HIF-1-mediated suppression of mitochondria electron transport chain function confers resistance to lidocaine-induced cell death.
HIF-1-mediated suppression of mitochondria electron transport chain function confers resistance to lidocaine-induced cell death.
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DOI：
10.1038/s41598-017-03980-7
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发表时间：
2017-06-19
影响因子：
4.6
通讯作者：
Hirota K
中科院分区：
文献类型：
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作者：
Okamoto A;Sumi C;Tanaka H;Kusunoki M;Iwai T;Nishi K;Matsuo Y;Harada H;Takenaga K;Bono H;Hirota K
局部麻醉剂利多卡因通过改变活性氧 (ROS) 的产生和线粒体电子传递链功能来诱导细胞死亡。由于缺氧诱导因子 1 (HIF-1) 参与决定氧代谢和线粒体功能，因此我们研究了 HIF-1 活性在利多卡因诱导的细胞死亡中的作用。我们研究了 HIF 激活对利多卡因诱导的 caspase 激活和缺乏功能性 von Hippel-Lindau (VHL) 蛋白的肾细胞来源的 RCC4 细胞死亡的作用。我们证明，HIF-1 以丙酮酸脱氢酶激酶 1 依赖性方式抑制氧消耗并促进糖酵解，并且 HIF-1 的激活赋予对利多卡因诱导的细胞死亡的抵抗力。我们还证明，通过 HIFα-羟化酶抑制或暴露于缺氧条件，外源性 HIF-1 激活不仅在 RCC4 细胞中，而且在神经元 SH-SY5Y 细胞中，通过抑制线粒体功能并产生 ROS 来减轻利多卡因毒性。总之，我们证明，VHL 缺失、小分子 HIFα-羟化酶抑制剂治疗以及暴露于缺氧条件导致的 HIF-1 激活会抑制线粒体呼吸链功能并赋予对利多卡因毒性的抵抗力。
The local anesthetic lidocaine induces cell death by altering reactive oxygen species (ROS) generation and mitochondrial electron transport chain function. Because hypoxia-inducible factor 1 (HIF-1) is involved in determining oxygen metabolism and mitochondria function, we investigated the involvement of HIF-1 activity in lidocaine-induced cell death. We investigated the role of HIF activation on lidocaine-induced caspase activation and cell death in renal cell-derived RCC4 cells lacking functional von Hippel-Lindau (VHL) protein. We demonstrate that HIF-1 suppressed oxygen consumption and facilitated glycolysis in a pyruvate dehydrogenase kinase-1-dependent manner and that activation of HIF-1 conferred resistance to lidocaine-induced cell death. We also demonstrated that exogenous HIF-1 activation, through HIFα-hydroxylase inhibition or exposure to hypoxic conditions, alleviates lidocaine toxicity by suppressing mitochondria function and generating ROS, not only in RCC4 cells, but also in the neuronal SH-SY5Y cells. In conclusion, we demonstrate that HIF-1 activation due to VHL deletion, treatment with small molecule HIFα-hydroxylase inhibitors, and exposure to hypoxic conditions suppresses mitochondrial respiratory chain function and confers resistance to lidocaine toxicity.