Mitochondrially localized PKA reverses mitochondrial pathology and dysfunction in a cellular model of Parkinson's disease
- 3 June 2011
- journal article
- research article
- Published by Springer Science and Business Media LLC in Cell Death & Differentiation
- Vol. 18 (12), 1914-1923
- https://doi.org/10.1038/cdd.2011.74
Abstract
Mutations in PTEN-induced kinase 1 (PINK1) are associated with a familial syndrome related to Parkinson's disease (PD). We previously reported that stable neuroblastoma SH-SY5Y cell lines with reduced expression of endogenous PINK1 exhibit mitochondrial fragmentation, increased mitochondria-derived superoxide, induction of compensatory macroautophagy/mitophagy and a low level of ongoing cell death. In this study, we investigated the ability of protein kinase A (PKA) to confer protection in this model, focusing on its subcellular targeting. Either: (1) treatment with pharmacological PKA activators; (2) transient expression of a constitutively active form of mitochondria-targeted PKA; or (3) transient expression of wild-type A kinase anchoring protein 1 (AKAP1), a scaffold that targets endogenous PKA to mitochondria, reversed each of the phenotypes attributed to loss of PINK1 in SH-SY5Y cells, and rescued parameters of mitochondrial respiratory dysfunction. Mitochondrial and lysosomal changes in primary cortical neurons derived from PINK1 knockout mice or subjected to PINK1 RNAi were also reversed by the activation of PKA. PKA phosphorylates the rat dynamin-related protein 1 isoform 1 (Drp1) at serine 656 (homologous to human serine 637), inhibiting its pro-fission function. Mimicking phosphorylation of Drp1 recapitulated many of the protective effects of AKAP1/PKA. These data indicate that redirecting endogenous PKA to mitochondria can compensate for deficiencies in PINK1 function, highlighting the importance of compartmentalized signaling networks in mitochondrial quality control.Keywords
This publication has 41 references indexed in Scilit:
- Perturbations in Mitochondrial Dynamics Induced by Human Mutant PINK1 Can Be Rescued by the Mitochondrial Division Inhibitor mdivi-1*Online Journal of Public Health Informatics, 2010
- Mitochondrial kinases in Parkinson’s disease: Converging insights from neurotoxin and genetic modelsMitochondrion, 2009
- Dephosphorylation by calcineurin regulates translocation of Drp1 to mitochondriaProceedings of the National Academy of Sciences of the United States of America, 2008
- Loss of PINK1 causes mitochondrial functional defects and increased sensitivity to oxidative stressProceedings of the National Academy of Sciences of the United States of America, 2008
- The PINK1/Parkin pathway regulates mitochondrial morphologyProceedings of the National Academy of Sciences of the United States of America, 2008
- Cytoplasmic Pink1 activity protects neurons from dopaminergic neurotoxin MPTPProceedings of the National Academy of Sciences of the United States of America, 2008
- Fission and selective fusion govern mitochondrial segregation and elimination by autophagyThe EMBO Journal, 2008
- Reversible phosphorylation of Drp1 by cyclic AMP‐dependent protein kinase and calcineurin regulates mitochondrial fission and cell deathEMBO Reports, 2007
- Reactive oxygen species are essential for autophagy and specifically regulate the activity of Atg4The EMBO Journal, 2007
- Functional Repression of cAMP Response Element in 6-Hydroxydopamine-treated Neuronal CellsOnline Journal of Public Health Informatics, 2006