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

Kostic, M; Ludtmann, M H R; Bading, H; Hershfinkel, M; Steer, E; Chu, C T; Abramov, A Y; Sekler, I

Authors

M Kostic

M H R Ludtmann

H Bading

M Hershfinkel

E Steer

C T Chu

A Y Abramov

I Sekler



Abstract

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.

Citation

Kostic, M., Ludtmann, M. H. R., Bading, H., Hershfinkel, M., Steer, E., Chu, C. T., …Sekler, I. (2015). PKA Phosphorylation of NCLX Reverses Mitochondrial Calcium Overload and Depolarization, Promoting Survival of PINK1-Deficient Dopaminergic Neurons. Cell Reports, 13(2), 376-386. https://doi.org/10.1016/j.celrep.2015.08.079

Journal Article Type Article
Acceptance Date Aug 28, 2015
Publication Date Oct 1, 2015
Deposit Date Jul 24, 2018
Publicly Available Date Nov 21, 2020
Journal Cell Reports
Print ISSN 2211-1247
Publisher Cell Press
Peer Reviewed Peer Reviewed
Volume 13
Issue 2
Pages 376-386
DOI https://doi.org/10.1016/j.celrep.2015.08.079
Public URL https://rvc-repository.worktribe.com/output/1399616

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