Abstact

As a key mitochondrial Ca2+ transporter, NCLX regulates intracellular Ca2+ signalling and vital mitochondrial processes1-3. The importance of NCLX in cardiac and nervous-system physiology is reflected by acute heart failure and neurodegenerative disorders caused by its malfunction4-9. 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+.