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Bax and Bak function as the outer membrane component of the mitochondrial permeability pore in regulating necrotic

Jason Karch1, Jennifer Q Kwong, Adam R Burr

  • 1Department of Pediatrics , Cincinnati Children's Hospital Medical Center, University of Cincinnati , Cincinnati , United States.

Elife
|August 31, 2013
PubMed

Insights

The mitochondrial permeability transition pore (MPTP) is crucial for cell death. Bax and Bak proteins facilitate MPTP outer membrane opening, regulating necrotic cell death.

Area of Science:

  • Cell Biology
  • Biochemistry
  • Molecular Biology

Background:

  • The opening of the mitochondrial permeability transition pore (MPTP) is a key event in ischemia-induced cell death.
  • The precise molecular components of the MPTP have remained elusive.
  • Bcl-2 family proteins, particularly Bax and Bak, are known regulators of apoptosis.

Purpose of the Study:

  • To identify the molecular components of the MPTP involved in necrotic cell death.
  • To elucidate the role of Bax and Bak in MPTP-dependent cell death pathways.

Main Methods:

  • Investigated the role of Bax and Bak in MPTP opening using genetic loss-of-function approaches.
  • Assessed mitochondrial outer and inner membrane permeability and conductance.
  • Utilized Bax mutants to dissect the function of oligomerization versus outer membrane permeabilization.

Main Results:

  • Loss of Bax and Bak significantly reduced outer mitochondrial membrane permeability and conductance, but not inner membrane MPTP function.
  • Cells lacking Bax/Bak exhibited resistance to mitochondrial calcium overload and necrotic cell death.
  • Reconstitution with Bax mutants capable of outer membrane permeabilization, but not pore formation, restored MPTP-dependent mitochondrial swelling and necrotic cell death.

Conclusions:

  • The MPTP is regulated at the inner mitochondrial membrane.
  • Bax and Bak facilitate MPTP-dependent necrotic cell death by enabling outer membrane swelling.
  • The outer mitochondrial membrane acts as a barrier to prevent cell death in the absence of Bax/Bak.
Keywords:
Mousecell deathmitochondrianecrosis

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