HIF-1-mediated suppression of mitochondria electron transport chain function confers resistance to lidocaine-induced cell death
Abstract 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...
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Nature Portfolio
2017
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oai:doaj.org-article:294620230aa444ba9ef9c38cbfc88f432021-12-02T15:04:59ZHIF-1-mediated suppression of mitochondria electron transport chain function confers resistance to lidocaine-induced cell death10.1038/s41598-017-03980-72045-2322https://doaj.org/article/294620230aa444ba9ef9c38cbfc88f432017-06-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-03980-7https://doaj.org/toc/2045-2322Abstract 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.Akihisa OkamotoChisato SumiHiromasa TanakaMunenori KusunokiTeppei IwaiKenichiro NishiYoshiyuki MatsuoHiroshi HaradaKeizo TakenagaHidemasa BonoKiichi HirotaNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-14 (2017) |
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Medicine R Science Q Akihisa Okamoto Chisato Sumi Hiromasa Tanaka Munenori Kusunoki Teppei Iwai Kenichiro Nishi Yoshiyuki Matsuo Hiroshi Harada Keizo Takenaga Hidemasa Bono Kiichi Hirota HIF-1-mediated suppression of mitochondria electron transport chain function confers resistance to lidocaine-induced cell death |
| description |
Abstract 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. |
| format |
article |
| author |
Akihisa Okamoto Chisato Sumi Hiromasa Tanaka Munenori Kusunoki Teppei Iwai Kenichiro Nishi Yoshiyuki Matsuo Hiroshi Harada Keizo Takenaga Hidemasa Bono Kiichi Hirota |
| author_facet |
Akihisa Okamoto Chisato Sumi Hiromasa Tanaka Munenori Kusunoki Teppei Iwai Kenichiro Nishi Yoshiyuki Matsuo Hiroshi Harada Keizo Takenaga Hidemasa Bono Kiichi Hirota |
| author_sort |
Akihisa Okamoto |
| title |
HIF-1-mediated suppression of mitochondria electron transport chain function confers resistance to lidocaine-induced cell death |
| title_short |
HIF-1-mediated suppression of mitochondria electron transport chain function confers resistance to lidocaine-induced cell death |
| title_full |
HIF-1-mediated suppression of mitochondria electron transport chain function confers resistance to lidocaine-induced cell death |
| title_fullStr |
HIF-1-mediated suppression of mitochondria electron transport chain function confers resistance to lidocaine-induced cell death |
| title_full_unstemmed |
HIF-1-mediated suppression of mitochondria electron transport chain function confers resistance to lidocaine-induced cell death |
| title_sort |
hif-1-mediated suppression of mitochondria electron transport chain function confers resistance to lidocaine-induced cell death |
| publisher |
Nature Portfolio |
| publishDate |
2017 |
| url |
https://doaj.org/article/294620230aa444ba9ef9c38cbfc88f43 |
| work_keys_str_mv |
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