Structure and mechanism of the mitochondrial calcium transporter NCLX

Minrui 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

doi:10.1038/s41586-025-09491-0

Structure and mechanism of the mitochondrial calcium transporter NCLX

Nature. 2025 Oct;646(8087):1272-1280. doi: 10.1038/s41586-025-09491-0. Epub 2025 Sep 10.

Authors

Minrui Fan^#¹, Chen-Wei Tsai^#^{2

3}, Jinru Zhang^#¹, Jianxiu Zhang^#¹, Aswini R Krishnan^#¹, Tsung-Yun Liu^{4

5}, Yu-Lun Huang^{4

5}, Deniz Aydin^{1

6

7

8}, Siyuan Du^{1

6

7

8

9}, Briana L Sobecks^{1

6

7

8

10}, Madison X Rodriguez⁴, Andrew H Reiter¹¹, Carolyn R Bertozzi^{9

12}, Ron O Dror^{1

6

7

8}, Ming-Feng Tsai^{13

14}, Liang Feng¹⁵

Affiliations

¹ Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA, USA.
² Department of Physiology and Biophysics, University of Colorado Anschutz Medical Campus, Aurora, CO, USA. nyc3zs@virginia.edu.
³ Department of Molecular Physiology and Biological Physics, University of Virginia, Charlottesville, VA, USA. nyc3zs@virginia.edu.
⁴ Department of Physiology and Biophysics, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
⁵ Department of Molecular Physiology and Biological Physics, University of Virginia, Charlottesville, VA, USA.
⁶ Department of Computer Science, Stanford University, Stanford, CA, USA.
⁷ Department of Structural Biology, Stanford University School of Medicine, Stanford, CA, USA.
⁸ Institute for Computational and Mathematical Engineering, Stanford University, Stanford, CA, USA.
⁹ Department of Chemistry, Stanford University, Stanford, CA, USA.
¹⁰ Department of Chemical Engineering, Stanford University, Stanford, CA, USA.
¹¹ Department of Biology, Stanford University, Stanford, CA, USA.
¹² Stanford Sarafan ChEM-H, Stanford University, Stanford, CA, USA.
¹³ Department of Physiology and Biophysics, University of Colorado Anschutz Medical Campus, Aurora, CO, USA. vmf6uw@virginia.edu.
¹⁴ Department of Molecular Physiology and Biological Physics, University of Virginia, Charlottesville, VA, USA. vmf6uw@virginia.edu.
¹⁵ Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA, USA. liangf@stanford.edu.

^# Contributed equally.

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⁺.

MeSH terms

Animals
Calcium / metabolism
Calcium Signaling
Cryoelectron Microscopy
Humans
Mitochondria / chemistry
Mitochondria / metabolism
Mitochondrial Membrane Transport Proteins* / chemistry
Mitochondrial Membrane Transport Proteins* / metabolism
Models, Molecular
Protein Conformation
Rats
Sodium-Calcium Exchanger* / chemistry
Sodium-Calcium Exchanger* / metabolism

Substances

Calcium
Sodium-Calcium Exchanger
Slc8b1 protein, rat
Mitochondrial Membrane Transport Proteins

Abstract

MeSH terms

Substances

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