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Supriya Srinivasan - One of the best experts on this subject based on the ideXlab platform.
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Oxygen Sensing neurons reciprocally regulate peripheral lipid metabolism via neuropeptide signaling in caenorhabditis elegans
PLOS Genetics, 2018Co-Authors: Rosalind Hussey, Nicole K Littlejohn, Emily Witham, Erik Vanstrum, Jaleh Mesgarzadeh, Harkaranveer Ratanpal, Supriya SrinivasanAbstract:The mechanisms by which the sensory environment influences metabolic homeostasis remains poorly understood. In this report, we show that Oxygen, a potent environmental signal, is an important regulator of whole body lipid metabolism. C. elegans Oxygen-Sensing neurons reciprocally regulate peripheral lipid metabolism under normoxia in the following way: under high Oxygen and food absence, URX sensory neurons are activated, and stimulate fat loss in the intestine, the major metabolic organ for C. elegans. Under lower Oxygen conditions or when food is present, the BAG sensory neurons respond by repressing the resting properties of the URX neurons. A genetic screen to identify modulators of this effect led to the identification of a BAG-neuron-specific neuropeptide called FLP-17, whose cognate receptor EGL-6 functions in URX neurons. Thus, BAG sensory neurons counterbalance the metabolic effect of tonically active URX neurons via neuropeptide communication. The combined regulatory actions of these neurons serve to precisely tune the rate and extent of fat loss to the availability of food and Oxygen, and provides an interesting example of the myriad mechanisms underlying homeostatic control.
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Oxygen Sensing neurons reciprocally regulate peripheral lipid metabolism via neuropeptide signaling in caenorhabditis elegans
bioRxiv, 2017Co-Authors: Rosalind Hussey, Emily Witham, Erik Vanstrum, Jaleh Mesgarzadeh, Harkaranveer Ratanpal, Supriya SrinivasanAbstract:The mechanisms by which the sensory environment instructs metabolic homeostasis remains poorly understood. In this report, we show that Oxygen, a potent environmental signal, is an important regulator of whole body lipid metabolism. C. elegans Oxygen-Sensing neurons reciprocally regulate peripheral lipid metabolism under normoxia in the following way: under high Oxygen and food absence, URX sensory neurons are activated, and stimulate fat loss in the intestine, the major metabolic organ for C. elegans . Under lower Oxygen conditions or when food is present, the BAG sensory neurons respond by repressing the resting properties of the URX neurons. A genetic screen to identify modulators of this effect led to the identification of a BAG-neuron-specific neuropeptide called FLP-17, whose cognate receptor EGL-6 functions in URX neurons. Thus, BAG sensory neurons counterbalance the metabolic effect of tonically active URX neurons via neuropeptide communication. The combined regulatory actions of these neurons serve to precisely tune the rate and extent of fat loss, to the availability of food and Oxygen.
Jaleh Mesgarzadeh - One of the best experts on this subject based on the ideXlab platform.
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Oxygen Sensing neurons reciprocally regulate peripheral lipid metabolism via neuropeptide signaling in caenorhabditis elegans
PLOS Genetics, 2018Co-Authors: Rosalind Hussey, Nicole K Littlejohn, Emily Witham, Erik Vanstrum, Jaleh Mesgarzadeh, Harkaranveer Ratanpal, Supriya SrinivasanAbstract:The mechanisms by which the sensory environment influences metabolic homeostasis remains poorly understood. In this report, we show that Oxygen, a potent environmental signal, is an important regulator of whole body lipid metabolism. C. elegans Oxygen-Sensing neurons reciprocally regulate peripheral lipid metabolism under normoxia in the following way: under high Oxygen and food absence, URX sensory neurons are activated, and stimulate fat loss in the intestine, the major metabolic organ for C. elegans. Under lower Oxygen conditions or when food is present, the BAG sensory neurons respond by repressing the resting properties of the URX neurons. A genetic screen to identify modulators of this effect led to the identification of a BAG-neuron-specific neuropeptide called FLP-17, whose cognate receptor EGL-6 functions in URX neurons. Thus, BAG sensory neurons counterbalance the metabolic effect of tonically active URX neurons via neuropeptide communication. The combined regulatory actions of these neurons serve to precisely tune the rate and extent of fat loss to the availability of food and Oxygen, and provides an interesting example of the myriad mechanisms underlying homeostatic control.
