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

 抽象的

巨自噬/自噬可以在恶性细胞光动力损伤后发挥细胞保护作用，具体取决于活性氧引发的亚细胞损伤的部位。当线粒体成为目标时，有证据表明存在这种保护。据报道，靶向溶酶体对于光杀伤更有效，这可能是因为自噬不提供细胞保护。然而，对溶酶体和线粒体的光动力损伤可以显着提高光杀伤的整体水平。已经提出了两种机制来解释这一结果。溶酶体光损伤导致钙离子释放，从而激活蛋白酶 CAPN（钙蛋白酶）。然后 CAPN 将 ATG5 切割成能够与线粒体相互作用以增强促凋亡信号的片段 (tATG5)。还有人提出，针对溶酶体进行光动力损伤可能会损害线粒体自噬，这一过程可以减轻线粒体靶向的促凋亡作用。抑制线粒体自噬所需的溶酶体光损伤水平尚不清楚。 “tATG5 途径”涉及 CAPN 的催化作用，由一定程度的溶酶体光损伤激活，而活性测定几乎无法检测到。内质网光损伤还可以引发细胞凋亡，这是一种即使在细胞凋亡受损且显然不受自噬影响的细胞类型中也能发挥作用的死亡途径。

缩写：ALLN：N-乙酰基-Leu-Leu-正亮氨酸（细胞渗透性钙蛋白酶抑制剂）； ATG：自噬相关； BPD：苯并卟啉衍生物（Visudyne）； ER：内质网； EtNBS：5-乙氨基-9-二乙氨基苯并[a]吩噻嗪氯化物； MTT：四唑鎓染料； NPe6：单N-天冬氨酰二氢卟酚e6； PDT：光动力疗法； ROS：活性氧