Bitter taste receptor agonists alter mitochondrial function and induce autophagy in airway smooth muscle cells.
Identifieur interne : 000D27 ( Main/Exploration ); précédent : 000D26; suivant : 000D28Bitter taste receptor agonists alter mitochondrial function and induce autophagy in airway smooth muscle cells.
Auteurs : Shi Pan [États-Unis] ; Pawan Sharma [États-Unis] ; Sushrut D. Shah [États-Unis] ; Deepak A. Deshpande [États-Unis]Source :
- American journal of physiology. Lung cellular and molecular physiology [ 1522-1504 ] ; 2017.
Descripteurs français
- KwdFr :
- Adénosine triphosphate (métabolisme), Autophagie (), Cellules cultivées, Dynamique mitochondriale (), Goût (), Gènes dominants, Humains, Mitochondries (), Mitochondries (métabolisme), Modèles biologiques, Mort cellulaire, Myocytes du muscle lisse (), Myocytes du muscle lisse (cytologie), Myocytes du muscle lisse (métabolisme), Petit ARN interférent (métabolisme), Potentiel de membrane mitochondriale (), Poumon (cytologie), Protéines associées aux microtubules (métabolisme), Protéines membranaires (métabolisme), Protéines mitochondriales (métabolisme), Protéines proto-oncogènes (métabolisme), Quinazolinones (pharmacologie), Récepteurs couplés aux protéines G (agonistes), Récepteurs couplés aux protéines G (métabolisme), dGTPases (métabolisme).
- MESH :
- agonistes : Récepteurs couplés aux protéines G.
- cytologie : Myocytes du muscle lisse, Poumon.
- métabolisme : Adénosine triphosphate, Mitochondries, Myocytes du muscle lisse, Petit ARN interférent, Protéines associées aux microtubules, Protéines membranaires, Protéines mitochondriales, Protéines proto-oncogènes, Récepteurs couplés aux protéines G, dGTPases.
- pharmacologie : Quinazolinones.
- Autophagie, Cellules cultivées, Dynamique mitochondriale, Goût, Gènes dominants, Humains, Mitochondries, Modèles biologiques, Mort cellulaire, Myocytes du muscle lisse, Potentiel de membrane mitochondriale.
English descriptors
- KwdEn :
- Adenosine Triphosphate (metabolism), Autophagy (drug effects), Cell Death, Cells, Cultured, GTP Phosphohydrolases (metabolism), Genes, Dominant, Humans, Lung (cytology), Membrane Potential, Mitochondrial (drug effects), Membrane Proteins (metabolism), Microtubule-Associated Proteins (metabolism), Mitochondria (drug effects), Mitochondria (metabolism), Mitochondrial Dynamics (drug effects), Mitochondrial Proteins (metabolism), Models, Biological, Myocytes, Smooth Muscle (cytology), Myocytes, Smooth Muscle (drug effects), Myocytes, Smooth Muscle (metabolism), Proto-Oncogene Proteins (metabolism), Quinazolinones (pharmacology), RNA, Small Interfering (metabolism), Receptors, G-Protein-Coupled (agonists), Receptors, G-Protein-Coupled (metabolism), Taste (drug effects).
- MESH :
- chemical , agonists : Receptors, G-Protein-Coupled.
- chemical , metabolism : Adenosine Triphosphate, GTP Phosphohydrolases, Membrane Proteins, Microtubule-Associated Proteins, Mitochondrial Proteins, Proto-Oncogene Proteins, RNA, Small Interfering, Receptors, G-Protein-Coupled.
- cytology : Lung, Myocytes, Smooth Muscle.
- drug effects : Autophagy, Membrane Potential, Mitochondrial, Mitochondria, Mitochondrial Dynamics, Myocytes, Smooth Muscle, Taste.
- metabolism : Mitochondria, Myocytes, Smooth Muscle.
- chemical , pharmacology : Quinazolinones.
