NCLX

更新于：2025-05-07

基本信息

别名

FLJ22233、Mitochondrial sodium/calcium exchanger protein、Na(+)/K(+)/Ca(2+)-exchange protein 6

+ [11]

简介

Mitochondrial sodium/calcium antiporter that mediates sodium-dependent calcium efflux from mitochondrion, by mediating the exchange of 3 sodium ions per 1 calcium ion (PubMed:15060069, PubMed:20018762, PubMed:22829870, PubMed:23056385, PubMed:24898248, PubMed:28130126, PubMed:28219928). Plays a central role in mitochondrial calcium homeostasis by mediating mitochondrial calcium extrusion: calcium efflux is essential for mitochondrial function and cell survival, notably in cardiomyocytes (By similarity). Regulates rates of glucose-dependent insulin secretion in pancreatic beta-cells during the first phase of insulin secretion: acts by mediating efflux of calcium from mitochondrion, thereby affecting cytoplasmic calcium responses (PubMed:23056385). Required for store-operated Ca(2+) entry (SOCE) and Ca(2+) release-activated Ca(2+) (CRAC) channel regulation: sodium transport by SLC8B1 leads to promote calcium-shuttling that modulates mitochondrial redox status, thereby regulating SOCE activity (PubMed:28219928). Involved in B-lymphocyte chemotaxis (By similarity). Able to transport Ca(2+) in exchange of either Li(+) or Na(+), explaining how Li(+) catalyzes Ca(2+) exchange (PubMed:15060069, PubMed:28130126). In contrast to other members of the family its function is independent of K(+) (PubMed:15060069).

关联

100 项与 NCLX 相关的临床结果

登录后查看更多信息

100 项与 NCLX 相关的转化医学

登录后查看更多信息

0 项与 NCLX 相关的专利（医药）

登录后查看更多信息

134

项与 NCLX 相关的文献（医药）

2024-12-01·Alzheimer's & Dementia

Reactive oxygen species from mitochondrial complex III are induced by NCLX to promote astrocytic STAT3‐linked transcription and dementia‐related pathology

Article

作者: Barnett, Daniel ; Chouchani, Edward T ; Orr, Anna G. ; Meadows, Samantha M. ; Xiao, Haopeng ; Booraem, Caroline ; Orr, Adam L ; Zimmer, Till S ; Palaguachi, Fernando

AbstractBackgroundMitochondrial reactive oxygen species (mROS), such as superoxide and hydrogen peroxide (H2O2), are implicated in aging‐associated neurological disorders, including Alzheimer’s Disease and frontotemporal dementia. Mitochondrial complex III of the respiratory chain has the highest capacity for mROS production and generates mROS toward the cytosol, poising it to regulate intracellular signaling and disease mechanisms. However, the exact triggers of complex III‐derived ROS (CIII‐ROS), its downstream molecular targets, and its functional roles in dementia‐related pathogenesis remain unclear.MethodHere, we investigated the drivers and consequences of CIII‐ROS production in primary mouse astrocytes and mouse models of dementia‐linked proteinopathy using site‐selective mROS suppressors and genetic approaches together with live‐cell imaging of sub‐compartmental H2O2 dynamics, stoichiometric redox proteomics, and transcriptomics.ResultWe found that specific disease‐related factors transiently increase astrocytic CIII‐ROS levels, and this effect is dependent on a mitochondrial sodium‐calcium exchanger. CIII‐ROS oxidized specific cysteines on astrocytic proteins associated with disease, amplified STAT3 phosphorylation and nuclear translocation, and promoted gene expression changes linked to STAT3 and related neuroimmune pathways. Inhibition of other sites of ROS production, including mitochondrial complex I and NADPH oxidase, had no effects on mROS responses or STAT3 signaling, demonstrating the specificity of CIII‐ROS induction and its context‐dependent modulation of STAT3 activities. Blockade of CIII‐ROS in transgenic mouse models of dementia with a site‐selective and brain‐penetrant suppressor reduced astrocytic alterations, neuropathology, and premature mortality.ConclusionOur data suggest that dementia‐associated factors induce site‐specific mROS production and that CIII‐ROS promote precise post‐translational redox modifications and amplify STAT3‐linked signaling and changes in gene expression. Together, our findings reveal CIII‐ROS as an important node of mitochondrial‐nuclear communication in pathogenic conditions, whereby mROS transients are converted into long‐lasting changes in gene transcription and cell function. CIII‐ROS and redox signaling offer new therapeutic opportunities for aging‐associated neurological disorders.

