Bad targets the permeability transition pore independent of Bax or Bak to switch between Ca2+-dependent cell survival

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08:35

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Published on: October 5, 2012

Soumya Sinha Roy1, Muniswamy Madesh, Erika Davies

  • 1Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, PA 19107, USA.

Molecular Cell
|February 17, 2009
PubMed

Insights

Stress factors like ceramide alter mitochondrial calcium signaling, promoting cell death. This study reveals how dephosphorylated Bad protein sensitizes the mitochondrial permeability transition pore (PTP) to calcium, bypassing Bax/Bak proteins.

Area of Science:

  • Mitochondrial biology
  • Cellular signaling
  • Apoptosis

Background:

  • Calcium oscillations regulate mitochondrial energy metabolism and cell death.
  • Stress factors alter mitochondrial calcium signaling outcomes, but the mechanism is unclear.

Purpose of the Study:

  • To elucidate the mechanism by which stress factors induce a proapoptotic switch in mitochondrial calcium signaling.
  • To identify the key molecular players involved in sensitizing the mitochondrial permeability transition pore (PTP) to calcium.

Main Methods:

  • Genetic, biochemical, pharmacological, and functional approaches were employed.
  • Investigated the role of ceramide, staurosporine, PP2A, protein kinases A and C, and the BH3-only protein Bad.
  • Examined the involvement of Bcl-xL, VDAC, Bax, and Bak in the PTP sensitization process.

Main Results:

  • Ceramide and staurosporine target PP2A and protein kinases A/C in a mitochondria-associated complex.
  • This leads to dephosphorylation of the BH3-only protein Bad.
  • Dephosphorylated Bad sensitizes the PTP to Ca2+ via a Bcl-xL- and VDAC-dependent mechanism, independent of Bax/Bak.

Conclusions:

  • Phospho-regulatory mechanisms converge on Bad to switch mitochondrial calcium signaling between survival and apoptosis.
  • BH3-only protein Bad can directly engage the PTP, bypassing Bax/Bak.
  • This provides a novel mechanism for stress-induced apoptosis mediated by mitochondrial calcium signaling.

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