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., Abramov, A. Y., & 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