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Oxygen Sensing neurons reciprocally regulate peripheral lipid metabolism via neuropeptide signaling in caenorhabditis elegans
bioRxiv, 2017Co-Authors: Rosalind Hussey, Emily Witham, Erik Vanstrum, Jaleh Mesgarzadeh, Harkaranveer Ratanpal, Supriya SrinivasanAbstract:The mechanisms by which the sensory environment instructs metabolic homeostasis remains poorly understood. In this report, we show that Oxygen, a potent environmental signal, is an important regulator of whole body lipid metabolism. C. elegans Oxygen-Sensing neurons reciprocally regulate peripheral lipid metabolism under normoxia in the following way: under high Oxygen and food absence, URX sensory neurons are activated, and stimulate fat loss in the intestine, the major metabolic organ for C. elegans . Under lower Oxygen conditions or when food is present, the BAG sensory neurons respond by repressing the resting properties of the URX neurons. A genetic screen to identify modulators of this effect led to the identification of a BAG-neuron-specific neuropeptide called FLP-17, whose cognate receptor EGL-6 functions in URX neurons. Thus, BAG sensory neurons counterbalance the metabolic effect of tonically active URX neurons via neuropeptide communication. The combined regulatory actions of these neurons serve to precisely tune the rate and extent of fat loss, to the availability of food and Oxygen.
Peter J. Ratcliffe - One of the best experts on this subject based on the ideXlab platform.
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Oxygen Sensing and hypoxia signalling pathways in animals the implications of physiology for cancer
The Journal of Physiology, 2013Co-Authors: Peter J. RatcliffeAbstract:Studies of regulation of the haematopoietic growth factor erythropoietin led to the unexpected discovery of a widespread system of direct Oxygen Sensing that regulates gene expression in animals. The Oxygen-sensitive signal is generated by a series of non-haem Fe(II)- and 2-oxoglutarate-dependent diOxygenases that catalyse the post-translational hydroxylation of specific residues in the transcription factor hypoxia-inducible factor (HIF). These hydroxylations promote both Oxygen-dependent degradation and Oxygen-dependent inactivation of HIF, but are suppressed in hypoxia, leading to the accumulation of HIF and assembly of an active transcriptional complex in hypoxic cells. Hypoxia-inducible factor activates an extensive transcriptional cascade that interfaces with other cell signalling pathways, microRNA networks and RNA-protein translational control systems. The relationship of these cellular signalling pathways to the integrated physiology of Oxygen homeostasis and the implication of dysregulating these massive physiological pathways in diseases such as cancer are discussed.
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The hypoxia-inducible transcription factor pathway regulates Oxygen Sensing in the simplest animal, Trichoplax adhaerens.
EMBO reports, 2010Co-Authors: Christoph Loenarz, Anna Boleininger, Bernd Schierwater, Mathew L. Coleman, Peter W. H. Holland, Peter J. Ratcliffe, Christopher J. SchofieldAbstract:The hypoxic response in humans is mediated by the hypoxia-inducible transcription factor (HIF), for which prolyl hydroxylases (PHDs) act as Oxygen-Sensing components. The evolutionary origins of the HIF system have been previously unclear. We demonstrate a functional HIF system in the simplest animal, Trichoplax adhaerens: HIF targets in T. adhaerens include glycolytic and metabolic enzymes, suggesting a role for HIF in the adaptation of basal multicellular animals to fluctuating Oxygen levels. Characterization of the T. adhaerens PHDs and cross-species complementation assays reveal a conserved Oxygen-Sensing mechanism. Cross-genomic analyses rationalize the relative importance of HIF system components, and imply that the HIF system is likely to be present in all animals, but is unique to this kingdom.
