Photodynamic therapy: autophagy and mitophagy, apoptosis and paraptosis
David Kessel1, John J Reiners1,2
1Department of Pharmacology, School of Medicine.
Abstract:
Macroautophagy/autophagy can play a cytoprotective role after photodynamic damage to malignant cells, depending on the site of subcellular damage initiated by reactive oxygen species. There is evidence for such protection when mitochondria are among the targets. Targeting lysosomes has been reported to be more effective for photokilling, perhaps because autophagy offers no cytoprotection. Photodynamic damage to both lysosomes and mitochondria can, however, markedly enhance the overall level of photokilling. Two mechanisms have been proposed to account for this result. Lysosomal photodamage leads to the release of calcium ions, resulting in the activation of the protease CAPN (calpain). CAPN then cleaves ATG5 to a fragment (tATG5) capable of interacting with mitochondria to enhance pro-apoptotic signals. It has also been proposed that targeting lysosomes for photodynamic damage can impair mitophagy, a process that could mitigate the pro-apoptotic effects of mitochondrial targeting. The level of lysosomal photodamage required for suppression of mitophagy is unclear. The "tATG5 route" involves the catalytic action of CAPN, activated by a degree of lysosomal photodamage barely detectible by a viability assay. ER photodamage can also initiate paraptosis, a death pathway functional even in cell types with impaired apoptosis and apparently unaffected by autophagy. Abbreviations: ALLN: N-acetyl-Leu-Leu-norleucinal (cell-permeable inhibitor of calpain); ATG: autophagy related; BPD: benzoporphyrin derivative (Visudyne); ER: endoplasmic reticulum; EtNBS: 5-ethylamino-9-diethyl-aminobenzo[a]phenothiazinium chloride; MTT: a tetrazolium dye; NPe6: mono N-aspartyl chlorin e6; PDT: photodynamic therapy; ROS: reactive oxygen species.
Insights
Autophagy protects malignant cells from photodynamic therapy (PDT) when mitochondria are damaged. Targeting lysosomes enhances photokilling by activating calpain (CAPN) and impairing mitophagy, leading to cell death.
Area of Science:
- Cellular Biology
- Molecular Mechanisms of Cell Death
- Photodynamic Therapy Research
Background:
- Macroautophagy/autophagy can protect malignant cells from photodynamic damage, particularly when mitochondria are targeted.
- Lysosome targeting in photodynamic therapy (PDT) may be more effective for cell killing, potentially due to autophagy's limited cytoprotective role.
- Simultaneous photodynamic damage to both lysosomes and mitochondria significantly enhances overall photokilling efficacy.
Purpose of the Study:
- To investigate the mechanisms underlying enhanced photokilling when lysosomes and mitochondria are co-targeted.
- To elucidate the role of calpain (CAPN) activation and ATG5 cleavage in response to lysosomal photodamage.
- To explore the impact of lysosomal photodamage on mitophagy and its implications for apoptosis.
Main Methods:
- Utilizing photodynamic damage to selectively target mitochondria and lysosomes in malignant cells.
- Assessing the activation of calpain (CAPN) and cleavage of ATG5 following lysosomal photodamage.
- Evaluating the effects of lysosomal photodamage on mitophagy and the induction of pro-apoptotic signals.
- Investigating paraptosis induction by endoplasmic reticulum (ER) photodamage.
Main Results:
- Lysosomal photodamage, even at low levels, activates calpain (CAPN), which cleaves ATG5 to tATG5, enhancing pro-apoptotic signals via mitochondrial interaction.
- Targeting lysosomes can impair mitophagy, potentially mitigating the pro-apoptotic effects of mitochondrial targeting.
- Endoplasmic reticulum (ER) photodamage can trigger paraptosis, a cell death pathway independent of autophagy and functional in cells with impaired apoptosis.
Conclusions:
- The interplay between lysosomal damage, calpain (CAPN) activation, ATG5 cleavage, and mitophagy significantly influences the outcome of photodynamic therapy (PDT).
- Lysosomal targeting can potentiate cancer cell killing by disrupting autophagy-related cytoprotective mechanisms and promoting apoptosis.
- Paraptosis represents an alternative cell death pathway activated by ER photodamage, offering a potential therapeutic strategy for resistant cancers.
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