Mechanisms of cell death pathway activation following drug-induced inhibition of mitochondrial complex I.
Mechanisms of cell death pathway activation following drug-induced inhibition of mitochondrial complex I.
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DOI：
10.1016/j.redox.2015.01.005
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发表时间：
2015
期刊：
影响因子：
11.4
通讯作者：
Boelsterli, Urs A.
中科院分区：
文献类型：
--
作者：
Imaizumi, Naoki;Lee, Kang Kwang;Zhang, Carmen;Boelsterli, Urs A.
药物和其他化学物质对呼吸复合物I的抑制已被认为是呼吸道介导的细胞损伤的常见模式。然而，导致细胞死亡途径激活的确切机制尚不完全清楚。本研究旨在探索复合物I抑制的三种不同后果对细胞损伤的相对贡献，即，ATP生物合成的损害，超氧化物的形成增加，因此，过氧亚硝酸盐，和线粒体蛋白脱乙酰酶，Sirt 3的抑制，由于NADH/NAD+比率的不平衡。我们使用抗病毒药物依法韦仑（EFV）模型药物诱导的复合物I抑制。将培养的小鼠肝细胞暴露于EFV导致细胞损伤迅速发生，特征为30 µM EFV时无作用水平，50 µM EFV时次最大作用。EFV引起细胞ATP水平的浓度依赖性降低。此外，EFV导致过氧亚硝酸盐的形成增加和线粒体蛋白硫醇的氧化，包括亲环素D（CypD）。这通过超氧化物清除剂Fe-TCP或过氧亚硝酸盐分解催化剂Fe-TMPyP来防止。这两种铁卟啉完全保护EFV诱导的细胞损伤，表明过氧亚硝酸盐的细胞损伤。最后，EFV增加了NADH/NAD+比率，抑制Sirt 3活性，并导致超乙酰化的赖氨酸残基，包括CypD中的那些。然而，与野生型对照相比，从Sirt 3缺失小鼠中分离的肝细胞对40 µM EFV具有保护作用。总之，这些数据是兼容的概念，化学抑制复合物I激活多种途径导致细胞损伤，其中，过氧亚硝酸盐的形成可能是最关键的。抗病毒药物依法韦仑（EFV）诱导复合物I抑制。复合物I抑制引起ATP消耗、ROS/RNS形成和Sirt 3抑制。铁卟啉保护肝细胞免受EFV诱导的致死性损伤。Sirt 3的基因切除（Sirt 3 −/−小鼠）可保护EFV毒性。过氧亚硝酸盐的形成是介导细胞损伤的主要机制。
Respiratory complex I inhibition by drugs and other chemicals has been implicated as a frequent mode of mitochondria-mediated cell injury. However, the exact mechanisms leading to the activation of cell death pathways are incompletely understood. This study was designed to explore the relative contributions to cell injury of three distinct consequences of complex I inhibition, i.e., impairment of ATP biosynthesis, increased formation of superoxide and, hence, peroxynitrite, and inhibition of the mitochondrial protein deacetylase, Sirt3, due to imbalance of the NADH/NAD+ ratio. We used the antiviral drug efavirenz (EFV) to model drug-induced complex I inhibition. Exposure of cultured mouse hepatocytes to EFV resulted in a rapid onset of cell injury, featuring a no-effect level at 30 µM EFV and submaximal effects at 50 µM EFV. EFV caused a concentration-dependent decrease in cellular ATP levels. Furthermore, EFV resulted in increased formation of peroxynitrite and oxidation of mitochondrial protein thiols, including cyclophilin D (CypD). This was prevented by the superoxide scavenger, Fe-TCP, or the peroxynitrite decomposition catalyst, Fe-TMPyP. Both ferroporphyrins completely protected from EFV-induced cell injury, suggesting that peroxynitrite contributed to the cell injury. Finally, EFV increased the NADH/NAD+ ratio, inhibited Sirt3 activity, and led to hyperacetylated lysine residues, including those in CypD. However, hepatocytes isolated from Sirt3-null mice were protected against 40 µM EFV as compared to their wild-type controls. In conclusion, these data are compatible with the concept that chemical inhibition of complex I activates multiple pathways leading to cell injury; among these, peroxynitrite formation may be the most critical. The antiviral drug efavirenz (EFV) induces complex I inhibition. Complex I inhibition causes ATP depletion, ROS/RNS formation, and Sirt3 inhibition. Iron porphyrins protect hepatocytes against EFV-induced lethal injury. Genetic ablation of Sirt3 (Sirt3−/− mice) protects against EFV toxicity. Peroxynitrite formation is a major mechanism of mitochondria-mediated cell injury.
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影响因子：
4.8
作者：
Davey, GP;Peuchen, S;Clark, JB
通讯作者：
Clark, JB
影响因子：
3.4
作者：
Burger, D;van der Heiden, I;van Schaik, R
通讯作者：
van Schaik, R
影响因子：
7.7
作者：
Lu, Zhongping;Bourdi, Mohammed;Sack, Michael N.
通讯作者：
Sack, Michael N.
DOI：
10.1073/pnas.0508215102
发表时间：
2005-12-27
影响因子：
11.1
作者：
Perier, C;Tieu, K;Vila, M
通讯作者：
Vila, M
影响因子：
4.3
作者：
Chan, Katie;Truong, Don;O'Brien, Peter J
通讯作者：
O'Brien, Peter J