Diazoxide affects mitochondrial bioenergetics by the opening of mKATP channel on submicromolar scale
Abstract Background Cytoprotection afforded by mitochondrial ATP-sensitive K+-channel (mKATP-channel) opener diazoxide (DZ) largely depends on the activation of potassium cycle with eventual modulation of mitochondrial functions and ROS production. However, generally these effects were studied in th...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2020-04-01
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| Series: | BMC Molecular and Cell Biology |
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| Online Access: | http://link.springer.com/article/10.1186/s12860-020-00275-0 |
| _version_ | 1818843366278823936 |
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| author | Olga Akopova Liudmila Kolchinskaya Valentina Nosar Iryna Mankovska Vadim Sagach |
| author_facet | Olga Akopova Liudmila Kolchinskaya Valentina Nosar Iryna Mankovska Vadim Sagach |
| author_sort | Olga Akopova |
| collection | DOAJ |
| description | Abstract Background Cytoprotection afforded by mitochondrial ATP-sensitive K+-channel (mKATP-channel) opener diazoxide (DZ) largely depends on the activation of potassium cycle with eventual modulation of mitochondrial functions and ROS production. However, generally these effects were studied in the presence of Mg∙ATP known to block K+ transport. Thus, the purpose of our work was the estimation of DZ effects on K+ transport, K+ cycle and ROS production in rat liver mitochondria in the absence of Mg∙ATP. Results Without Mg·ATP, full activation of native mKATP-channel, accompanied by the increase in ATP-insensitive K+ uptake, activation of K+-cycle and respiratory uncoupling, was reached at ≤0.5 μM of DZ,. Higher diazoxide concentrations augmented ATP-insensitive K+ uptake, but not mKATP-channel activity. mKATP-channel was blocked by Mg·ATP, reactivated by DZ, and repeatedly blocked by mKATP-channel blockers glibenclamide and 5-hydroxydecanoate, whereas ATP-insensitive potassium transport was blocked by Mg2+ and was not restored by DZ. High sensitivity of potassium transport to DZ in native mitochondria resulted in suppression of mitochondrial ROS production caused by the activation of K+-cycle on sub-micromolar scale. Based on the oxygen consumption study, the share of mKATP-channel in respiratory uncoupling by DZ was found. Conclusions The study of mKATP-channel activation by diazoxide in the absence of MgATP discloses novel, not described earlier, aspects of mKATP-channel interaction with this drug. High sensitivity of mKATP-channel to DZ results in the modulation of mitochondrial functions and ROS production by DZ on sub-micromolar concentration scale. Our experiments led us to the hypothesis that under the conditions marked by ATP deficiency affinity of mKATP-channel to DZ can increase, which might contribute to the high effectiveness of this drug in cardio- and neuroprotection. |
| first_indexed | 2024-12-19T04:56:43Z |
| format | Article |
| id | doaj.art-01479c49d4eb4c4d8114b264c1dd9b28 |
| institution | Directory Open Access Journal |
| issn | 2661-8850 |
| language | English |
| last_indexed | 2024-12-19T04:56:43Z |
| publishDate | 2020-04-01 |
| publisher | BMC |
| record_format | Article |
| series | BMC Molecular and Cell Biology |
| spelling | doaj.art-01479c49d4eb4c4d8114b264c1dd9b282022-12-21T20:35:12ZengBMCBMC Molecular and Cell Biology2661-88502020-04-0121111410.1186/s12860-020-00275-0Diazoxide affects mitochondrial bioenergetics by the opening of mKATP channel on submicromolar scaleOlga Akopova0Liudmila Kolchinskaya1Valentina Nosar2Iryna Mankovska3Vadim Sagach4Circulation department, Bogomoletz Institute of Physiology, NAS of UkraineCirculation department, Bogomoletz Institute of Physiology, NAS of UkraineHypoxic States Research Department, Bogomoletz Institute of Physiology, NAS of UkraineHypoxic States Research Department, Bogomoletz Institute of Physiology, NAS of UkraineCirculation department, Bogomoletz Institute of Physiology, NAS of UkraineAbstract Background Cytoprotection afforded by mitochondrial ATP-sensitive K+-channel (mKATP-channel) opener diazoxide (DZ) largely depends on the activation of potassium cycle with eventual modulation of mitochondrial functions and ROS production. However, generally these effects were studied in the presence of Mg∙ATP known to block K+ transport. Thus, the purpose of our work was the estimation of DZ effects on K+ transport, K+ cycle and ROS production in rat liver mitochondria in the absence of Mg∙ATP. Results Without Mg·ATP, full activation of native mKATP-channel, accompanied by the increase in ATP-insensitive K+ uptake, activation of K+-cycle and respiratory uncoupling, was reached at ≤0.5 μM of DZ,. Higher diazoxide concentrations augmented ATP-insensitive K+ uptake, but not mKATP-channel activity. mKATP-channel was blocked by Mg·ATP, reactivated by DZ, and repeatedly blocked by mKATP-channel blockers glibenclamide and 5-hydroxydecanoate, whereas ATP-insensitive potassium transport was blocked by Mg2+ and was not restored by DZ. High sensitivity of potassium transport to DZ in native mitochondria resulted in suppression of mitochondrial ROS production caused by the activation of K+-cycle on sub-micromolar scale. Based on the oxygen consumption study, the share of mKATP-channel in respiratory uncoupling by DZ was found. Conclusions The study of mKATP-channel activation by diazoxide in the absence of MgATP discloses novel, not described earlier, aspects of mKATP-channel interaction with this drug. High sensitivity of mKATP-channel to DZ results in the modulation of mitochondrial functions and ROS production by DZ on sub-micromolar concentration scale. Our experiments led us to the hypothesis that under the conditions marked by ATP deficiency affinity of mKATP-channel to DZ can increase, which might contribute to the high effectiveness of this drug in cardio- and neuroprotection.http://link.springer.com/article/10.1186/s12860-020-00275-0DiazoxidePotassium transportmKATP-channelPotassium cycleMild uncouplingROS production |
| spellingShingle | Olga Akopova Liudmila Kolchinskaya Valentina Nosar Iryna Mankovska Vadim Sagach Diazoxide affects mitochondrial bioenergetics by the opening of mKATP channel on submicromolar scale BMC Molecular and Cell Biology Diazoxide Potassium transport mKATP-channel Potassium cycle Mild uncoupling ROS production |
| title | Diazoxide affects mitochondrial bioenergetics by the opening of mKATP channel on submicromolar scale |
| title_full | Diazoxide affects mitochondrial bioenergetics by the opening of mKATP channel on submicromolar scale |
| title_fullStr | Diazoxide affects mitochondrial bioenergetics by the opening of mKATP channel on submicromolar scale |
| title_full_unstemmed | Diazoxide affects mitochondrial bioenergetics by the opening of mKATP channel on submicromolar scale |
| title_short | Diazoxide affects mitochondrial bioenergetics by the opening of mKATP channel on submicromolar scale |
| title_sort | diazoxide affects mitochondrial bioenergetics by the opening of mkatp channel on submicromolar scale |
| topic | Diazoxide Potassium transport mKATP-channel Potassium cycle Mild uncoupling ROS production |
| url | http://link.springer.com/article/10.1186/s12860-020-00275-0 |
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