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Cell Rep. 2015 Oct 13;13(2):376-86. doi: 10.1016/j.celrep.2015.08.079. Epub 2015 Oct 1.

PKA Phosphorylation of NCLX Reverses Mitochondrial Calcium Overload and Depolarization, Promoting Survival of PINK1-Deficient Dopaminergic Neurons.

Author information

1
Department of Physiology and Cell Biology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA.
2
Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA.
3
Department of Neurobiology, University of Heidelberg, Heidelberg 69120, Germany, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA.
4
Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA.
5
Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA; Center for Neuroscience, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA.
6
Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA. Electronic address: a.abramov@ucl.ac.uk.
7
Department of Physiology and Cell Biology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA. Electronic address: sekler@bgu.ac.il.

Abstract

Mitochondrial Ca(2+) overload is a critical, preceding event in neuronal damage encountered during neurodegenerative and ischemic insults. We found that loss of PTEN-induced putative kinase 1 (PINK1) function, implicated in Parkinson disease, inhibits the mitochondrial Na(+)/Ca(2+) exchanger (NCLX), leading to impaired mitochondrial Ca(2+) extrusion. NCLX activity was, however, fully rescued by activation of the protein kinase A (PKA) pathway. We further show that PKA rescues NCLX activity by phosphorylating serine 258, a putative regulatory NCLX site. Remarkably, a constitutively active phosphomimetic mutant of NCLX (NCLX(S258D)) prevents mitochondrial Ca(2+) overload and mitochondrial depolarization in PINK1 knockout neurons, thereby enhancing neuronal survival. Our results identify an mitochondrial Ca(2+) transport regulatory pathway that protects against mitochondrial Ca(2+) overload. Because mitochondrial Ca(2+) dyshomeostasis is a prominent feature of multiple disorders, the link between NCLX and PKA may offer a therapeutic target.

PMID:
26440884
PMCID:
PMC4709126
DOI:
10.1016/j.celrep.2015.08.079
[Indexed for MEDLINE]
Free PMC Article

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