Intracellular sites of photodamage as a factor in apoptotic cell death

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Abstract
The cytotoxic response to photodynamic therapy can involve apoptosis, necrosis or both. Using agents with known patterns of sub-cellular localization, we assessed different sites of photodamage as a determinant of cell death, using murine leukemia cells in vitro. Mitochondrial or mitochondrial + lysosomal photodamage led to a rapid apoptotic response, associated with the release of cytochrome c from mitochondria into the cytosol. This occurred immediately after irradiation of photosensitized cells. When photodamaged cells were warmed to 37 °C, there was a rapid apoptotic response. Lysosomal photodamage led to the immediate release of cathepsins and other proteolytic enzymes. During a subsequent incubation at 37 °C, there was a slow loss of the mitochondrial membrane potential, with cytochrome c appearing in the cytosol within 30 min. These effects derive from proteolytic effects of lysosomal enzymes on mitochondria. The apoptotic response to lysosomal photodamage was both slow and incomplete, with many non-viable cells not exhibiting apoptotic morphology. The latter result was correlated with photodamage to procaspase-3, an effect not observed when mitochondria were the predominant target for photodamage. Depending on the sub-cellular target, photodynamic therapy can either activate or inhibit critical elements of apoptosis.

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