- Cell Death, Cells, Cultured, Genes, Dominant, Humans, Models, Biological.
Abstract
Airway remodeling, including increased airway smooth muscle (ASM) mass, is a hallmark feature of asthma and COPD. We previously identified the expression of bitter taste receptors (TAS2Rs) on human ASM cells and demonstrated that known TAS2R agonists could promote ASM relaxation and bronchodilation and inhibit mitogen-induced ASM growth. In this study, we explored cellular mechanisms mediating the antimitogenic effect of TAS2R agonists on human ASM cells. Pretreatment of ASM cells with TAS2R agonists chloroquine and quinine resulted in inhibition of cell survival, which was largely reversed by bafilomycin A1, an autophagy inhibitor. Transmission electron microscope studies demonstrated the presence of double-membrane autophagosomes and deformed mitochondria. In ASM cells, TAS2R agonists decreased mitochondrial membrane potential and increased mitochondrial ROS and mitochondrial fragmentation. Inhibiting dynamin-like protein 1 (DLP1) reversed TAS2R agonist-induced mitochondrial membrane potential change and attenuated mitochondrial fragmentation and cell death. Furthermore, the expression of mitochondrial protein BCL2/adenovirus E1B 19-kDa protein-interacting protein 3 (Bnip3) and mitochondrial localization of DLP1 were significantly upregulated by TAS2R agonists. More importantly, inhibiting Bnip3 mitochondrial localization by dominant-negative Bnip3 significantly attenuated cell death induced by TAS2R agonist. Collectively the TAS2R agonists chloroquine and quinine modulate mitochondrial structure and function, resulting in ASM cell death. Furthermore, Bnip3 plays a central role in TAS2R agonist-induced ASM functional changes via a mitochondrial pathway. These findings further establish the cellular mechanisms of antimitogenic effects of TAS2R agonists and identify a novel class of receptors and pathways that can be targeted to mitigate airway remodeling as well as bronchoconstriction in obstructive airway diseases.
DOI: 10.1152/ajplung.00106.2017
PubMed: 28450286
Affiliations:
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Shah</name><affiliation wicri:level="2"><nlm:affiliation>Center for Translational Medicine, Jane and Leonard Korman Lung Center, Thomas Jefferson University, Philadelphia, Pennsylvania.</nlm:affiliation><country xml:lang="fr">États-Unis</country><placeName><region type="state">Pennsylvanie</region></placeName><wicri:cityArea>Center for Translational Medicine, Jane and Leonard Korman Lung Center, Thomas Jefferson University, Philadelphia</wicri:cityArea></affiliation></author><author><name sortKey="Deshpande, Deepak A" sort="Deshpande, Deepak A" uniqKey="Deshpande D" first="Deepak A" last="Deshpande">Deepak A. Deshpande</name><affiliation wicri:level="3"><nlm:affiliation>Center for Translational Medicine, Jane and Leonard Korman Lung Center, Thomas Jefferson University, Philadelphia, Pennsylvania deepak.deshpande@jefferson.edu.</nlm:affiliation><country wicri:rule="url">États-Unis</country><wicri:regionArea>Center for Translational Medicine, Jane and Leonard Korman Lung Center, Thomas Jefferson University, Philadelphia</wicri:regionArea><placeName><settlement type="city">Philadelphie</settlement><region type="state">Pennsylvanie</region></placeName></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PubMed</idno><date when="2017">2017</date><idno type="RBID">pubmed:28450286</idno><idno type="pmid">28450286</idno><idno type="doi">10.1152/ajplung.00106.2017</idno><idno type="wicri:Area/PubMed/Corpus">000165</idno><idno