Propofol induces a metabolic switch to glycolysis and cell death in a mitochondrial electron transport chain-dependent manner.
Propofol induces a metabolic switch to glycolysis and cell death in a mitochondrial electron transport chain-dependent manner.
复制标题
DOI：
10.1371/journal.pone.0192796
复制
发表时间：
2018
期刊：
影响因子：
3.7
通讯作者：
Hirota K
中科院分区：
文献类型：
--
作者：
Sumi C;Okamoto A;Tanaka H;Nishi K;Kusunoki M;Shoji T;Uba T;Matsuo Y;Adachi T;Hayashi JI;Takenaga K;Hirota K
静脉麻醉剂丙泊酚（2，6-二异丙基苯酚）已被用于重症患者护理中的麻醉和镇静的诱导和维持。然而，可能发生罕见但严重的并发症丙泊酚输注综合征（PRIS），特别是在长时间接受高剂量丙泊酚的患者中。体内和体外研究表明，丙泊酚的毒性与线粒体功能受损有关。然而，潜在的分子机制仍然未知。因此，我们研究了丙泊酚对细胞代谢和死亡的影响，使用一系列已建立的细胞系的各种来源，包括神经元，肌细胞，和trans-mitochondrial cybrids，与定义的线粒体DNA缺陷。我们证明，不低于50 μM的丙泊酚的临床外浓度干扰线粒体功能，并通过靶向线粒体复合物I、II和III诱导从氧化磷酸化到糖酵解的代谢转换。线粒体电子传递的这种紊乱引起活性氧的产生，导致细胞凋亡。我们还发现，由基因突变或双胍类药物（如二甲双胍和苯丙氨酸）对电子传递链的药理学抑制引起的线粒体功能障碍倾向，促进了丙泊酚诱导的半胱天冬酶激活和不超过25 μM的临床相关浓度丙泊酚诱导的细胞死亡。通过进一步的实验与适当的体内模型，它是可能的过程，构成PRIS的分子基础被确定。
The intravenous anesthetic propofol (2,6-diisopropylphenol) has been used for the induction and maintenance of anesthesia and sedation in critical patient care. However, the rare but severe complication propofol infusion syndrome (PRIS) can occur, especially in patients receiving high doses of propofol for prolonged periods. In vivo and in vitro evidence suggests that the propofol toxicity is related to the impaired mitochondrial function. However, underlying molecular mechanisms remain unknown. Therefore, we investigated effects of propofol on cell metabolism and death using a series of established cell lines of various origins, including neurons, myocytes, and trans-mitochondrial cybrids, with defined mitochondrial DNA deficits. We demonstrated that supraclinical concentrations of propofol in not less than 50 μM disturbed the mitochondrial function and induced a metabolic switch, from oxidative phosphorylation to glycolysis, by targeting mitochondrial complexes I, II and III. This disturbance in mitochondrial electron transport caused the generation of reactive oxygen species, resulting in apoptosis. We also found that a predisposition to mitochondrial dysfunction, caused by a genetic mutation or pharmacological suppression of the electron transport chain by biguanides such as metformin and phenformin, promoted propofol-induced caspase activation and cell death induced by clinical relevant concentrations of propofol in not more than 25 μM. With further experiments with appropriate in vivo model, it is possible that the processes to constitute the molecular basis of PRIS are identified.
登录
查看更多内容
影响因子：
3.9
作者：
BRANCA, D;ROBERTI, MS;SCUTARI, G
通讯作者：
SCUTARI, G
影响因子：
2.1
作者：
Bains, R.;Moe, M. C.;Berg-Johnsen, J.
通讯作者：
Berg-Johnsen, J.
影响因子：
--
作者：
Cui, Wen-Yao;Liu, Yan;Wang, Qiu-Shi
通讯作者：
Wang, Qiu-Shi
影响因子：
56.9
作者：
Ishikawa, Kaori;Takenaga, Keizo;Hayashi, Jun-Ichi
通讯作者：
Hayashi, Jun-Ichi
影响因子：
4.8
作者：
El-Mir, MY;Nogueira, V;Leverve, X
通讯作者：
Leverve, X