对由敲除 IP3受体或线粒体 Ca2+ 单向转运体诱导的 Ca2+ 信号传导慢性丢失的代谢适应

Metabolic adaptation to the chronic loss of Ca2+ signaling induced by

knockout of IP 3 receptors or the mitochondrial Ca2+ uniporter

Keywords：IP(3) receptor, TCA cycle, Bioenergetics, Calcium signaling, Glycolysis,Mitochondrial calcium uniporter, Mitochondrial metabolism
关键词：IP(3) 受体、TCA 循环、生物能量学、钙信号传导、糖酵解、线粒体钙单向转运体、线粒体代谢

细胞系：HEK细胞系（HEK293细胞系，人体胚胎肾细胞）
作者：Young MP, Schug ZT, Booth DM, Yule DI, Mikoshiba K, Hajnóczky G, Joseph SK 
出版期刊：《JOURNAL OF BIOLOGICAL CHEMISTRY》 2021/11/19

Abstract：

Calcium signaling is essential for regulating many biological processes. Endoplasmic reticulum (ER) inositol trisphosphate receptors (IP3Rs) and the mitochondrial Ca2+ uniporter (MCU) are key proteins that regulate intracellular Ca2+ concentration. Mitochondrial Ca2+ accumulation activates Ca2+-sensitive dehydrogenases of the tricarboxylic acid (TCA) cycle that maintain the biosynthetic and bioenergetics needs of both normal and cancer cells. However, the interplay between calcium signaling and metabolism is not well understood. In this study, we used human cancer cell lines (HEK293, HeLa) with stable knockouts of all three IP3R isoforms (TKO) or MCU to examine metabolic and bioenergetic responses to the chronic loss of cytosolic and/or mitochondrial Ca2+ signaling. Our results show that TKO cells (exhibiting total loss of Ca2+ signaling) are viable, displaying a lower proliferation and oxygen consumption rate, with no significant changes in ATP levels, even when made to rely solely on the TCA cycle for energy production. MCU KO cells also maintained normal ATP levels, but showed increased proliferation, oxygen consumption, and metabolism of both glucose and glutamine. However, MCU KO cells were unable to maintain ATP levels and died when relying solely on the TCA cycle for energy. We conclude that constitutive Ca2+ signaling is dispensable for the bioenergetic needs of both IP3R TKO and MCU KO human cancer cells, likely due to adequate basal glycolytic and TCA cycle flux. However, in MCU KO cells, the higher energy expenditure associated with increased proliferation and oxygen consumption makes these cells more prone to bioenergetic failure under conditions of metabolic stress. 

文章摘要：

钙信号对于调节许多生物过程至关重要。内质网 (ER) 三磷酸肌醇受体 (IP3Rs) 和线粒体 Ca2+ 单向转运体 (MCU) 是调节细胞内 Ca2+ 浓度的关键蛋白。线粒体 Ca2+ 积累激活三羧酸 (TCA) 循环的 Ca2+ 敏感脱氢酶，维持正常细胞和癌细胞的生物合成和生物能量学需求。然而，钙信号传导和代谢之间的相互作用尚不清楚。在这项研究中，我们使用稳定敲除所有三种 IP3R 亚型 (TKO) 或 MCU 的人类癌细胞系 (HEK293、HeLa) 来检查对细胞溶质和/或线粒体 Ca2+ 信号慢性丢失的代谢和生物能量反应。我们的研究结果表明，TKO 细胞（表现出完全丧失 Ca2+ 信号传导）是可行的，显示出较低的增殖和耗氧率，ATP 水平没有显着变化，即使仅依赖 TCA 循环产生能量也是如此。 MCU KO 细胞也维持正常的 ATP 水平，但显示出增加的增殖、耗氧量以及葡萄糖和谷氨酰胺的代谢。然而，MCU KO 细胞无法维持 ATP 水平并在仅依靠 TCA 循环获取能量时死亡。我们得出结论，本构 Ca2+ 信号对于 IP3R TKO 和 MCU KO 人类癌细胞的生物能量需求是可有可无的，这可能是由于足够的基础糖酵解和 TCA 循环通量。然而，在 MCU KO 细胞中，与增殖和耗氧量增加相关的更高能量消耗使这些细胞在代谢应激条件下更容易出现生物能量衰竭。 • 关键词：IP(3) 受体、TCA 循环、生物能量学、钙信号传导、糖酵解、线粒体钙单向转运体、线粒体代谢

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