PKA Phosphorylation of NCLX Reverses Mitochondrial Calcium Overload and Depolarization, Promoting Survival of PINK1-Deficient Dopaminergic Neurons
Marko Kostic,
Marthe H.R. Ludtmann,
Hilmar Bading,
Michal Hershfinkel,
Erin Steer,
Charleen T. Chu,
Andrey Y. Abramov,
Israel Sekler
Affiliations
Marko Kostic
Department of Physiology and Cell Biology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA
Marthe H.R. Ludtmann
Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA
Hilmar Bading
Department of Neurobiology, University of Heidelberg, Heidelberg 69120, Germany, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA
Michal Hershfinkel
Department of Physiology and Cell Biology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA
Erin Steer
Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA
Charleen T. Chu
Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA
Andrey Y. Abramov
Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA
Israel Sekler
Department of Physiology and Cell Biology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA
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.