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Oxygen Sensing hypoxia inducible factor 1 and the regulation of mammalian gene expression
The Journal of Experimental Biology, 1998Co-Authors: Peter J. Ratcliffe, Patrick H Maxwell, J F Orourke, Christopher W. PughAbstract:A great many aspects of the anatomy and physiology of large animals are constrained by the need to match Oxygen supply to cellular metabolism and appear likely to involve the regulation of gene expression by Oxygen. Some insight into possible underlying mechanisms has been provided by studies of erythropoietin, a haemopoietic growth factor which stimulates red cell production in response to hypoxia. Studies of hypoxia-inducible cis-acting sequences from the erythropoietin gene have led to the recognition of a widespread transcriptional response to hypoxia based on the activation of a DNA-binding complex termed hypoxia-inducible factor-1 (HIF-1). Perturbation of the transcriptional response by particular transition metal ions, iron chelators and certain redox-active agents have suggested a specific Oxygen Sensing mechanism, perhaps involving a haem protein in a flavoprotein/cytochrome system. In addition to erythropoietin, HIF-1-responsive genes include examples with functions in cellular energy metabolism, iron metabolism, catecholamine metabolism, vasomotor control and angiogenesis, suggesting an important role in the coordination of Oxygen supply and cellular metabolism. In support of this, we have demonstrated an important role for HIF-1 in tumour angiogenesis. HIF-1 itself consists of a heterodimer of two basic-helix-loop-helix proteins of the PAS family, termed HIF-1alpha and HIF-1beta, although other closely related members of this family may also contribute to the response to hypoxia. We have fused domains of HIF-1 genes to heterologous transcription factors to assay for regulatory function. These experiments have defined several domains in HIF-1alpha which can independently confer the hypoxia-inducible property, and they suggest a mechanism of HIF-1 activation in which post-translational activation/derepression of HIF-1alpha is amplified by changes in HIF-1alpha abundance most probably arising from suppression of proteolytic breakdown. Pursuit of the mechanism(s) underlying these processes should ultimately lead to better definition of the Oxygen-Sensing process.
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inducible operation of the erythropoietin 3 enhancer in multiple cell lines evidence for a widespread Oxygen Sensing mechanism
Proceedings of the National Academy of Sciences of the United States of America, 1993Co-Authors: Patrick H Maxwell, Christopher W. Pugh, Peter J. RatcliffeAbstract:Abstract Adaptive responses to hypoxia occur in many biological systems. A well-characterized example is the hypoxic induction of the synthesis of erythropoietin, a hormone which regulates erythropoiesis and hence blood Oxygen content. The restricted expression of the erythropoietin gene in subsets of cells within kidney and liver has suggested that this specific Oxygen-Sensing mechanism is restricted to specialized cells in those organs. Using transient transfection of reporter genes coupled to a transcriptional enhancer lying 3' to the erythropoietin gene, we show that an Oxygen-Sensing system similar, or identical, to that controlling erythropoietin expression is wide-spread in mammalian cells. The extensive distribution of this Sensing mechanism contrasts with the restricted expression of erythropoietin, suggesting that it mediates other adaptive responses to hypoxia.
Natascha Sommer - One of the best experts on this subject based on the ideXlab platform.
