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Examining BCL-2 Family Function with Large Unilamellar Vesicles
Published on: October 5, 2012
Evidence that bcl-2 is the target of three photosensitizers that induce a rapid apoptotic response
1Department of Pharmacology, Wayne State University School of Medicine, Detroit, MI 48201, USA. dhkessel@med.wayne.edu
Abstract:
We originally proposed that the subcellular target for one class of photosensitizing agents was the mitochondrion. This classification was based on effects that occur within minutes of irradiation of photosensitized cells: rapid loss of the mitochondrial membrane potential (delta psi m), release of cytochrome c into the cytosol and activation of caspase-3. These effects were followed by the appearance of an apoptotic morphology within 30-90 min. Fluorescence localization studies on three sensitizers initially classified as 'mitochondrial' revealed that these agents bind to a variety of intracellular membranes. The earliest detectable effect of photodamage is the selective loss of the antiapoptotic protein bcl-2 leaving the proapoptotic protein bax undamaged. Bcl-2 photodamage can be detected directly after irradiation of cells at 10 degrees C. Subsequent warming of cultures to 37 degrees C results in loss of delta psi m, release of cytochrome c and activation of caspase-3. The latter appears to amplify the other two effects. Based on results reported here we propose that the apoptotic response to these photosensitizers is derived from selective photodamage to the antiapoptotic protein bcl-2 while leaving the proapoptotic protein bax unaffected.
Insights
Photosensitizing agents induce apoptosis by damaging the antiapoptotic protein bcl-2, not mitochondria directly. This selective photodamage triggers cell death pathways, impacting mitochondrial membrane potential and cytochrome c release.
Area of Science:
- Cell Biology
- Biochemistry
- Photodynamic Therapy
Background:
- Mitochondria were previously identified as the primary subcellular target for photosensitizing agents.
- Observed rapid cellular responses included loss of mitochondrial membrane potential, cytochrome c release, and caspase-3 activation.
Purpose of the Study:
- To re-evaluate the subcellular targets of photosensitizing agents.
- To investigate the earliest molecular events following photosensitizer-mediated photodamage.
Main Methods:
- Fluorescence localization studies to determine sensitizer binding sites.
- Assessment of mitochondrial membrane potential (delta psi m) and cytochrome c release.
- Analysis of caspase-3 activation and apoptotic morphology.
- Direct detection of photodamage to specific proteins (bcl-2, bax) at low temperatures.
Main Results:
- Photosensitizers bind to various intracellular membranes, not exclusively mitochondria.
- Earliest photodamage selectively affects the antiapoptotic protein bcl-2, leaving bax intact.
- Subsequent warming initiates mitochondrial dysfunction (loss of delta psi m, cytochrome c release) and caspase-3 activation.
- Caspase-3 activation appears to amplify the observed mitochondrial effects.
Conclusions:
- The apoptotic response to these photosensitizers originates from selective photodamage to bcl-2.
- Mitochondrial dysfunction is a downstream consequence of bcl-2 photodamage, not the primary event.
- This finding refines the understanding of photosensitizer mechanisms in inducing apoptosis.
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