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Structure paper

TitleStructure and mechanism of the mitochondrial calcium transporter NCLX.
Journal, issue, pagesNature, Vol. 646, Issue 8087, Page 1272-1280, Year 2025
Publish dateSep 10, 2025
AuthorsMinrui Fan / Chen-Wei Tsai / Jinru Zhang / Jianxiu Zhang / Aswini R Krishnan / Tsung-Yun Liu / Yu-Lun Huang / Deniz Aydin / Siyuan Du / Briana L Sobecks / Madison X Rodriguez / Andrew H Reiter / Carolyn R Bertozzi / Ron O Dror / Ming-Feng Tsai / Liang Feng /
PubMed AbstractAs 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 ...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.
External linksNature / PubMed:40931067 / PubMed Central
MethodsEM (single particle)
Resolution2.15 - 4.29 Å
Structure data

71819

9ps1

EMDB-71819, PDB-9ps1:
Cryo-EM structure of NCLX with calcium (class 3a)
Method: EM (single particle) / Resolution: 2.6 Å

71820

9ps2

EMDB-71820, PDB-9ps2:
Cryo-EM structure of NCLX with calcium (class 4a)
Method: EM (single particle) / Resolution: 2.15 Å

71821

9ps3

EMDB-71821, PDB-9ps3:
Cryo-EM structure of NCLX at low pH (class 4b)
Method: EM (single particle) / Resolution: 2.62 Å

71822

9ps4

EMDB-71822, PDB-9ps4:
Cryo-EM structure of NCLX without calcium (class 1)
Method: EM (single particle) / Resolution: 3.29 Å

71824

9ps6

EMDB-71824, PDB-9ps6:
Cryo-EM structure of NCLX without calcium (class 3)
Method: EM (single particle) / Resolution: 4.29 Å

71826

9ps8

EMDB-71826, PDB-9ps8:
Cryo-EM structure of NCLX with calcium (class 2a)
Method: EM (single particle) / Resolution: 2.97 Å

Chemicals

ChemComp-CA:
Unknown entry

ChemComp-HOH:
WATER

Source
  • Homo sapiens (human)
  • rattus norvegicus (Norway rat)
KeywordsMEMBRANE PROTEIN / Membrane transporter

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