斯坦福大学医学院冯亮课题组提出了线粒体钙转运体NCLX的结构与机制。2025年9月10日出版的《自然》发表了这项成果。

本文报道了NCLX的低温电镜结构，揭示了其结构、组装、主要构象态和以前未描述的交替存取机制。功能分析进一步揭示了NCLX作为H⁺/Ca²⁺交换剂的意外转运功能，而不是广泛认为的Na⁺/Ca²⁺交换剂。这些发现为线粒体Ca²⁺稳态和信号传导提供了重要的见解，为开发治疗与线粒体Ca²⁺异常相关疾病的疗法提供了线索。

据了解，作为一个关键的线粒体Ca²⁺转运体，NCLX调节细胞内Ca²⁺信号传导和重要的线粒体过程。NCLX在心脏和神经系统生理学中的重要性反映在急性心力衰竭和由其功能障碍引起的神经退行性疾病中。尽管在该领域取得了实质性进展，但NCLX的转运机制仍不清楚。

附：英文原文

Title: Structure and mechanism of the mitochondrial calcium transporter NCLX

Author: Fan, Minrui, Tsai, Chen-Wei, Zhang, Jinru, Zhang, Jianxiu, Krishnan, Aswini R., Liu, Tsung-Yun, Huang, Yu-Lun, Aydin, Deniz, Du, Siyuan, Sobecks, Briana L., Rodriguez, Madison X., Reiter, Andrew H., Bertozzi, Carolyn R., Dror, Ron O., Tsai, Ming-Feng, Feng, Liang

Issue&Volume: 2025-09-10

Abstract: As a key mitochondrial Ca2+ transporter, NCLX regulates intracellular Ca2+ signalling and vital mitochondrial processes1,2,3. The importance of NCLX in cardiac and nervous-system physiology is reflected by acute heart failure and neurodegenerative disorders caused by its malfunction4,5,6,7,8,9. Despite substantial advances in the field, the transport mechanisms of NCLX remain unclear. Here we report the cryo-electron microscopy structures of NCLX, revealing its architecture, assembly, major conformational states and a previously undescribed mechanism for alternating access. Functional analyses further reveal an unexpected transport function of NCLX as a H+/Ca2+ exchanger, rather than as a Na+/Ca2+ exchanger as widely believed1. These findings provide critical insights into mitochondrial Ca2+ homeostasis and signalling, offering clues for developing therapies to treat diseases related to abnormal mitochondrial Ca2+.

DOI: 10.1038/s41586-025-09491-0

Source: https://www.nature.com/articles/s41586-025-09491-0