title: Mitochondrially localized PKA reverses mitochondrial pathology and dysfunction in a cellular model of Parkinson's disease.
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.
authors.affiliation: Department of Pathology, University of Pittsburgh School of Medicine, 200 Lothrop Street, Pittsburgh, PA 15261, USA.
authors.forename: R K
authors.initials: RK
authors.lastname: Dagda
authors.forename: A M
authors.initials: AM
authors.lastname: Gusdon
authors.forename: I
authors.initials: I
authors.lastname: Pien
authors.forename: S
authors.initials: S
authors.lastname: Strack
authors.forename: S
authors.initials: S
authors.lastname: Green
authors.forename: C
authors.initials: C
authors.lastname: Li
authors.forename: B
authors.initials: B
authors.lastname: Van Houten
authors.forename: S J
authors.initials: SJ
authors.lastname: Cherra
authors.forename: C T
authors.initials: CT
authors.lastname: Chu
mesh_terms: D054758:A Kinase Anchor Proteins / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D045744:Cell Line, Tumor; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D034281:Dynamins; D020536:Enzyme Activators / Q000494:pharmacology; D020558:GTP Phosphohydrolases / Q000378:metabolism; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism* / Q000473:pathology; D051336:Mitochondrial Membranes / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000378:metabolism*; D010300:Parkinson Disease; D010766:Phosphorylation; D011494:Protein Kinases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000099202:PTEN-Induced Putative Kinase
chemical_list: D054758:A Kinase Anchor Proteins; D017868:Cyclic AMP-Dependent Protein Kinases; D034281:Dynamins; D020536:Enzyme Activators; D020558:GTP Phosphohydrolases; D008869:Microtubule-Associated Proteins; D024101:Mitochondrial Proteins; D011494:Protein Kinases; D000099202:PTEN-Induced Putative Kinase; C105137:AKAP1 protein, human; C110768:DNM1L protein, human