it did stimulate respiration of myoblasts in suspension. While cytochrome c content increased during differentiation, there was no correlation with respiratory rate or reliance on oxidative metabolism. There was no correlation between COX specific activity and oxidative metabolism between cell type or in relation to differentiation. These studies show that, despite the very low activities of COX, undifferentiated myoblasts and pre-adipocytes possess a reserve of COX capacity and changes in COX with differentiation do not trigger the shift in metabolic phenotype.Key words: oxidative phosphorylation, myogenesis, nitric oxide, reactive oxygen species, cytochrome c oxidase.

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