type="wicri:explorRef" wicri:stream="PubMed" wicri:step="Corpus" wicri:corpus="PubMed">000165</idno><idno type="wicri:Area/PubMed/Curation">000165</idno><idno type="wicri:explorRef" wicri:stream="PubMed" wicri:step="Curation">000165</idno><idno type="wicri:Area/PubMed/Checkpoint">000178</idno><idno type="wicri:explorRef" wicri:stream="Checkpoint" wicri:step="PubMed">000178</idno><idno type="wicri:Area/Ncbi/Merge">000386</idno><idno type="wicri:Area/Ncbi/Curation">000386</idno><idno type="wicri:Area/Ncbi/Checkpoint">000386</idno><idno type="wicri:Area/Main/Merge">000D27</idno><idno type="wicri:Area/Main/Curation">000D27</idno><idno type="wicri:Area/Main/Exploration">000D27</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en">Bitter taste receptor agonists alter mitochondrial function and induce autophagy in airway smooth muscle cells.</title><author><name sortKey="Pan, Shi" sort="Pan, Shi" uniqKey="Pan S" first="Shi" last="Pan">Shi Pan</name><affiliation wicri:level="2"><nlm:affiliation>Center for Translational Medicine, Jane and Leonard Korman Lung Center, Thomas Jefferson University, Philadelphia, Pennsylvania.</nlm:affiliation><country xml:lang="fr">États-Unis</country><placeName><region type="state">Pennsylvanie</region></placeName><wicri:cityArea>Center for Translational Medicine, Jane and Leonard Korman Lung Center, Thomas Jefferson University, Philadelphia</wicri:cityArea></affiliation></author><author><name sortKey="Sharma, Pawan" sort="Sharma, Pawan" uniqKey="Sharma P" first="Pawan" last="Sharma">Pawan Sharma</name><affiliation wicri:level="2"><nlm:affiliation>Center for Translational Medicine, Jane and Leonard Korman Lung Center, Thomas Jefferson University, Philadelphia, Pennsylvania.</nlm:affiliation><country xml:lang="fr">États-Unis</country><placeName><region type="state">Pennsylvanie</region></placeName><wicri:cityArea>Center for Translational Medicine, Jane and Leonard Korman Lung Center, Thomas Jefferson University, Philadelphia</wicri:cityArea></affiliation></author><author><name sortKey="Shah, Sushrut D" sort="Shah, Sushrut D" uniqKey="Shah S" first="Sushrut D" last="Shah">Sushrut D. Shah</name><affiliation wicri:level="2"><nlm:affiliation>Center for Translational Medicine, Jane and Leonard Korman Lung Center, Thomas Jefferson University, Philadelphia, Pennsylvania.</nlm:affiliation><country xml:lang="fr">États-Unis</country><placeName><region type="state">Pennsylvanie</region></placeName><wicri:cityArea>Center for Translational Medicine, Jane and Leonard Korman Lung Center, Thomas Jefferson University, Philadelphia</wicri:cityArea></affiliation></author><author><name sortKey="Deshpande, Deepak A" sort="Deshpande, Deepak A" uniqKey="Deshpande D" first="Deepak A" last="Deshpande">Deepak A. Deshpande</name><affiliation wicri:level="3"><nlm:affiliation>Center for Translational Medicine, Jane and Leonard Korman Lung Center, Thomas Jefferson University, Philadelphia, Pennsylvania deepak.deshpande@jefferson.edu.</nlm:affiliation><country wicri:rule="url">États-Unis</country><wicri:regionArea>Center for Translational Medicine, Jane and Leonard Korman Lung Center, Thomas Jefferson University, Philadelphia</wicri:regionArea><placeName><settlement type="city">Philadelphie</settlement><region type="state">Pennsylvanie</region></placeName></affiliation></author></analytic><series><title level="j">American journal of physiology. Lung cellular and molecular physiology</title><idno type="eISSN">1522-1504</idno><imprint><date when="2017" type="published">2017</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Adenosine Triphosphate (metabolism)</term><term>Autophagy (drug effects)</term><term>Cell