线粒体钠/钙交换器 (NCLX) 通过钙信号传导调节基础和饥饿诱导的自噬,bioRxiv - Cell Biology

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线粒体钠/钙交换器 (NCLX) 通过钙信号传导调节基础和饥饿诱导的自噬
bioRxiv - Cell Biology Pub Date : 2023-11-20 , DOI: 10.1101/2023.03.17.533187
Vitor de Miranda Ramos , Julian D.C. Serna , Eloisa A. Vilas-Boas , João Victor Cabral-Costa , Fernanda M. da Cunha , Tetsushi Kataura , Viktor I. Korolchuk , Alicia J. Kowaltowski

线粒体通过线粒体钙单向转运蛋白的 Ca 2+ 摄取和 Na ⁺^/ Ca ^2+交换器⁽ NCLX)的流出的协调活动来形成细胞内 Ca 2+ 信号传导。^{在这里，我们描述了 NCLX、细胞内 Ca 2+}和自噬活性之间的新关系。体内和体外刺激自噬的条件（例如热量限制和营养剥夺）会上调肝组织和细胞中的 NCLX 表达。相反，NCLX 的敲低会损害基础自噬和饥饿诱导的自噬。同样，CGP 37157 急性抑制 NCLX 活性会影响本体自噬和内质网自噬 (ER-phagy)，但对线粒体自噬没有显着影响。从机制上讲，CGP 37157 抑制 FIP200 斑点的形成和下游自噬体生物发生。NCLX 的抑制导致胞质 Ca ²⁺水平降低，细胞内 Ca ²⁺螯合同样抑制自噬。此外，螯合对 NCLX 对自噬的抑制没有表现出累加效应，这表明线粒体 Ca ²⁺流出通过调节 Ca ²⁺信号传导来调节自噬。总的来说，我们的结果表明，通过 NCLX 的线粒体 Ca ²⁺挤出途径是连接营养限制和自噬调节的重要调节节点。

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Mitochondrial Sodium/Calcium Exchanger (NCLX) Regulates Basal and Starvation-Induced Autophagy Through Calcium Signaling

Mitochondria shape intracellular Ca²⁺ signaling through the concerted activity of Ca²⁺ uptake via mitochondrial calcium uniporter, and efflux from by Na⁺/Ca²⁺ exchangers (NCLX). Here, we describe a novel relationship between NCLX, intracellular Ca²⁺, and autophagic activity. Conditions that stimulate autophagy in vivo and in vitro, such as caloric restriction and nutrient deprivation, upregulate NCLX expression in hepatic tissue and cells. Conversely, knockdown of NCLX impairs basal and starvation-induced autophagy. Similarly, acute inhibition of NCLX activity by CGP 37157 affects bulk and endoplasmic reticulum autophagy (ER-phagy) without significant impacts on mitophagy. Mechanistically, CGP 37157 inhibited the formation of FIP200 puncta and downstream autophagosome biogenesis. Inhibition of NCLX caused decreased cytosolic Ca²⁺ levels, and intracellular Ca²⁺ chelation similarly suppressed autophagy. Furthermore, chelation did not exhibit an additive effect on NCLX inhibition of autophagy, demonstrating that mitochondrial Ca²⁺ efflux regulates autophagy through the modulation of Ca²⁺ signaling. Collectively, our results show that the mitochondrial Ca²⁺ extrusion pathway through NCLX is an important regulatory node linking nutrient restriction and autophagy regulation.

更新日期：2023-11-22

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