title: PKA Phosphorylation of NCLX Reverses Mitochondrial Calcium Overload and Depolarization, Promoting Survival of PINK1-Deficient Dopaminergic Neurons.
abstract: Mitochondrial Ca(2+) 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(+)/Ca(2+) exchanger (NCLX), leading to impaired mitochondrial Ca(2+) 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 (NCLX(S258D)) prevents mitochondrial Ca(2+) overload and mitochondrial depolarization in PINK1 knockout neurons, thereby enhancing neuronal survival. Our results identify an mitochondrial Ca(2+) transport regulatory pathway that protects against mitochondrial Ca(2+) overload. Because mitochondrial Ca(2+) dyshomeostasis is a prominent feature of multiple disorders, the link between NCLX and PKA may offer a therapeutic target.
authors.affiliation: 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.
authors.forename: Marko
authors.initials: M
authors.lastname: Kostic
authors.affiliation: Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA.
authors.forename: Marthe H R
authors.initials: MH
authors.lastname: Ludtmann
authors.affiliation: Department of Neurobiology, University of Heidelberg, Heidelberg 69120, Germany, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA.
authors.forename: Hilmar
authors.initials: H
authors.lastname: Bading
authors.affiliation: 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.
authors.forename: Michal
authors.initials: M
authors.lastname: Hershfinkel
authors.affiliation: Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA.
authors.forename: Erin
authors.initials: E
authors.lastname: Steer
authors.affiliation: Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA; Center for Neuroscience, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA.
authors.forename: Charleen T
authors.initials: CT
authors.lastname: Chu
authors.affiliation: Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA. Electronic address: a.abramov@ucl.ac.uk.
authors.forename: Andrey Y
authors.initials: AY
authors.lastname: Abramov
authors.affiliation: 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. Electronic address: sekler@bgu.ac.il.
authors.forename: Israel
authors.initials: I
authors.lastname: Sekler
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism* / Q000633:toxicity; D045744:Cell Line, Tumor; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D059290:Dopaminergic Neurons / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D053078:Membrane Potential, Mitochondrial; D051379:Mice; D008928:Mitochondria / Q000378:metabolism; D010766:Phosphorylation; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism*; D019831:Sodium-Calcium Exchanger / Q000235:genetics / Q000378:metabolism*; D000099202:PTEN-Induced Putative Kinase
chemical_list: D002118:Calcium; D017868:Cyclic AMP-Dependent Protein Kinases; D011494:Protein Kinases; D019831:Sodium-Calcium Exchanger; D000099202:PTEN-Induced Putative Kinase; C588042:Slc8b1protein, mouse