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bypassing mitochondrial complex iii using alternative oxidase inhibits acute pulmonary Oxygen Sensing
Science Advances, 2020Co-Authors: Natascha Sommer, Oleg Pak, Susan Scheibe, Fenja Knoepp, Ievgen Strielkov, Nasim Alebrahimdehkordi, Eric Dufour, Ana Andjelkovic, Akylbek Sydykov, Alireza SarajiAbstract:Mitochondria play an important role in Sensing both acute and chronic hypoxia in the pulmonary vasculature, but their primary Oxygen-Sensing mechanism and contribution to stabilization of the hypoxia-inducible factor (HIF) remains elusive. Alteration of the mitochondrial electron flux and increased superoxide release from complex III has been proposed as an essential trigger for hypoxic pulmonary vasoconstriction (HPV). We used mice expressing a tunicate alternative oxidase, AOX, which maintains electron flux when respiratory complexes III and/or IV are inhibited. Respiratory restoration by AOX prevented acute HPV and hypoxic responses of pulmonary arterial smooth muscle cells (PASMC), acute hypoxia-induced redox changes of NADH and cytochrome c, and superoxide production. In contrast, AOX did not affect the development of chronic hypoxia-induced pulmonary hypertension and HIF-1α stabilization. These results indicate that distal inhibition of the mitochondrial electron transport chain in PASMC is an essential initial step for acute but not chronic Oxygen Sensing.
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mitochondrial complex iv subunit 4 isoform 2 is essential for acute pulmonary Oxygen Sensing
Circulation Research, 2017Co-Authors: Natascha Sommer, Maik Huttemann, Oleg Pak, Susan Scheibe, Fenja Knoepp, Christopher Sinkler, Monika Malczyk, Mareike Gierhardt, Azadeh Esfandiary, Simone KrautAbstract:Rationale: Acute pulmonary Oxygen Sensing is essential to avoid life-threatening hypoxemia via hypoxic pulmonary vasoconstriction (HPV) which matches perfusion to ventilation. Hypoxia-induced mitochondrial superoxide release has been suggested as critical step in the signaling pathway underlying HPV. However, the identity of the primary Oxygen sensor and mechanism of superoxide release in acute hypoxia, as well as its relevance for chronic pulmonary Oxygen Sensing remains unresolved. Objective: To investigate the role of the pulmonary specific isoform 2 of subunit 4 of mitochondrial complex IV (Cox4i2) and the subsequent mediators superoxide and hydrogen peroxide for pulmonary Oxygen Sensing and signaling. Methods and Results: Isolated ventilated and perfused lungs from Cox4i2 -/- mice lacked acute HPV. In parallel, pulmonary arterial smooth muscle cells (PASMCs) from Cox4i2 -/- mice showed no hypoxia-induced increase of intracellular calcium. Hypoxia-induced superoxide release which was detected by electron spin resonance spectroscopy in wild type (WT) PASMCs was absent in Cox4i2 -/- PASMCs and was dependent on cysteine residues of Cox4i2. HPV could be inhibited by mitochondrial superoxide inhibitors proving functional relevance of superoxide release for HPV. Mitochondrial hyperpolarization, which can promote mitochondrial superoxide release, was detected during acute hypoxia in WT but not Cox4i2 -/- PASMCs. Downstream signaling determined by patch clamp measurements showed decreased hypoxia-induced cellular membrane depolarization in Cox4i2 -/- PASMCs compared to WT PASMCs, which could be normalized by application of hydrogen peroxide. In contrast, chronic hypoxia-induced pulmonary hypertension and pulmonary vascular remodeling were not or only slightly affected by Cox4i2 deficiency, respectively. Conclusions: Cox4i2 is essential for acute but not chronic pulmonary Oxygen Sensing by triggering mitochondrial hyperpolarization and release of mitochondrial superoxide which, after conversion to hydrogen peroxide, contributes to cellular membrane depolarization and HPV. These findings provide a new model for Oxygen Sensing processes in the lung and possibly also in other organs.