2024-12-01·Molecular Biology Reports

Inhibition of mitochondrial calcium transporters alters adp-induced platelet responses

Article

作者: Barki, Saima ; Bertaggia Calderara, Debora ; Aliotta, Alessandro ; Alam, Muhammad Rizwan ; Shehwar, Durre ; Veuthey, Lucas ; Alberio, Lorenzo

INTRODUCTIONADP-stimulated elevation of cytosolic Ca²⁺ is an important effector mechanism for platelet activation. The rapidly elevating cytosolic Ca²⁺ is also transported to mitochondrial matrix via Mitochondrial Ca²⁺ Uniporter (MCU) and extruded via Na⁺/Ca²⁺/Li⁺ Exchanger (NCLX). However, the exact contribution of MCU and NCLX in ADP-mediated platelet responses remains incompletely understood.METHODS AND RESULTSThe present study aimed to elucidate the role of mitochondrial Ca²⁺ transport in ADP-stimulated platelet responses by inhibition of MCU and NCLX with mitoxantrone (MTX) and CGP37157 (CGP), respectively. As these inhibitory strategies are reported to cause distinct effects on matrix Ca²⁺ concentration, we hypothesized to observe opposite impact of MTX and CGP on ADP-induced platelet responses. Platelet aggregation profiling was performed by microplate-based spectrophotometery while p-selectin externalization and integrin αIIbβ3 activation were analyzed by fluorescent immunolabeling using flow cytometery. Our results confirmed the expression of both MCU and NCLX mRNAs with relatively low abundance of NCLX in human platelets. In line with our hypothesis, MTX caused a dose-dependent inhibition of ADP-induced platelet aggregation without displaying any cytotoxicity. Likewise, ADP-induced p-selectin externalization and integrin αIIbβ3 activation was also significantly attenuated in MTX-treated platelets. Concordantly, inhibition of NCLX with CGP yielded an accelerated ADP-stimulated platelet aggregation which was associated with an elevation of p-selectin surface expression and αIIbβ3 activation.CONCLUSIONTogether, these findings uncover a vital and hitherto poorly characterized role of mitochondrial Ca²⁺ transporters in ADP-induced platelet activation.

2024-11-01·Redox Biology

The mitochondrial Na+/Ca2+ exchanger NCLX is implied in the activation of hypoxia-inducible factors

Article

作者: Navarro, Elisa ; López, Manuela G ; Hernansanz-Agustín, Pablo ; Ríos, Cristóbal de Los ; Ríos, Cristóbal de los ; Choya-Foces, Carmen ; Martínez-Ruiz, Antonio ; López, Manuela G. ; Egea, Javier

Eukaryotic cells and organisms depend on oxygen for basic living functions, and they display a panoply of adaptations to situations in which oxygen availability is diminished (hypoxia). A number of these responses in animals are mediated by changes in gene expression programs directed by hypoxia-inducible factors (HIFs), whose main mechanism of stabilization and functional activation in response to decreased cytosolic oxygen concentration was elucidated two decades ago. Human acute responses to hypoxia have been known for decades, although their precise molecular mechanism for oxygen sensing is not fully understood. It is already known that a redox component, linked with reactive oxygen species (ROS) production of mitochondrial origin, is implied in these responses. We have recently described a mechanism by which the mitochondrial sodium/calcium exchanger, NCLX, participates in mitochondrial electron transport chain regulation and ROS production in response to acute hypoxia. Here we show that NCLX is also implied in the response to hypoxia mediated by the HIFs. By using a NCLX inhibitor and interference RNA we show that NCLX activity is necessary for HIF-α subunits stabilization in hypoxia and for HIF-1-dependent transcriptional activity. We also show that hypoxic mitochondrial ROS production is not required for HIF-1α stabilization under all circumstances, suggesting that the basal cytosolic redox state or other mechanism(s) could be operating in the NCLX-mediated response to hypoxia that operates through HIF-α stabilization. This finding provides a link between acute and medium-term responses to hypoxia, reinforcing a central role of mitochondrial cell signalling in the response to hypoxia.

