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Mitochondrial photodamage and PDT-induced apoptosis
1Department of Pharmacology, Wayne State University School of Medicine, Detroit, MI 48201, USA. dhkessel@med.wayne.edu
Abstract:
Four photosensitizers with specific targets (mitochondria, lysosomes and plasma membrane) were used to delineate the mechanism of PDT-induced apoptosis in murine leukemia cells. Additional studies were carried out with two sensitizers which caused photodamage to both mitochondria and lysosomes, but varied with regard to membrane photodamage. PDT induced an apoptotic response after mitochondrial photodamage, but not after selective damage to lysosomes or to the cell membrane. Moreover, the latter could delay or inhibit the appearance of apoptosis after mitochondrial photodamage. We had previously reported that exposure of cells to high porphycene concentrations caused an apoptotic response in the dark; this was also associated with mitochondrial damage. These results are consistent with recent proposals that release of mitochondrial components can trigger an apoptotic response. ATP depletion after mitochondrial photodamage does not appear to play a role in initiation of the apoptotic program.
Insights
Photodynamic therapy (PDT) induces apoptosis in leukemia cells primarily through mitochondrial photodamage, not lysosome or plasma membrane damage. This mitochondrial damage, not ATP depletion, initiates the cell death pathway.
Area of Science:
- Cell Biology
- Cancer Research
- Photochemistry
Background:
- Photodynamic therapy (PDT) is a cancer treatment modality that uses photosensitizers and light to generate reactive oxygen species, leading to cell death.
- The precise mechanisms by which PDT induces apoptosis, a programmed cell death, in cancer cells are complex and involve various cellular targets.
- Previous research suggested that damage to mitochondria, lysosomes, or the plasma membrane could all contribute to PDT-induced cell death.
Purpose of the Study:
- To elucidate the specific cellular targets and mechanisms responsible for initiating apoptosis in murine leukemia cells following photodynamic therapy.
- To differentiate the roles of mitochondrial, lysosomal, and plasma membrane photodamage in the induction of apoptosis.
- To investigate the contribution of ATP depletion and mitochondrial damage to the apoptotic cascade.
Main Methods:
- Utilized four photosensitizers with distinct subcellular localizations (mitochondria, lysosomes, plasma membrane) in murine leukemia cells.
- Administered photodynamic therapy (PDT) and assessed the induction of apoptosis.
- Investigated the effects of selective photodamage to different cellular compartments and measured ATP levels.
Main Results:
- Photodynamic therapy (PDT) induced apoptosis specifically after mitochondrial photodamage.
- Selective photodamage to lysosomes or the plasma membrane did not trigger apoptosis.
- Damage to lysosomes or the plasma membrane could delay or inhibit apoptosis initiated by mitochondrial photodamage; ATP depletion was not implicated in initiating apoptosis.
Conclusions:
- Mitochondrial photodamage is the critical initiating event for PDT-induced apoptosis in murine leukemia cells.
- Lysosomal and plasma membrane photodamage are not sufficient to induce apoptosis and can interfere with the mitochondrial pathway.
- The findings support the hypothesis that the release of mitochondrial components triggers apoptosis, independent of significant ATP depletion.