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Assessment of Open Probability of the Mitochondrial Permeability Transition Pore in the Setting of Coenzyme Q Excess
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Assessment of Open Probability of the Mitochondrial Permeability Transition Pore in the Setting of Coenzyme Q Excess

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The mitochondrial permeability transition regulates cytochrome c release for apoptosis during endoplasmic reticulum

Dawei Zhang1, Chao Lu2, Matthew Whiteman3

  • 1Department of Biochemistry, National University of Singapore, Singapore 117597, Singapore; Institute of Bioengineering and Nanotechnology, Singapore 138669, Singapore.

The Journal of Biological Chemistry
|December 7, 2007
PubMed

Insights

The mitochondrial permeability transition (MPT) regulates apoptosis during endoplasmic reticulum stress by remodeling cristae junctions. This process is essential for releasing cytochrome c and depends on the mitochondrial electron transport chain.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Biochemistry

Background:

  • The role of the mitochondrial permeability transition (MPT) in cell death pathways like apoptosis and necrosis remains debated.
  • Endoplasmic reticulum (ER) stress is a cellular condition with significant implications for cell fate and disease.

Purpose of the Study:

  • To investigate the precise role of MPT in apoptosis induced by ER stress.
  • To elucidate the molecular mechanisms by which MPT influences the release of key apoptotic factors.

Main Methods:

  • Utilized various cell lines (CEM, HCT116, murine embryo fibroblasts) treated with the ER stressor thapsigargin (THG).
  • Employed RNA interference (RNAi) to knock down Bax expression.
  • Performed experiments on isolated mitochondria to assess MPT-dependent release.
  • Investigated the role of mitochondrial electron transport chain and reactive oxygen species (ROS).

Main Results:

  • THG treatment induced cyclophilin D-dependent release of optic atrophy 1 (OPA1) and cytochrome c, leading to apoptosis.
  • Bax was essential for cytochrome c release mediated by MPT, but not for the MPT itself.
  • MPT-induced release of OPA1 and cytochrome c occurred independently of the outer mitochondrial membrane, identifying MPT as an inner membrane event.
  • MPT was regulated by the mitochondrial electron transport chain, but not by mitochondrial ROS.

Conclusions:

  • MPT remodeling of cristae junctions is a critical step for cytochrome c release and apoptosis during ER stress.
  • The mitochondrial electron transport chain is indispensable for MPT-mediated apoptosis.
  • These findings clarify the controversial role of MPT in programmed cell death.

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