Muthukrishnan Nandhini, Johnson Gregory A, Lim Jongdoo, Simanek Eric E, Pellois Jean-Philippe
Department of Biochemistry and Biophysics, Texas A&M University, College Station, TX 77843, USA.
Biochim Biophys Acta. 2012 Nov;1820(11):1734-43. doi: 10.1016/j.bbagen.2012.06.020. Epub 2012 Jul 3.
Lysis of endocytic organelles is a necessary step in many cellular delivery methodologies. This is achieved efficiently in the photochemical internalization approach but the cell death that accompanies this process remains a problem.
We investigate the mechanisms of cell death that accompanies photochemical internalization of the fluorescent peptide TMR-TAT.
TMR-TAT kills cells after endocytosis and light irradiation. The lysis of endocytic organelles by TMR-TAT causes a rapid increase in the concentration of calcium in the cytosol. TMR-TAT co-localizes with endocytic organelles containing calcium prior to irradiation and photochemical internalization leads to the release of the lumenal content of these organelles. Ruthenium red and cyclosporin A, inhibitors of calcium import in mitochondria and of the mitochondria permeability transition pore, inhibit cell death.
TMR-TAT mediated photochemical internalization leads to a disruption of calcium homeostasis. The subsequent import of calcium in mitochondria is a causative factor of the cell death that accompanies photochemical internalization. General significance Understanding how the lysis of endocytic organelles affects cellular physiology and causes cell death is crucial to the development of optimal delivery methodologies.
在许多细胞递送方法中，内吞细胞器的裂解是一个必要步骤。在光化学内化方法中可有效实现这一点，但该过程伴随的细胞死亡仍是一个问题。
我们研究了荧光肽TMR-TAT光化学内化伴随的细胞死亡机制。
TMR-TAT在胞吞作用和光照后杀死细胞。TMR-TAT对内吞细胞器的裂解导致胞质溶胶中钙浓度迅速增加。在照射前，TMR-TAT与含有钙的内吞细胞器共定位，光化学内化导致这些细胞器腔内内容物的释放。线粒体钙摄取抑制剂钌红和环孢素A以及线粒体通透性转换孔抑制剂可抑制细胞死亡。
TMR-TAT介导的光化学内化导致钙稳态破坏。随后线粒体对钙的摄取是光化学内化伴随的细胞死亡的一个致病因素。一般意义了解内吞细胞器的裂解如何影响细胞生理学并导致细胞死亡对于开发最佳递送方法至关重要。
