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TitleMolecular mechanisms of mitochondrial Ca exchanger NCLX.
Journal, issue, pagesNat Commun, Year 2026
Publish dateJul 10, 2026
AuthorsLi Zhang / Yan Han / Weizhong Zeng / Jing Xue / Yan Wang / Youxing Jiang /
PubMed AbstractMitochondrial Ca²⁺ homeostasis is maintained through coordinated influx and efflux processes, with NCLX long recognized as the primary Ca²⁺ extruder operating via Na⁺/Ca²⁺ exchange. Here, ...Mitochondrial Ca²⁺ homeostasis is maintained through coordinated influx and efflux processes, with NCLX long recognized as the primary Ca²⁺ extruder operating via Na⁺/Ca²⁺ exchange. Here, we report cryo-EM structures of rat NCLX in cytosolic-facing occluded and open states. The central transmembrane (TM) domain of NCLX comprises ten helices arranged in two inverted, structurally similar halves, with two α-repeats forming a central ion-binding pocket. Peripheral TMs 1 and 6 are loosely associated with the core and likely mediate alternative access to this site. These structural features closely resemble those of NCXs, indicating a conserved ion exchange mechanism. While NCLX retains the canonical Ca²⁺-binding site, it lacks several key Na⁺-binding residues found in NCXs, suggesting broader ion selectivity. Consistently, cell-based Ca²⁺ uptake assays show that NCLX mediates Ca²⁺ exchange using Na⁺, K⁺, Li⁺, and potentially protons as counterions. Based on the structural symmetry of NCLX and its bidirectional exchange capability, we propose a matrix-facing model and an alternating-access mechanism in which TMs 1 and 6 undergo sliding motions to enable ion exchange between cytosolic and matrix sides, analogous to NCX. These findings provide a structural and mechanistic framework for understanding NCLX-mediated Ca²⁺ transport in mitochondria.
External linksNat Commun / PubMed:42431881
MethodsEM (single particle)
Resolution3.15 - 3.62 Å
Structure data

73804

9z4i

EMDB-73804, PDB-9z4i:
Cryo-EM structure of the mitochondrial NCLX in its monomeric state
Method: EM (single particle) / Resolution: 3.62 Å

73805

9z4j

EMDB-73805, PDB-9z4j:
Cryo-EM structure of the mitochondrial NCLX in its trimeric state
Method: EM (single particle) / Resolution: 3.15 Å

Chemicals

ChemComp-NA:
Unknown entry

ChemComp-CA:
Unknown entry

ChemComp-ZN:
Unknown entry

Source
  • rattus norvegicus (Norway rat)
KeywordsMEMBRANE PROTEIN / NCLX / exchanger

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