Structure and mechanism of the mitochondrial calcium transporter NCLX.

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.