Статья

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

Marko KostićDepartment 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, USAMarthe H. R. LudtmannDepartment of Molecular Neuroscience, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USAHilmar BadingDepartment of Neurobiology, University of Heidelberg, Heidelberg 69120, Germany, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USAMichal HershfinkelDepartment 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, USAErin SteerDepartment of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USACharleen T. ChuDepartment of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA; Center for Neuroscience, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USAAndrey Y. AbramovDepartment 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: [email protected]Israel SeklerDepartment 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: [email protected]

2015en

ABI

Аннотация

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.

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Идентификаторы

DOI: 10.1016/j.celrep.2015.08.079

Цитирования и источники

Цитирований: 2Использованных источников: 0

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