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Diazoxide affects mitochondrial bioenergetics by the opening of mKATP channel on submicromolar scale.
BMC Molecular and Cell Biology ( IF 2.4 ) Pub Date : 2020-04-19 , DOI: 10.1186/s12860-020-00275-0
Olga Akopova 1 , Liudmila Kolchinskaya 1 , Valentina Nosar 2 , Iryna Mankovska 2 , Vadim Sagach 1
Affiliation  

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.

中文翻译:

二氮嗪通过打开亚微摩尔级的mKATP通道来影响线粒体生物能。

背景技术线粒体ATP敏感的K +通道(mKATP通道)开放剂二氮嗪(DZ)提供的细胞保护作用很大程度上取决于钾循环的激活,最终调节线粒体功能和ROS的产生。但是,通常在已知会阻止K +转运的Mg∙ATP存在下研究这些作用。因此,我们的工作目的是在缺乏Mg∙ATP的情况下估算DZ对大鼠肝线粒体中K +转运,K +循环和ROS产生的影响。结果在没有Mg·ATP的情况下,DZ≤0.5μM时,天然mKATP通道完全激活,伴随着对ATP不敏感的K +吸收增加,K +循环激活和呼吸解偶联。较高的重氮氧化物浓度会增加ATP敏感性K +吸收,但不会增加mKATP通道活性。mKATP通道被Mg·ATP阻断,被DZ激活,并被mKATP通道阻滞剂glibenclamide和5-羟基癸酸酯反复阻滞,而对ATP不敏感的钾转运被Mg2 +阻滞,而未被DZ恢复。钾转运对天然线粒体中DZ的高敏感性导致抑制亚线粒体K +循环激活引起的线粒体ROS产生。根据耗氧量研究,发现DZ在呼吸解耦中mKATP通道的份额。结论在不存在MgATP的情况下,二氮嗪对mKATP通道激活的研究揭示了mKATP通道与该药物相互作用的新颖方面,但未在前面进行描述。mKATP通道对DZ的高敏感性导致亚微摩尔浓度范围内DZ调节线粒体功能和产生ROS。
更新日期:2020-04-22
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