2
views
0
recommends
+1 Recommend
0 collections
    0
    shares
      • Record: found
      • Abstract: found
      • Article: found
      Is Open Access

      Molecular Mechanisms of Acute Oxygen Sensing by Arterial Chemoreceptor Cells. Role of Hif2α

      review-article

      Read this article at

      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          Carotid body glomus cells are multimodal arterial chemoreceptors able to sense and integrate changes in several physical and chemical parameters in the blood. These cells are also essential for O 2 homeostasis. Glomus cells are prototypical peripheral O 2 sensors necessary to detect hypoxemia and to elicit rapid compensatory responses (hyperventilation and sympathetic activation). The mechanisms underlying acute O 2 sensing by glomus cells have been elusive. Using a combination of mouse genetics and single-cell optical and electrophysiological techniques, it has recently been shown that activation of glomus cells by hypoxia relies on the generation of mitochondrial signals (NADH and reactive oxygen species), which modulate membrane ion channels to induce depolarization, Ca 2+ influx, and transmitter release. The special sensitivity of glomus cell mitochondria to changes in O 2 tension is due to Hif2α-dependent expression of several atypical mitochondrial subunits, which are responsible for an accelerated oxidative metabolism and the strict dependence of mitochondrial complex IV activity on O 2 availability. A mitochondrial-to-membrane signaling model of acute O 2 sensing has been proposed, which explains existing data and provides a solid foundation for future experimental tests. This model has also unraveled new molecular targets for pharmacological modulation of carotid body activity potentially relevant in the treatment of highly prevalent medical conditions.

          Related collections

          Most cited references126

          • Record: found
          • Abstract: found
          • Article: not found

          A SARS-CoV-2 Protein Interaction Map Reveals Targets for Drug-Repurposing

          SUMMARY The novel coronavirus SARS-CoV-2, the causative agent of COVID-19 respiratory disease, has infected over 2.3 million people, killed over 160,000, and caused worldwide social and economic disruption 1,2 . There are currently no antiviral drugs with proven clinical efficacy, nor are there vaccines for its prevention, and these efforts are hampered by limited knowledge of the molecular details of SARS-CoV-2 infection. To address this, we cloned, tagged and expressed 26 of the 29 SARS-CoV-2 proteins in human cells and identified the human proteins physically associated with each using affinity-purification mass spectrometry (AP-MS), identifying 332 high-confidence SARS-CoV-2-human protein-protein interactions (PPIs). Among these, we identify 66 druggable human proteins or host factors targeted by 69 compounds (29 FDA-approved drugs, 12 drugs in clinical trials, and 28 preclinical compounds). Screening a subset of these in multiple viral assays identified two sets of pharmacological agents that displayed antiviral activity: inhibitors of mRNA translation and predicted regulators of the Sigma1 and Sigma2 receptors. Further studies of these host factor targeting agents, including their combination with drugs that directly target viral enzymes, could lead to a therapeutic regimen to treat COVID-19.
            Bookmark
            • Record: found
            • Abstract: found
            • Article: not found

            Succinate links TCA cycle dysfunction to oncogenesis by inhibiting HIF-alpha prolyl hydroxylase.

            Several mitochondrial proteins are tumor suppressors. These include succinate dehydrogenase (SDH) and fumarate hydratase, both enzymes of the tricarboxylic acid (TCA) cycle. However, to date, the mechanisms by which defects in the TCA cycle contribute to tumor formation have not been elucidated. Here we describe a mitochondrion-to-cytosol signaling pathway that links mitochondrial dysfunction to oncogenic events: succinate, which accumulates as a result of SDH inhibition, inhibits HIF-alpha prolyl hydroxylases in the cytosol, leading to stabilization and activation of HIF-1alpha. These results suggest a mechanistic link between SDH mutations and HIF-1alpha induction, providing an explanation for the highly vascular tumors that develop in the absence of VHL mutations.
              Bookmark
              • Record: found
              • Abstract: found
              • Article: found
              Is Open Access

              Why COVID-19 Silent Hypoxemia Is Baffling to Physicians

              Patients with coronavirus disease (COVID-19) are described as exhibiting oxygen levels incompatible with life without dyspnea. The pairing—dubbed happy hypoxia but more precisely termed silent hypoxemia—is especially bewildering to physicians and is considered as defying basic biology. This combination has attracted extensive coverage in media but has not been discussed in medical journals. It is possible that coronavirus has an idiosyncratic action on receptors involved in chemosensitivity to oxygen, but well-established pathophysiological mechanisms can account for most, if not all, cases of silent hypoxemia. These mechanisms include the way dyspnea and the respiratory centers respond to low levels of oxygen, the way the prevailing carbon dioxide tension (PaCO2 ) blunts the brain’s response to hypoxia, effects of disease and age on control of breathing, inaccuracy of pulse oximetry at low oxygen saturations, and temperature-induced shifts in the oxygen dissociation curve. Without knowledge of these mechanisms, physicians caring for patients with hypoxemia free of dyspnea are operating in the dark, placing vulnerable patients with COVID-19 at considerable risk. In conclusion, features of COVID-19 that physicians find baffling become less strange when viewed in light of long-established principles of respiratory physiology; an understanding of these mechanisms will enhance patient care if the much-anticipated second wave emerges.
                Bookmark

                Author and article information

                Contributors
                Journal
                Front Physiol
                Front Physiol
                Front. Physiol.
                Frontiers in Physiology
                Frontiers Media S.A.
                1664-042X
                23 November 2020
                2020
                : 11
                : 614893
                Affiliations
                [1] 1Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla , Seville, Spain
                [2] 2Departamento de Fisiología Médica y Biofísica, Facultad de Medicina, Universidad de Sevilla , Seville, Spain
                [3] 3Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED) , Madrid, Spain
                Author notes

                Edited by: Gregory D. Funk, University of Alberta, Canada

                Reviewed by: Colin A. Nurse, McMaster University, Canada; Christopher Wyatt, Wright State University, United States

                *Correspondence: Patricia Ortega-Sáenz, gortega1@ 123456us.es
                José López-Barneo, lbarneo@ 123456us.es

                This article was submitted to Respiratory Physiology, a section of the journal Frontiers in Physiology

                Article
                10.3389/fphys.2020.614893
                7719705
                33329066
                2823cc50-a564-42c3-acbd-f3504a9c11ba
                Copyright © 2020 Ortega-Sáenz, Moreno-Domínguez, Gao and López-Barneo.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 07 October 2020
                : 03 November 2020
                Page count
                Figures: 4, Tables: 0, Equations: 0, References: 126, Pages: 13, Words: 11379
                Funding
                Funded by: Spanish Ministries of Science and Innovation and Health
                Award ID: SAF2012-39343
                Award ID: SAF2016-74990-R
                Funded by: European Research Council 10.13039/501100000781
                Award ID: ERC-ADGPRJ201502629
                Categories
                Physiology
                Review

                Anatomy & Physiology
                carotid body,glomus cells,acute o2 sensing,electron transport chain,mitochondrial signaling,ion channels,mechanism of disease,paraganglioma

                Comments

                Comment on this article