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PMID:20018762

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Citation

Palty, R, Silverman, WF, Hershfinkel, M, Caporale, T, Sensi, SL, Parnis, J, Nolte, C, Fishman, D, Shoshan-Barmatz, V, Herrmann, S, Khananshvili, D and Sekler, I (2010) NCLX is an essential component of mitochondrial Na+/Ca2+ exchange. Proc. Natl. Acad. Sci. U.S.A. 107:436-41

Abstract

Mitochondrial Ca(2+) efflux is linked to numerous cellular activities and pathophysiological processes. Although it is established that an Na(+)-dependent mechanism mediates mitochondrial Ca(2+) efflux, the molecular identity of this transporter has remained elusive. Here we show that the Na(+)/Ca(2+) exchanger NCLX is enriched in mitochondria, where it is localized to the cristae. Employing Ca(2+) and Na(+) fluorescent imaging, we demonstrate that mitochondrial Na(+)-dependent Ca(2+) efflux is enhanced upon overexpression of NCLX, is reduced by silencing of NCLX expression by siRNA, and is fully rescued by the concomitant expression of heterologous NCLX. NCLX-mediated mitochondrial Ca(2+) transport was inhibited, moreover, by CGP-37157 and exhibited Li(+) dependence, both hallmarks of mitochondrial Na(+)-dependent Ca(2+) efflux. Finally, NCLX-mediated mitochondrial Ca(2+) exchange is blocked in cells expressing a catalytically inactive NCLX mutant. Taken together, our results converge to the conclusion that NCLX is the long-sought mitochondrial Na(+)/Ca(2+) exchanger.

Links

PubMed PMC2806722 Online version:10.1073/pnas.0908099107

Keywords

Animals; Brain/cytology; Brain/metabolism; Calcium/metabolism; Clonazepam/analogs & derivatives; Clonazepam/metabolism; Homeostasis; Humans; Mice; Mitochondria/metabolism; Mitochondria/ultrastructure; Mitochondrial Membranes/metabolism; Mitochondrial Membranes/ultrastructure; Myocardium/cytology; Myocardium/metabolism; Rats; Sodium/metabolism; Sodium-Calcium Exchanger/antagonists & inhibitors; Sodium-Calcium Exchanger/genetics; Sodium-Calcium Exchanger/metabolism; Thiazepines/metabolism

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

RAT:NCLX

located_in

GO:0005739: mitochondrion

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

RAT:NCLX

enables

GO:0042802: identical protein binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

RAT:NCLX

located_in

GO:0030061: mitochondrial crista

ECO:0000314: direct assay evidence used in manual assertion

C

  • part_of:(UBERON:0000955)

Seeded From UniProt

complete

RAT:NCLX

located_in

GO:0005739: mitochondrion

ECO:0000314: direct assay evidence used in manual assertion

C

  • part_of:(UBERON:0000948)

Seeded From UniProt

complete

RAT:NCLX

enables

GO:0005432: calcium:sodium antiporter activity

ECO:0000250: sequence similarity evidence used in manual assertion

UniProtKB:Q925Q3

F

Seeded From UniProt

complete

RAT:NCLX

involved_in

GO:0051480: regulation of cytosolic calcium ion concentration

ECO:0000250: sequence similarity evidence used in manual assertion

UniProtKB:Q925Q3

P

Seeded From UniProt

complete

RAT:NCLX

involved_in

GO:0051560: mitochondrial calcium ion homeostasis

ECO:0000250: sequence similarity evidence used in manual assertion

UniProtKB:Q925Q3

P

Seeded From UniProt

complete

RAT:NCLX

enables

GO:0042803: protein homodimerization activity

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q6AXS0

F

  • occurs_in:(UBERON:0000948)

Seeded From UniProt

complete

HUMAN:NCLX

acts_upstream_of_or_within

GO:0006851: mitochondrial calcium ion transmembrane transport

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:NCLX

located_in

GO:0030061: mitochondrial crista

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:NCLX

involved_in

GO:0086036: regulation of cardiac muscle cell membrane potential

ECO:0000304: author statement supported by traceable reference used in manual assertion

P

Seeded From UniProt

complete

HUMAN:NCLX

enables

GO:0086038: calcium:sodium antiporter activity involved in regulation of cardiac muscle cell membrane potential

ECO:0000304: author statement supported by traceable reference used in manual assertion

F

Seeded From UniProt

complete

HUMAN:NCLX

enables

GO:0005432: calcium:sodium antiporter activity

ECO:0000315: mutant phenotype evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:NCLX

involved_in

GO:0051480: regulation of cytosolic calcium ion concentration

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:NCLX

involved_in

GO:0051560: mitochondrial calcium ion homeostasis

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:NCLX

enables

GO:0042803: protein homodimerization activity

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q6J4K2

F

Seeded From UniProt

complete

MOUSE:NCLX

located_in

GO:0005739: mitochondrion

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:NCLX

involved_in

GO:0006851: mitochondrial calcium ion transmembrane transport

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:NCLX

enables

GO:0005432: calcium:sodium antiporter activity

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

MOUSE:NCLX

involved_in

GO:0051480: regulation of cytosolic calcium ion concentration

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:NCLX

involved_in

GO:0051560: mitochondrial calcium ion homeostasis

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:NCLX

located_in

GO:0005739: mitochondrion

ECO:0000314: direct assay evidence used in manual assertion

C

  • part_of:(UBERON:0000948)|part_of:(UBERON:0000955)

Seeded From UniProt

complete

MOUSE:NCLX

involved_in

GO:0086036: regulation of cardiac muscle cell membrane potential

ECO:0000305: curator inference used in manual assertion

GO:0005432
GO:0005739

P

Seeded From UniProt

complete

MOUSE:NCLX

enables

GO:0086038: calcium:sodium antiporter activity involved in regulation of cardiac muscle cell membrane potential

ECO:0000305: curator inference used in manual assertion

GO:0005432
GO:0005739

F

Seeded From UniProt

complete

MOUSE:NCLX

located_in

GO:0030061: mitochondrial crista

ECO:0000250: sequence similarity evidence used in manual assertion

UniProtKB:Q6AXS0

C

Seeded From UniProt

complete

MOUSE:NCLX

enables

GO:0042803: protein homodimerization activity

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q925Q3

F

  • occurs_in:(UBERON:0000948)|occurs_in:(UBERON:0000955)

Seeded From UniProt

complete


See also

References

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