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

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: Jul 24, 2018
• 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