Death</term><term>Cells, Cultured</term><term>GTP Phosphohydrolases (metabolism)</term><term>Genes, Dominant</term><term>Humans</term><term>Lung (cytology)</term><term>Membrane Potential, Mitochondrial (drug effects)</term><term>Membrane Proteins (metabolism)</term><term>Microtubule-Associated Proteins (metabolism)</term><term>Mitochondria (drug effects)</term><term>Mitochondria (metabolism)</term><term>Mitochondrial Dynamics (drug effects)</term><term>Mitochondrial Proteins (metabolism)</term><term>Models, Biological</term><term>Myocytes, Smooth Muscle (cytology)</term><term>Myocytes, Smooth Muscle (drug effects)</term><term>Myocytes, Smooth Muscle (metabolism)</term><term>Proto-Oncogene Proteins (metabolism)</term><term>Quinazolinones (pharmacology)</term><term>RNA, Small Interfering (metabolism)</term><term>Receptors, G-Protein-Coupled (agonists)</term><term>Receptors, G-Protein-Coupled (metabolism)</term><term>Taste (drug effects)</term></keywords><keywords scheme="KwdFr" xml:lang="fr"><term>Adénosine triphosphate (métabolisme)</term><term>Autophagie ()</term><term>Cellules cultivées</term><term>Dynamique mitochondriale ()</term><term>Goût ()</term><term>Gènes dominants</term><term>Humains</term><term>Mitochondries ()</term><term>Mitochondries (métabolisme)</term><term>Modèles biologiques</term><term>Mort cellulaire</term><term>Myocytes du muscle lisse ()</term><term>Myocytes du muscle lisse (cytologie)</term><term>Myocytes du muscle lisse (métabolisme)</term><term>Petit ARN interférent (métabolisme)</term><term>Potentiel de membrane mitochondriale ()</term><term>Poumon (cytologie)</term><term>Protéines associées aux microtubules (métabolisme)</term><term>Protéines membranaires (métabolisme)</term><term>Protéines mitochondriales (métabolisme)</term><term>Protéines proto-oncogènes (métabolisme)</term><term>Quinazolinones (pharmacologie)</term><term>Récepteurs couplés aux protéines G (agonistes)</term><term>Récepteurs couplés aux protéines G (métabolisme)</term><term>dGTPases (métabolisme)</term></keywords><keywords scheme="MESH" type="chemical" qualifier="agonists" xml:lang="en"><term>Receptors, G-Protein-Coupled</term></keywords><keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>Adenosine Triphosphate</term><term>GTP Phosphohydrolases</term><term>Membrane Proteins</term><term>Microtubule-Associated Proteins</term><term>Mitochondrial Proteins</term><term>Proto-Oncogene Proteins</term><term>RNA, Small Interfering</term><term>Receptors, G-Protein-Coupled</term></keywords><keywords scheme="MESH" qualifier="agonistes" xml:lang="fr"><term>Récepteurs couplés aux protéines G</term></keywords><keywords scheme="MESH" qualifier="cytologie" xml:lang="fr"><term>Myocytes du muscle lisse</term><term>Poumon</term></keywords><keywords scheme="MESH" qualifier="cytology" xml:lang="en"><term>Lung</term><term>Myocytes, Smooth Muscle</term></keywords><keywords scheme="MESH" qualifier="drug effects" xml:lang="en"><term>Autophagy</term><term>Membrane Potential, Mitochondrial</term><term>Mitochondria</term><term>Mitochondrial Dynamics</term><term>Myocytes, Smooth Muscle</term><term>Taste</term></keywords><keywords scheme="MESH" qualifier="metabolism" xml:lang="en"><term>Mitochondria</term><term>Myocytes, Smooth Muscle</term></keywords><keywords scheme="MESH" qualifier="métabolisme" xml:lang="fr"><term>Adénosine triphosphate</term><term>Mitochondries</term><term>Myocytes du muscle lisse</term><term>Petit ARN interférent</term><term>Protéines associées aux microtubules</term><term>Protéines membranaires</term><term>Protéines mitochondriales</term><term>Protéines proto-oncogènes</term><term>Récepteurs