9ps5
Cryo-EM structure of NCLX without calcium (class 2)
Structural highlights
FunctionNCLX_RAT Mitochondrial sodium/calcium antiporter that mediates sodium-dependent calcium efflux from mitochondrion, by mediating the exchange of 3 sodium ions per 1 calcium ion. Plays a central role in mitochondrial calcium homeostasis by mediating mitochondrial calcium extrusion: calcium efflux is essential for mitochondrial function and cell survival, notably in cardiomyocytes (By similarity). Regulates rates of glucose-dependent insulin secretion in pancreatic beta-cells during the first phase of insulin secretion: acts by mediating efflux of calcium from mitochondrion, thereby affecting cytoplasmic calcium responses. Required for store-operated Ca(2+) entry (SOCE) and Ca(2+) release-activated Ca(2+) (CRAC) channel regulation: sodium transport by SLC8B1 leads to promote calcium-shuttling that modulates mitochondrial redox status, thereby regulating SOCE activity (By similarity). Involved in B-lymphocyte chemotaxis (By similarity). Able to transport Ca(2+) in exchange of either Li(+) or Na(+), explaining how Li(+) catalyzes Ca(2+) exchange. In contrast to other members of the family its function is independent of K(+) (By similarity).[UniProtKB:Q6J4K2][UniProtKB:Q925Q3] Publication Abstract from PubMedAs 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+). Structure and mechanism of the mitochondrial calcium transporter NCLX.,Fan M, Tsai CW, Zhang J, Zhang J, Krishnan AR, Liu TY, Huang YL, Aydin D, Du S, Sobecks BL, Rodriguez MX, Reiter AH, Bertozzi CR, Dror RO, Tsai MF, Feng L Nature. 2025 Oct;646(8087):1272-1280. doi: 10.1038/s41586-025-09491-0. Epub 2025 , Sep 10. PMID:40931067[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
| ||||||||||||||||||
