| Summary: | In cells, photosensitizer (PS) activation by visible light irradiation triggers reactive oxygen species (ROS) formation, followed by a cascade of cellular responses involving calcium (Ca<sup>2+</sup>) and other second messengers, resulting in cell demise. Cytotoxic effects spread to nearby cells not exposed to light by poorly characterized so-called “bystander effects”. To elucidate the mechanisms involved in bystander cell death, we used both genetically encoded biosensors and fluorescent dyes. In particular, we monitored the kinetics of interorganellar Ca<sup>2+</sup> transfer and the production of mitochondrial superoxide anion (O<sub>2</sub><sup>−</sup><b>∙</b>) and hydrogen peroxide (H<sub>2</sub>O<sub>2</sub>) in irradiated and bystander B16-F10 mouse melanoma cancer cells. We determined that focal PS photoactivation in a single cell triggers Ca<sup>2+</sup> release from the endoplasmic reticulum (ER) also in the surrounding nonexposed cells, paralleled by mitochondrial Ca<sup>2+</sup> uptake. Efficient Ca<sup>2+</sup> efflux from the ER was required to promote mitochondrial O<sub>2</sub><sup>−</sup><b>∙</b> production in these bystander cells. Our results support a key role for ER−mitochondria communication in the induction of ROS-mediated apoptosis in both direct and indirect photodynamical cancer cell killing.
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