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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| Hauptverfasser: | , , , , , , , |
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| Dokumenttyp: | Article (Journal) |
| Sprache: | Englisch |
| Veröffentlicht: |
October 1, 2015
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| In: |
Cell reports
Year: 2015, Jahrgang: 13, Heft: 2, Pages: 376-386 |
| ISSN: | 2211-1247 |
| DOI: | 10.1016/j.celrep.2015.08.079 |
| Online-Zugang: | 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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| Verfasserangaben: | 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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| 245 | 1 | 0 | |a PKA phosphorylation of NCLX reverses mitochondrial calcium overload and depolarization, promoting survival of PINK1-deficient dopaminergic neurons |c 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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| 520 | |a 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. | ||
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| 700 | 1 | |a Sekler, Israel |e VerfasserIn |4 aut | |
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