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

R. K. Dagda, A. M. Gusdon, I. Pien, S. Strack, S. Green, C. Li, B. Van Houten, S. J. Cherra, C. T. Chu

Research output: Contribution to journalArticlepeer-review

123 Scopus citations

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.

Original languageEnglish
Pages (from-to)1914-1923
Number of pages10
JournalCell Death and Differentiation
Volume18
Issue number12
DOIs
StatePublished - Dec 2011

Bibliographical note

Funding Information:
Acknowledgements. We thank Simon Watkins and Center for Biological Imaging (CBI) staff Mara Sullivan and Ming Sun at the University of Pittsburgh for assistance with EM imaging. This research was supported by the National Institutes of Health (AG026389, NS065789). CTC is recipient of an AFAR/Ellison Medical Foundation Julie Martin Mid-Career Award in Aging Research. RKD was supported in part by F32 AG030821 and by a Pathology Post-doctoral Research Training Program (PPRTP) grant (University of Pittsburgh).

Keywords

  • 6-hydroxydopamine
  • AKAP1
  • PINK1
  • PKA
  • mitochondria and mitophagy
  • neurodegeneration

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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