NCX3 regulates mitochondrial Ca2+ handling through the AKAP121-anchored signaling complex and prevents hypoxia-induced neuronal death

Antonella Scorziello, Claudia Savoia, Maria Jose Sisalli, Annagrazia Adornetto, Agnese Secondo, Francesca Boscia, Alba Esposito, Elena V. Polishchuk, Roman S. Polishchuk, Pasquale Molinaro, Annalisa Carlucci, Luca Lignitto, Gianfranco Di Renzo, Antonio Feliciello, Lucio Annunziato

Research output: Contribution to journalArticlepeer-review

Abstract

The mitochondrial influx and efflux of Ca2+ play a relevant role in cytosolic and mitochondrial Ca2+ homeostasis, and contribute to the regulation of mitochondrial functions in neurons. The mitochondrial Na+/Ca2+ exchanger, which was first postulated in 1974, has been primarily investigated only from a functional point of view, and its identity and localization in the mitochondria have been a matter of debate over the past three decades. Recently, a Li+-dependent Na+/Ca2+ exchanger extruding Ca2+ from the matrix has been found in the inner mitochondrial membrane of neuronal cells. However, evidence has been provided that the outer membrane is impermeable to Ca2+ efflux into the cytoplasm. In this study, we demonstrate for the first time that the nuclear-encoded NCX3 isoform (1) is located on the outer mitochondrial membrane (OMM) of neurons; (2) colocalizes and immunoprecipitates with AKAP121 (also known as AKAP1), a member of the protein kinase A anchoring proteins (AKAPs) present on the outer membrane; (3) extrudes Ca2+ from mitochondria through AKAP121 interaction in a PKA-mediated manner, both under normoxia and hypoxia; and (4) improves cell survival when it works in the Ca2+ efflux mode at the level of theOMM.C.ollectively, these results suggest that, in neurons, NCX3 regulates mitochondrial Ca2+ handling from the OMM through an AKAP121-anchored signaling complex, thus promoting cell survival during hypoxia.

Original languageEnglish
Pages (from-to)5566-5577
Number of pages12
JournalJournal of Cell Science
Volume126
Issue number24
DOIs
Publication statusPublished - Dec 15 2013

Keywords

  • AKAP1
  • AKAP121
  • Ca flux
  • Mitochondria
  • NCX3

ASJC Scopus subject areas

  • Cell Biology

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