Pandrangi Santhi L, Chittineedi Prasanthi, Manthari Ram K, Suhruth Balaji
Department of Life Sciences, School of Science, GITAM (Deemed to be) University, Visakhapatnam, India.
J Cell Physiol. 2024 Dec;239(12):e31421. doi: 10.1002/jcp.31421. Epub 2024 Aug 26.
By delivering the environmental inputs to transport nutrients and growth factors, Mechanistic Target of Rapamycin (mTOR) plays a significant role in the growth and metabolism of eukaryotic cells through the regulation of numerous elementary cellular processes such as autophagy, protein synthesis, via translation of mitochondrial protein transcription factor A mitochondrial, mitochondrial ribosomal proteins, and mitochondrial respiratory complexes I &V that are encoded in the nucleus with the help of translation initiation factor 4E-BP. These mitochondrial proteins are involved in cell signaling to regulate proper cell growth, proliferation, and death which are essential for tumor growth and proliferation. This suggests that tumor cells are dependent on mTORC1 for various metabolic pathways. However, this crucial regulator is activated and regulated by calcium homeostasis. Mounting evidence suggests the role of calcium ions in regulating mitochondrial enzymes and proteins. Hence, disrupting calcium homeostasis leads to calcium-dependent cell death called "Oxytosis" through hampering the expression of various mitochondrial proteins. "Oxytosis" is a novel non-apoptotic cell death characterized by glutamate cytotoxicity and ferritin degradation. The present review focuses on the crosstalk between mTORC1 and mitochondrial proteins in the cancer pathophysiology and the impact of calcium ions on disrupting mTORC1 leading to the induction of "Oxytosis."
通过传递环境输入以运输营养物质和生长因子，雷帕霉素机制靶点（mTOR）通过调节众多基本细胞过程，如自噬、蛋白质合成，在真核细胞的生长和代谢中发挥重要作用。蛋白质合成通过翻译线粒体蛋白转录因子A线粒体、线粒体核糖体蛋白以及线粒体呼吸复合体I和V来实现，这些蛋白由细胞核编码，并借助翻译起始因子4E-BP完成。这些线粒体蛋白参与细胞信号传导，以调节适当的细胞生长、增殖和死亡，而这些对于肿瘤的生长和增殖至关重要。这表明肿瘤细胞在各种代谢途径上依赖于mTORC1。然而，这个关键调节因子由钙稳态激活和调节。越来越多的证据表明钙离子在调节线粒体酶和蛋白质方面的作用。因此，破坏钙稳态会通过阻碍各种线粒体蛋白的表达导致称为“氧化应激诱导的细胞死亡（Oxytosis）”的钙依赖性细胞死亡。“氧化应激诱导的细胞死亡”是一种新型非凋亡性细胞死亡，其特征为谷氨酸细胞毒性和铁蛋白降解。本综述重点关注癌症病理生理学中mTORC1与线粒体蛋白之间的相互作用，以及钙离子对破坏mTORC1从而导致“氧化应激诱导的细胞死亡”的诱导作用。
