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PKA phosphorylation of NCLX reverses mitochondrial calcium overload and depolarization, promoting survival of PINK1-deficient dopaminergic neurons

Mitochondrial Ca2+ 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+/Ca2+ exchanger (NCLX), leadi...

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Main Authors: Kostic, Marko (Author) , Ludtmann, Marthe H. R. (Author) , Bading, Hilmar (Author) , Hershfinkel, Michal (Author) , Steer, Erin (Author) , Chu, Charleen T. (Author) , Abramov, Andrey Y. (Author) , Sekler, Israel (Author)
Format: Article (Journal)
Language:English
Published: October 1, 2015
In: Cell reports
Year: 2015, Volume: 13, Issue: 2, Pages: 376-386
ISSN:2211-1247
DOI:10.1016/j.celrep.2015.08.079
Online Access:Resolving-System, lizenzpflichtig, Volltext: https://doi.org/10.1016/j.celrep.2015.08.079
Verlag, lizenzpflichtig, Volltext: http://www.sciencedirect.com/science/article/pii/S2211124715009924
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Author Notes:Marko Kostic, Marthe H.R. Ludtmann, Hilmar Bading, Michal Hershfinkel, Erin Steer, Charleen T. Chu, Andrey Y. Abramov, and Israel Sekler
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Summary:Mitochondrial Ca2+ 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+/Ca2+ exchanger (NCLX), leading to impaired mitochondrial Ca2+ 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 (NCLXS258D) prevents mitochondrial Ca2+ overload and mitochondrial depolarization in PINK1 knockout neurons, thereby enhancing neuronal survival. Our results identify an mitochondrial Ca2+ transport regulatory pathway that protects against mitochondrial Ca2+ overload. Because mitochondrial Ca2+ dyshomeostasis is a prominent feature of multiple disorders, the link between NCLX and PKA may offer a therapeutic target.
Item Description:Gesehen am 22.07.2020
Physical Description:Online Resource
ISSN:2211-1247
DOI:10.1016/j.celrep.2015.08.079

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