[HTML][HTML] Mitochondrially localized PKA reverses mitochondrial pathology and dysfunction in a cellular model of Parkinson's disease

RK Dagda, AM Gusdon, I Pien, S Strack… - Cell Death & …, 2011 - nature.com
RK Dagda, AM Gusdon, I Pien, S Strack, S Green, C Li, B Van Houten, SJ Cherra, CT Chu
Cell Death & Differentiation, 2011nature.com
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 …
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.
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