项与 NCLX 相关的新闻（医药）

2023-02-23

·生物探索

Cell子刊：高盐饮食伤害免疫细胞，免疫系统可能因此失控！

在中国古代，盐的生产和贩卖通常掌握在官府手里。通过对盐税的征收变相地征收人头税，从一个侧面体现出盐在每个人生活中的不可或缺。不过，到了现在，人们则更多关注高盐饮食将会对健康造成的不良影响。虽然难以在研究中将盐的摄入量与其他饮食生活方式完全剥离，但我们确实知道，高盐饮食会诱发高血压、骨质疏松、胃炎、糖尿病、哮喘等疾病。此外还已经证实，高盐饮食会使免疫细胞由平衡状态转向促炎状态。在我们的免疫系统中，调节性T细胞（Regulatory cells，Tregs）担任着“监督者”的职责，具有免疫抑制作用，通过抑制或下调其他T细胞的诱导和增殖，来确保免疫反应以可控的方式发生。当Treg细胞功能失调，将出现种种自身免疫性疾病，如多发性硬化症（MS）、系统性红斑狼疮（SLE）、类风湿性关节炎（RA）或1型糖尿病（T1D）和慢性感染等。有意思的是，高盐诱导下的Treg细胞表现出与常在自身免疫性疾病患者身上观察到的功能失调的Treg细胞有着极高的相似性。这暗示过量的盐摄入可能导致整体免疫失衡，可能是导致疾病的风险因素之一。近年来，免疫代谢方面的研究表明，许多免疫反应是通过细胞代谢的变化来控制的。而对于Treg细胞来说，线粒体呼吸对其功能的维持至关重要。在多发性硬化症患者身上，也发现分离出的Treg细胞的最大呼吸水平降低，线粒体基因失调，线粒体功能缺陷。另一方面，已有研究阐明，在单核细胞和巨噬细胞中，钠离子通过Na+/Ca2+交换器（NCLX）进入线粒体，随后抑制位于线粒体内膜上的电子传输链（electron transport chain，ETC）并减弱ATP的产生。那么，这一机制是否也适用于Treg细胞呢？为此，Max Delbrück分子医学中心和实验与临床研究中心的Dominik Müller授团队围绕Treg细胞在高盐环境下展现出的表型变化及背后机制进行了研究，相关结果以“Sodium perturbs mitochondrial respiration and induces dysfunctional Tregs”为题发表于Cell Metabolism。图1 研究成果（图源：[1]）研究发现：01高盐诱导的Treg细胞表型特征类似于功能失调的自身免疫性Treg细胞研究人员在体外模拟了高盐饮食后或炎症期间在间质组织中发现的Na+浓度增加现象，结果发现Treg细胞对其他免疫细胞的抑制能力减弱，表达细胞因子IFN-γ，增殖的水平也更高，与自身免疫疾病中观察到的功能失调的Treg细胞特征相似，RNA测序的结果进一步证实了这一点，即Treg细胞发生了代谢重编程。图2 高盐诱导的Treg细胞表型和功能变化与人类自身免疫性Treg细胞非常相似（图源：[1]）02高盐会扰乱Treg细胞的线粒体呼吸高盐条件下，丙酮酸代谢和三羧酸（TCA）循环的关键节点下调，尿素循环上调。TCA循环中，琥珀酸脱氢酶（Succinate dehydrogenase，SDH）受到抑制，导致琥珀酸累积，通过电子传输链的电子减少，细胞氧化磷酸化（oxidative phosphorylation，OXPHOS）的能力下调。氧化磷酸化是Treg细胞的主要代谢方式。高盐条件下，Treg细胞的最大呼吸显著降低，ATP的产生显著减少，线粒体膜电位崩溃。RNA-seq分析显示，高盐处理与细胞呼吸抑制剂抗霉素A处理呈现出高度重叠的基因特征。对小鼠基因敲除使线粒体ETC复合物III消融，其基因表达模式和功能失调表型同样与高盐处理高度类似。进一步的scRNA-seq分析表明，高盐或抗霉素A处理将使得FOXP3基因快速下调，FOXP3是Treg细胞发育和功能的关键转录因子之一，因此这可能是Treg细胞功能丧失的原因。