Structure and mechanism of the mitochondrial calcium transporter NCLX.

Abstract

As a key mitochondrial Ca²⁺ transporter, NCLX regulates intracellular Ca²⁺ signalling and vital mitochondrial processes^1-3. The importance of NCLX in cardiac and nervous-system physiology is reflected by acute heart failure and neurodegenerative disorders caused by its malfunction^4-9. 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⁺.