Repnik Urška, Hafner Česen Maruša, Turk Boris
Department of Biochemistry and Molecular and Structural Biology, Jožef Stefan Institute, Jamova 39, 1000 Ljubljana, Slovenia; Department of Biosciences, University of Oslo, Blindernveien 31, 0371 Oslo, Norway.
Department of Biochemistry and Molecular and Structural Biology, Jožef Stefan Institute, Jamova 39, 1000 Ljubljana, Slovenia.
Mitochondrion. 2014 Nov;19 Pt A:49-57. doi: 10.1016/j.mito.2014.06.006. Epub 2014 Jun 28.
Late endocytic compartments include late endosomes, lysosomes and hybrid organelles. In the acidic lumen, cargo material derived from endocytosed and phagocytosed extracellular material and autophagy-derived intracellular material is degraded. In the event of lysosomal membrane permeabilization (LMP), the function of endo/lysosomal compartment is affected and the luminal contents are released into the cytosol to various extents. LMP can be a result of osmotic lysis or direct membranolytic activity of the compounds that accumulate in the lumen of endo/lysosomes. In addition to several synthetic compounds, such as dipeptide methyl esters and lysosomotropic detergents, endogenous agents that can cause LMP include ROS and lipid metabolites such as sphingosine and phosphatidic acid. Depending on the cell type and the dose, LMP can initiate the lysosomal apoptotic pathway, pyroptosis or necrosis. LMP can also amplify cell death signaling that was initiated outside the endocytic compartment, and hamper cell recovery via autophagy. However, mechanisms that connect LMP with cell death signaling are poorly understood, with the exception of the proteolytic activation of Bid by aspartic cathepsin D and cysteine cathepsins. Determination of LMP in a cell model system is methodologically challenging. Even more difficult is to prove that LMP is the primary event leading to cell death. Nevertheless, LMP may prove to be a valuable approach in therapy, either as a trigger of cell death or as a mechanism of therapeutic drug release in the case of delivery systems that target the endocytic pathway.
晚期内吞区室包括晚期内体、溶酶体和混合细胞器。在酸性内腔中，源自内吞和吞噬的细胞外物质以及自噬衍生的细胞内物质的货物会被降解。如果溶酶体膜通透性增加（LMP），内吞/溶酶体区室的功能就会受到影响，腔内物质会不同程度地释放到细胞质中。LMP可能是由于在内吞/溶酶体腔内积累的化合物的渗透裂解或直接膜溶解活性导致的。除了几种合成化合物，如二肽甲酯和溶酶体促渗剂外，可导致LMP的内源性物质还包括活性氧（ROS）和脂质代谢物，如鞘氨醇和磷脂酸。根据细胞类型和剂量的不同，LMP可引发溶酶体凋亡途径、焦亡或坏死。LMP还可放大在内吞区室外部启动的细胞死亡信号，并通过自噬阻碍细胞恢复。然而，除了天冬氨酸组织蛋白酶D和半胱氨酸组织蛋白酶对Bid的蛋白水解激活外，将LMP与细胞死亡信号联系起来的机制还知之甚少。在细胞模型系统中测定LMP在方法上具有挑战性。更困难的是证明LMP是导致细胞死亡的主要事件。尽管如此，LMP可能被证明是一种有价值的治疗方法，要么作为细胞死亡的触发因素，要么作为靶向内吞途径的递送系统中治疗药物释放的机制。
