Impairment of mitochondrial function by minocycline
Impairment of mitochondrial function by minocycline
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DOI：
10.1111/j.1742-4658.2009.06904.x
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发表时间：
2009-03-01
期刊：
影响因子：
5.4
通讯作者：
Schoenfeld, Peter
中科院分区：
文献类型：
--
作者：
Kupsch, Kathleen;Hertel, Silvia;Schoenfeld, Peter
米诺环素(MC)是一种四环素类抗生素，在促进线粒体介导的细胞凋亡的条件下，对于保存线粒体功能是否存在有益的影响，一直存在争议。在这里，我们提出了一个多参数的研究，MC对悬浮在KCl基或蔗糖基介质中的分离的大鼠肝线粒体(RLM)的影响。我们发现，所用的孵育液对RLM对MC的反应有很大的影响。在以KCl为基础的培养液中，MC可引起线粒体肿胀和细胞色素c的释放，而在蔗糖为基础的培养液中则不能。MC依赖的肿胀与线粒体去极化和状态3的降低以及解偶联呼吸有关。RLm在KCl基介质中的溶胀表明MC能使线粒体内膜(IMM)通透K(+)和Cl(-)。这一观点被我们的发现所支持，即MC在KCl基介质中引起的肿胀被N，N‘-二环己基碳二亚胺(IMM连接的K(+)转运的抑制剂)和三丁基锡(内膜阴离子通道的抑制剂)部分抑制，而当RLM悬浮在以氯化胆碱为基础的介质中时，肿胀不那么明显。此外，我们观察到MC诱导的RLM内源性镁(2+)的快速耗尽，这一事件被认为激活了IMM内的离子传导通路。此外，无论使用何种孵育介质，MC都可通过触发通透性转变来取消RLm的钙保持能力。综上所述，我们发现低微摩尔浓度的MC在体外损害了线粒体的几个能量依赖功能。
There is an ongoing debate on the presence of beneficial effects of minocycline (MC), a tetracycline-like antibiotic, on the preservation of mitochondrial functions under conditions promoting mitochondria-mediated apoptosis. Here, we present a multiparameter study on the effects of MC on isolated rat liver mitochondria (RLM) suspended either in a KCl-based or in a sucrose-based medium. We found that the incubation medium used strongly affects the response of RLM to MC. In KCl-based medium, but not in sucrose-based medium, MC triggered mitochondrial swelling and cytochrome c release. MC-dependent swelling was associated with mitochondrial depolarization and a decrease in state 3 as well as uncoupled respiration. Swelling of RLM in KCl-based medium indicates that MC permeabilizes the inner mitochondrial membrane (IMM) to K(+) and Cl(-). This view is supported by our findings that MC-induced swelling in the KCl-based medium was partly suppressed by N, N'-dicyclohexylcarbodiimide (an inhibitor of IMM-linked K(+)-transport) and tributyltin (an inhibitor of the inner membrane anion channel) and that swelling was less pronounced when RLM were suspended in choline chloride-based medium. In addition, we observed a rapid MC-induced depletion of endogenous Mg(2+) from RLM, an event that is known to activate ion-conducting pathways within the IMM. Moreover, MC abolished the Ca(2+) retention capacity of RLM irrespective of the incubation medium used, most likely by triggering permeability transition. In summary, we found that MC at low micromolar concentrations impairs several energy-dependent functions of mitochondria in vitro.