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p62 prevents carbonyl cyanide m-chlorophenyl hydrazine (CCCP)-induced apoptotic cell death by activating Nrf2

Jeong Su Park1, Dong Hoon Kang2, Soo Han Bae1

  • 1Severance Biomedical Science Institute, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul 120-752, South Korea; Yonsei Biomedical Research Institute, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul 120-752, South Korea.

Biochemical and Biophysical Research Communications
|July 26, 2015
PubMed

Insights

Carbonyl cyanide m-chlorophenyl hydrazone (CCCP) triggers cell death by increasing reactive oxygen species (ROS). This study reveals p62 protein is key in degrading Keap1, activating Nrf2, and protecting cells from oxidative stress.

Area of Science:

  • Cellular Biology
  • Molecular Mechanisms
  • Oxidative Stress

Background:

  • Carbonyl cyanide m-chlorophenyl hydrazone (CCCP) induces cell death via reactive oxygen species (ROS).
  • The Nrf2-Keap1 pathway is vital for cellular defense against ROS.
  • The precise regulation of Nrf2-Keap1 in CCCP-induced cell death remains unclear.

Purpose of the Study:

  • To elucidate the molecular mechanism of Nrf2-Keap1 pathway regulation during CCCP-induced cell death.
  • To investigate the role of p62 in CCCP-mediated cellular responses.

Main Methods:

  • Investigated CCCP's effect on Keap1 degradation and Nrf2 activation.
  • Assessed the involvement of autophagy and the p62 protein in this process.
  • Utilized p62 knockout models to evaluate cellular susceptibility to oxidative stress.

Main Results:

  • CCCP treatment promotes Keap1 degradation, leading to Nrf2 activation.
  • Keap1 degradation is partially dependent on autophagy and primarily relies on the adaptor protein p62.
  • Absence of p62 inhibited Keap1 degradation and Nrf2 activation, increasing ROS accumulation and oxidative stress susceptibility.

Conclusions:

  • p62 is crucial for CCCP-induced Keap1 degradation and subsequent Nrf2 activation.
  • p62 plays a protective role against oxidative stress by modulating the Nrf2-Keap1 pathway.
  • These findings highlight a novel mechanism of cellular defense against ROS-induced damage.
Keywords:
AutophagyCCCPKeap1Nrf2p62

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