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Oxygen Sensing and signal transduction in hypoxic pulmonary vasoconstriction
European Respiratory Journal, 2016Co-Authors: Natascha Sommer, Ievgen Strielkov, Norbert WeissmannAbstract:Hypoxic pulmonary vasoconstriction (HPV), also known as the von Euler-Liljestrand mechanism, is an essential response of the pulmonary vasculature to acute and sustained alveolar hypoxia. During local alveolar hypoxia, HPV matches perfusion to ventilation to maintain optimal arterial Oxygenation. In contrast, during global alveolar hypoxia, HPV leads to pulmonary hypertension. The Oxygen Sensing and signal transduction machinery is located in the pulmonary arterial smooth muscle cells (PASMCs) of the pre-capillary vessels, albeit the physiological response may be modulated in vivo by the endothelium. While factors such as nitric oxide modulate HPV, reactive Oxygen species (ROS) have been suggested to act as essential mediators in HPV. ROS may originate from mitochondria and/or NADPH oxidases but the exact Oxygen Sensing mechanisms, as well as the question of whether increased or decreased ROS cause HPV, are under debate. ROS may induce intracellular calcium increase and subsequent contraction of PASMCs via direct or indirect interactions with protein kinases, phospholipases, sarcoplasmic calcium channels, transient receptor potential channels, voltage-dependent potassium channels and L-type calcium channels, whose relevance may vary under different experimental conditions. Successful identification of factors regulating HPV may allow development of novel therapeutic approaches for conditions of disturbed HPV.
Paul T Schumacker - One of the best experts on this subject based on the ideXlab platform.
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Oxygen Sensing in hypoxic pulmonary vasoconstriction using new tools to answer an age old question
Experimental Physiology, 2008Co-Authors: Gregory B Waypa, Paul T SchumackerAbstract:Hypoxic pulmonary vasoconstriction (HPV) becomes activated in response to alveolar hypoxia and, although the characteristics of HPV have been well described, the underlying mechanism of O2 Sensing which initiates the HPV response has not been fully established. Mitochondria have long been considered as a putative site of Oxygen Sensing because they consume O2 and therefore represent the intracellular site with the lowest Oxygen tension. However, two opposing theories have emerged regarding mitochondria-dependent O2 Sensing during hypoxia. One model suggests that there is a decrease in mitochondrial reactive Oxygen species (ROS) levels during the transition from normoxia to hypoxia, resulting in the shift in cytosolic redox to a more reduced state. An alternative model proposes that hypoxia paradoxically increases mitochondrial ROS signalling in pulmonary arterial smooth muscle. Experimental resolution of the question of whether the mitochondrial ROS levels increase or decrease during hypoxia has been problematic owing to the technical limitations of the tools used to assess oxidant stress as well as the pharmacological agents used to inhibit the mitochondrial electron transport chain. However, recent developments in genetic techniques and redox-sensitive probes may allow us eventually to reach a consensus concerning the O2 Sensing mechanism underlying HPV.
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Oxygen Sensing by mitochondria at complex iii the paradox of increased reactive Oxygen species during hypoxia
Experimental Physiology, 2006Co-Authors: Robert D Guzy, Paul T SchumackerAbstract:All eukaryotic cells utilize oxidative phosphorylation to maintain their high-energy phosphate stores. Mitochondrial Oxygen consumption is required for ATP generation, and cell survival is threatened when cells are deprived of O(2). Consequently, all cells have the ability to sense O(2), and to activate adaptive processes that will enhance the likelihood of survival in anticipation that Oxygen availability might become limiting. Mitochondria have long been considered a likely site of Oxygen Sensing, and we propose that the electron transport chain acts as an O(2) sensor by releasing reactive Oxygen species (ROS) in response to hypoxia. The ROS released during hypoxia act as signalling agents that trigger diverse functional responses, including activation of gene expression through the stabilization of the transcription factor hypoxia-inducible factor (HIF)-alpha. The primary site of ROS production during hypoxia appears to be complex III. The paradoxical increase in ROS production during hypoxia may be explained by an effect of O(2) within the mitochondrial inner membrane on: (a) the lifetime of the ubisemiquinone radical in complex III; (b) the relative release of mitochondrial ROS towards the matrix compartment versus the intermembrane space; or (c) the ability of O(2) to access the ubisemiquinone radical in complex III. In summary, the process of Oxygen Sensing is of fundamental importance in biology. An ability to control the Oxygen Sensing mechanism in cells, potentially using small molecules that do not disrupt Oxygen consumption, would open valuable therapeutic avenues that could have a profound impact on a diverse range of diseases.
