Bcl-2 family proteins are known to competitively regulate Ca(2+); however, the specific inter-organelle signaling pathways and related cellular functions are not fully elucidated. In this study, a portion of Bcl-xL was detected at the ER-mitochondrion interface or MAM (mitochondria-associated ER membrane) in association with type 3 inositol 1,4,5-trisphosphate receptors (IP3R3); an association facilitated by the BH4 and transmembrane domains of Bcl-xL. Moreover, increasing Bcl-xL expression enhanced transient mitochondrial Ca(2+) levels upon ER Ca(2+) depletion induced by short-term, non-apoptotic incubation with thapsigargin (Tg), while concomitantly reducing cytosolic Ca(2+) release. These mitochondrial changes appear to be IP3R3-dependent and resulted in decreased NAD/NADH ratios and higher electron transport chain oxidase activity. Interestingly, extended Tg exposure stimulated ER stress, but not apoptosis, and further enhanced TCA cycling. Indeed, confocal analysis indicated that Bcl-xL translocated to the MAM and increased its interaction with IP3R3 following extended Tg treatment. Thus, the MAM is a critical cell-signaling junction whereby Bcl-xL dynamically interacts with IP3R3 to coordinate mitochondrial Ca(2+) transfer and alters cellular metabolism in order to increase the cells' bioenergetic capacity, particularly during periods of stress.

中文翻译：

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Bcl-xL 的非凋亡作用：调节 ER-线粒体界面的 Ca(2+) 信号传导和生物能学。

已知 Bcl-2 家族蛋白可竞争性调节 Ca(2+)；然而，具体的细胞器间信号通路和相关的细胞功能尚未完全阐明。在这项研究中，在 ER-线粒体界面或 MAM（线粒体相关 ER 膜）处检测到了一部分 Bcl-xL 与 3 型肌醇 1,4,5-三磷酸受体 (IP3R3) 相关；由 BH4 和 Bcl-xL 跨膜结构域促进的关联。此外，增加 Bcl-xL 表达可增强短期非凋亡性毒胡萝卜素 (Tg) 孵育诱导的 ER Ca(2+) 耗竭后瞬时线粒体 Ca(2+) 水平，同时减少胞质 Ca(2+) 释放。这些线粒体变化似乎是 IP3R3 依赖性的，导致 NAD/NADH 比率降低和电子传递链氧化酶活性升高。有趣的是，延长 Tg 暴露会刺激 ER 应激，但不会刺激细胞凋亡，并进一步增强 TCA 循环。事实上，共聚焦分析表明，在延长 Tg 处理后，Bcl-xL 易位至 MAM，并增加了其与 IP3R3 的相互作用。因此，MAM 是一个关键的细胞信号传导连接点，Bcl-xL 通过它与 IP3R3 动态相互作用，协调线粒体 Ca(2+) 转移并改变细胞代谢，以增加细胞的生物能能力，特别是在应激期间。