03高盐会扰乱Treg细胞的线粒体呼吸针对健康志愿者每日盐摄入量分析Treg细胞表型，发现高盐组（>7克/天）Treg细胞中IL-10的表达显著降低，且与盐摄入呈负相关；FOXP3减少，IFN-γ表达增加。小鼠实验表明，Treg细胞的过继转移可以改善实验性自身免疫性脑脊髓炎（experimental autoimmune encephalomyelitis，EAE），这可能是由于Treg细胞产生的IL-10。但高盐预处理的Treg细胞无法改善EAE的进展，疾病评分显著提高。在异种移植物抗宿主病（xenogeneic graft vs. host disease，xGvHD）模型中，对小鼠移植了人效应T细胞和不同条件处理的人Treg细胞，结果表明，仅仅使用高盐或抗霉素A预孵育6小时，人Treg细胞就出现功能丧失，无法预防小鼠的xGvHD。这表明，即使线粒体呼吸被高盐短暂扰动，也可能导致人/鼠体内Treg细胞功能的长期破坏。图3 xGvHD模型中，仅未处理Treg细胞能预防xGvHD（图源：[1]）03高盐诱导的线粒体功能障碍取决于NCLX，抑制NCLX可恢复Treg细胞功能检查高盐对电子传输链的影响，发现在在无细胞和无线粒体的测定中，Na+使复合物II的功能降低了近50%。NaCl浓度增加时，完整纯化线粒体中复合物II/III的功能抑制程度依赖于NaCl的剂量。表明，高盐在ETC复合物II/III水平上诱导Treg细胞的线粒体呼吸紊乱。低氧条件下，Na+通过NCLX流入线粒体，考虑到Na+对复合物II/III活性的直接影响，研究人员测试了NCLX抑制剂能否逆转这种影响。结果表明，NCLX抑制剂能够在体内恢复受高盐扰动的Treg细胞功能，证明了NCLX在Treg细胞免疫代谢紊乱和功能障碍中的关键作用。图4 NCLX控制Treg细胞免疫代谢和功能的示意图（图源：[1]）研究的通讯作者、哈塞尔特大学VIB转化免疫调节实验室的Markus Kleinewietfeld教授表示，了解导致自身免疫性Treg细胞功能障碍的因素和潜在分子机制不仅对于该领域十分重要，“由于Treg细胞也在癌症或心血管疾病等疾病中发挥作用，进一步探索这种钠引起的效应还将有可能为改变不同类型疾病中的Treg细胞功能提供新策略。”但同样，更详细的分子机制及其与疾病之间的关系需要进一步的研究。题图来源：curie.bio，仅用于学术交流。责编|风立宵校对|木子久End参考资料：[1]Côrte-Real BF, Hamad I, Arroyo Hornero R, et al. Sodium perturbs mitochondrial respiration and induces dysfunctional Tregs. Cell Metab. 2023 Feb 7;35(2):299-315.e8. doi: 10.1016/j.cmet.2023.01.009. PMID: 36754020. [2]https://www.mdc-berlin.de/news/press/salt-cuts-energy-supply-immune-regulators 本文系生物探索原创，欢迎个人转发分享。其他任何媒体、网站如需转载，须在正文前注明来源生物探索。往期精选围观 ‍Nature子刊：发现新的细胞死亡机制，可为癌症治疗提供新策略热文倡议捐精冲上热搜！供精者精子合格率不足20%，男性生育力何以提升？热文百度并购GBI Health，中国医疗版“ChatGPT”来了！AI技术打破数据边界，颠覆医疗行业传统模式热文研究发现塑料中的这种化学物质可改变精子，危害延续后代两代人热文不仅投钱，还帮助运营公司！这家风投公司将如何颠覆生物科技公司创建模式？点击“阅读原文”，了解更多~

细胞疗法临床研究免疫疗法