线粒体钙转运蛋白NCLX的结构与机制

Structure and mechanism of the mitochondrial calcium transporter NCLX.

作者信息

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

机构信息

Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA, USA.

Department of Physiology and Biophysics, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.

出版信息

Nature. 2025 Sep 10. doi: 10.1038/s41586-025-09491-0.

DOI:10.1038/s41586-025-09491-0

PMID:40931067

Abstract

As a key mitochondrial Ca transporter, NCLX regulates intracellular Ca signalling and vital mitochondrial processes. The importance of NCLX in cardiac and nervous-system physiology is reflected by acute heart failure and neurodegenerative disorders caused by its malfunction. 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/Ca exchanger, rather than as a Na/Ca exchanger as widely believed. These findings provide critical insights into mitochondrial Ca homeostasis and signalling, offering clues for developing therapies to treat diseases related to abnormal mitochondrial Ca.

摘要

作为关键的线粒体钙转运蛋白，NCLX调节细胞内钙信号传导和重要的线粒体过程。急性心力衰竭和由其功能障碍引起的神经退行性疾病反映了NCLX在心脏和神经系统生理学中的重要性。尽管该领域取得了重大进展，但NCLX的转运机制仍不清楚。在这里，我们报告了NCLX的冷冻电子显微镜结构，揭示了其结构、组装、主要构象状态以及一种以前未描述的交替访问机制。功能分析进一步揭示了NCLX作为H/Ca交换器而非广泛认为的Na/Ca交换器的意外转运功能。这些发现为线粒体钙稳态和信号传导提供了关键见解，为开发治疗与线粒体钙异常相关疾病的疗法提供了线索。