Department of Experimental and Diagnostic Medicine, Section of General Pathology, Interdisciplinary Center for the Study of Inflammation (ICSI), Laboratory for Technologies of Advanced Therapies (LTTA), University of Ferrara, Ferrara, Italy.
Cell Death Dis. 2012 May 3;3(5):e304. doi: 10.1038/cddis.2012.45.
Ca²⁺ transfer from endoplasmic reticulum (ER) to mitochondria can trigger apoptotic pathways by inducing release of mitochondrial pro-apoptotic factors. Three different types of inositol 1,4,5-trisphosphate receptor (IP₃R) serve to discharge Ca²⁺ from ER, but possess some peculiarities, especially in apoptosis induction. The anti-apoptotic protein Akt can phosphorylate all IP₃R isoforms and protect cells from apoptosis, reducing ER Ca²⁺ release. However, it has not been elucidated which IP₃R subtypes mediate these effects. Here, we show that Akt activation in COS7 cells, which lack of IP₃R I, strongly suppresses IP₃-mediated Ca²⁺ release and apoptosis. Conversely, in SH-SY 5Y cells, which are type III-deficient, Akt is unable to modulate ER Ca²⁺ flux, losing its anti-apoptotic activity. In SH-SY 5Y-expressing subtype III, Akt recovers its protective function on cell death, by reduction of Ca²⁺ release. Moreover, regulating Ca²⁺ flux to mitochondria, Akt maintains the mitochondrial integrity and delays the trigger of apoptosis, in a type III-dependent mechanism. These results demonstrate a specific activity of Akt on IP₃R III, leading to diminished Ca²⁺ transfer to mitochondria and protection from apoptosis, suggesting an additional level of cell death regulation mediated by Akt.
内质网 (ER) 中的 Ca²⁺转移到线粒体可以通过诱导线粒体促凋亡因子的释放来触发凋亡途径。三种不同类型的肌醇 1,4,5-三磷酸受体 (IP₃R) 可用于从 ER 中排出 Ca²⁺，但具有一些特性，尤其是在诱导凋亡方面。抗凋亡蛋白 Akt 可以磷酸化所有 IP₃R 同工型并保护细胞免受凋亡，从而减少 ER Ca²⁺释放。然而，尚未阐明哪种 IP₃R 亚型介导这些作用。在这里，我们表明在缺乏 IP₃R I 的 COS7 细胞中 Akt 的激活强烈抑制 IP₃ 介导的 Ca²⁺释放和凋亡。相反，在 SH-SY 5Y 细胞中，Akt 无法调节 ER Ca²⁺通量，从而失去其抗凋亡活性。在表达亚型 III 的 SH-SY 5Y 细胞中，Akt 通过减少 Ca²⁺释放，恢复其对细胞死亡的保护功能。此外，通过调节 Ca²⁺向线粒体的流动，Akt 维持线粒体的完整性并延迟凋亡的触发，这是一种依赖于亚型 III 的机制。这些结果表明 Akt 对 IP₃R III 具有特定的活性，导致 Ca²⁺向线粒体的转移减少并防止凋亡，表明 Akt 介导的细胞死亡调节的另一个层次。
