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Proapoptotic BAX and BAK: a requisite gateway to mitochondrial dysfunction and death
1Howard Hughes Medical Institute, Departments of Pathology and Medicine, Harvard Medical School, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
Science (New York, N.Y.)
|April 28, 2001
Summary
The activation of BAX or BAK proteins is essential for initiating mitochondrial dysfunction and cell death. Cells lacking both BAX and BAK resist multiple apoptotic stimuli, highlighting their critical role in apoptosis.
Area of Science:
- Cell Biology
- Molecular Biology
- Biochemistry
Background:
- Mitochondrial dysfunction is a key event in apoptosis, but the initiating trigger remains unclear.
- The BH3-only protein tBID activates proapoptotic BAX or BAK, leading to cytochrome c release.
- The precise role of BAX and BAK in initiating mitochondrial apoptosis in vivo is not fully understood.
Purpose of the Study:
- To determine the critical initiating event for mitochondrial dysfunction during apoptosis.
- To investigate the essential role of BAX and BAK in tBID-induced apoptosis and other death stimuli.
- To elucidate the gateway mechanism for mitochondrial outer membrane permeabilization.
Main Methods:
- Utilized knockout cell models lacking Bax and/or Bak.
- Induction of apoptosis using various stimuli including tBID, staurosporine, UV radiation, and ER stress agents.
- Assessed cytochrome c release and cell viability to measure apoptosis.
Main Results:
- Cells lacking both Bax and Bak were completely resistant to tBID-induced cytochrome c release and apoptosis.
- Doubly deficient cells showed resistance to multiple apoptotic stimuli, including staurosporine, UV, growth factor deprivation, etoposide, thapsigargin, and tunicamycin.
- Single deficiency in Bax or Bak did not confer complete resistance.
Conclusions:
- Activation of either BAX or BAK is an essential gateway for mitochondrial dysfunction in apoptosis.
- BAX and BAK act as a critical convergence point for diverse apoptotic stimuli leading to cell death.
- These findings clarify the central role of BAX/BAK in initiating mitochondrial apoptosis in vivo.
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