couplés aux protéines G</term><term>dGTPases</term></keywords><keywords scheme="MESH" qualifier="pharmacologie" xml:lang="fr"><term>Quinazolinones</term></keywords><keywords scheme="MESH" type="chemical" qualifier="pharmacology" xml:lang="en"><term>Quinazolinones</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Cell Death</term><term>Cells, Cultured</term><term>Genes, Dominant</term><term>Humans</term><term>Models, Biological</term></keywords><keywords scheme="MESH" xml:lang="fr"><term>Autophagie</term><term>Cellules cultivées</term><term>Dynamique mitochondriale</term><term>Goût</term><term>Gènes dominants</term><term>Humains</term><term>Mitochondries</term><term>Modèles biologiques</term><term>Mort cellulaire</term><term>Myocytes du muscle lisse</term><term>Potentiel de membrane mitochondriale</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Airway remodeling, including increased airway smooth muscle (ASM) mass, is a hallmark feature of asthma and COPD. We previously identified the expression of bitter taste receptors (TAS2Rs) on human ASM cells and demonstrated that known TAS2R agonists could promote ASM relaxation and bronchodilation and inhibit mitogen-induced ASM growth. In this study, we explored cellular mechanisms mediating the antimitogenic effect of TAS2R agonists on human ASM cells. Pretreatment of ASM cells with TAS2R agonists chloroquine and quinine resulted in inhibition of cell survival, which was largely reversed by bafilomycin A1, an autophagy inhibitor. Transmission electron microscope studies demonstrated the presence of double-membrane autophagosomes and deformed mitochondria. In ASM cells, TAS2R agonists decreased mitochondrial membrane potential and increased mitochondrial ROS and mitochondrial fragmentation. Inhibiting dynamin-like protein 1 (DLP1) reversed TAS2R agonist-induced mitochondrial membrane potential change and attenuated mitochondrial fragmentation and cell death. Furthermore, the expression of mitochondrial protein BCL2/adenovirus E1B 19-kDa protein-interacting protein 3 (Bnip3) and mitochondrial localization of DLP1 were significantly upregulated by TAS2R agonists. More importantly, inhibiting Bnip3 mitochondrial localization by dominant-negative Bnip3 significantly attenuated cell death induced by TAS2R agonist. Collectively the TAS2R agonists chloroquine and quinine modulate mitochondrial structure and function, resulting in ASM cell death. Furthermore, Bnip3 plays a central role in TAS2R agonist-induced ASM functional changes via a mitochondrial pathway. These findings further establish the cellular mechanisms of antimitogenic effects of TAS2R agonists and identify a novel class of receptors and pathways that can be targeted to mitigate airway remodeling as well as bronchoconstriction in obstructive airway diseases.</div></front></TEI><affiliations><list><country><li>États-Unis</li></country><region><li>Pennsylvanie</li></region><settlement><li>Philadelphie</li></settlement></list><tree><country name="États-Unis"><region name="Pennsylvanie"><name sortKey="Pan, Shi" sort="Pan, Shi" uniqKey="Pan S" first="Shi" last="Pan">Shi Pan</name></region><name sortKey="Deshpande, Deepak A" sort="Deshpande, Deepak A" uniqKey="Deshpande D" first="Deepak A" last="Deshpande">Deepak A. Deshpande</name><name sortKey="Shah, Sushrut D" sort="Shah, Sushrut D" uniqKey="Shah S" first="Sushrut D" last="Shah">Sushrut D. Shah</name><name sortKey="Sharma, Pawan" sort="Sharma, Pawan" uniqKey="Sharma P" first="Pawan" last="Sharma">Pawan Sharma</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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