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

Cell Rep. 2015 Oct 13;13(2):376-86. doi: 10.1016/j.celrep.2015.08.079. Epub 2015 Oct 1.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Calcium / metabolism*
  • Calcium / toxicity
  • Cell Line, Tumor
  • Cyclic AMP-Dependent Protein Kinases / metabolism*
  • Dopaminergic Neurons / metabolism*
  • HEK293 Cells
  • Humans
  • Membrane Potential, Mitochondrial*
  • Mice
  • Mitochondria / metabolism
  • Phosphorylation
  • Protein Kinases / genetics
  • Protein Kinases / metabolism*
  • Sodium-Calcium Exchanger / genetics
  • Sodium-Calcium Exchanger / metabolism*

Substances

  • Slc8b1protein, mouse
  • Sodium-Calcium Exchanger
  • Protein Kinases
  • PTEN-induced putative kinase
  • Cyclic AMP-Dependent Protein Kinases
  • Calcium