Structure and mechanism of the mitochondrial calcium transporter NCLX.

As a key mitochondrial Ca(2+) transporter, NCLX regulates intracellular Ca(2+) 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(+)/Ca(2+) exchanger, rather than as a Na(+)/Ca(2+) exchanger as widely believed(1). These findings provide critical insights into mitochondrial Ca(2+) homeostasis and signalling, offering clues for developing therapies to treat diseases related to abnormal mitochondrial Ca(2+).