Kritskaya Kristina A, Stelmashchuk Olga A, Abramov Andrey Y
Institute of Cell Biophysics of the Russian Academy of Sciences, Puschino, Russia.
Orel State University named after I.S. Turgenev, Orel, Russia.
J Cell Physiol. 2025 Jan;240(1):e31521. doi: 10.1002/jcp.31521.
Programmed cell death (apoptosis) is essential part of the process of tissue regeneration that also plays role in the mechanism of pathology. The phenomenon of fast and transient permeability of mitochondrial membranes by various triggers, known as permeability transition pore (mPTP) leads to the release of proapoptotic proteins and acts as an initial step in initiation of apoptosis. However, a role for mPTP was also suggested for physiology and it is unclear if there is a threshold in number of mitochondria with mPTP which induces cell death and how this mechanism is regulated in different tissues. Using simultaneous measurements of mitochondrial membrane potential and a fluorescent marker for caspase-3 activation we studied the number of mitochondria with calcium-induced mPTP opening necessary for induction of apoptosis in rat primary cortical neurons, astrocytes, fibroblasts, and cancer (BT-474) cells. The induction of apoptosis was correlated with 80%-90% mitochondrial signal loss in neural cells but only 35% in fibroblasts, and in BT-474 cancer cells over 90% of mitochondria opens mPTP before apoptosis becomes obvious. The number of mitochondria with mPTP which induce cell death did not correlate with total expression levels of proapoptotic proteins but was consistent with the Bax/Bcl-2 ratio in these cells. Calcium-induced mPTP opening increased levels of necrosis which was higher in fibroblasts compared to neurons, astrocytes and BT-474 cells. Thus, different tissues require specific numbers of mitochondria with PTP opening to induce apoptosis and it correlates to the proapoptotic/antiapoptotic proteins expression ratio in them.
程序性细胞死亡（凋亡）是组织再生过程的重要组成部分，在病理机制中也发挥作用。各种触发因素导致线粒体膜快速短暂通透的现象，即通透性转换孔（mPTP）的开放，会导致促凋亡蛋白的释放，并作为凋亡起始的第一步。然而，mPTP在生理过程中的作用也被提及，目前尚不清楚具有mPTP的线粒体数量是否存在一个阈值会诱导细胞死亡，以及该机制在不同组织中是如何被调节的。通过同时测量线粒体膜电位和半胱天冬酶 - 3激活的荧光标记物，我们研究了在大鼠原代皮质神经元、星形胶质细胞、成纤维细胞和癌细胞（BT - 474）中，钙诱导的mPTP开放诱导凋亡所需的具有mPTP的线粒体数量。凋亡的诱导与神经细胞中线粒体信号损失80% - 90%相关，但在成纤维细胞中仅为35%，而在BT - 474癌细胞中，超过90%的线粒体在凋亡明显之前就开放了mPTP。诱导细胞死亡的具有mPTP的线粒体数量与促凋亡蛋白的总表达水平无关，但与这些细胞中的Bax/Bcl - 2比值一致。钙诱导的mPTP开放增加了坏死水平，成纤维细胞中的坏死水平高于神经元、星形胶质细胞和BT - 474细胞。因此，不同组织诱导凋亡需要特定数量的具有PTP开放的线粒体，这与它们中促凋亡/抗凋亡蛋白的表达比例相关。
