HIF-1-mediated suppression of mitochondria electron transport chain function confers resistance to lidocaine-induced cell death

• Okamoto, Akihisa

• Sumi, Chisato

• Tanaka, Hiromasa

• Kusunoki, Munenori

• Iwai, Teppei

• Nishi, Kenichiro

• Matsuo, Yoshiyuki

• Harada, Hiroshi

• Takenaga, Keizo

• Bono, Hidemasa

• Hirota, Kiichi

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.

Journal

• Scientific Reports

  Scientific Reports 7 3816-, 2017-06-19

  Springer Nature

Keywords

• Apoptosis
• Molecular medicine

Details

• CRID: 1050001335851929472
• NII Article ID: 120006364104
• ISSN: 20452322
• DOI: 10.1038/s41598-017-03980-7
• HANDLE: 2433/227899
• Web Site: https://www.nature.com/articles/s41598-017-03980-7.pdf
• Web Site: https://www.nature.com/articles/s41598-017-03980-7
• Text Lang: en
• Article Type: journal article
• Data Source:
  • IRDB
  • Crossref
  • CiNii Articles
  • KAKEN