Abstract
Parkinson's disease (PD) has multiple proposed etiologies with implication of abnormalities in cellular homeostasis ranging from proteostasis to mitochondrial dynamics to energy metabolism. PINK1 mutations are associated with familial PD and here we discover a novel PINK1 mechanism in cellular stress response. Using hypoxia as a physiological trigger of oxidative stress and disruption in energy metabolism, we demonstrate that PINK1(-/-) mouse cells exhibited significantly reduced induction of HIF-1α protein, HIF-1α transcriptional activity, and hypoxia-responsive gene upregulation. Loss of PINK1 impairs both hypoxia-induced 4E-BP1 dephosphorylation and increase in the ratio of internal ribosomal entry site (IRES)-dependent to cap-dependent translation. These data suggest that PINK1 mediates adaptive responses by activating IRES-dependent translation, and the impairments in translation and the HIF-1α pathway may contribute to PINK1-associated PD pathogenesis that manifests under cellular stress.
Keywords:
4EBP; IRES; PINK1; Parkinson's disease; hypoxia; translation.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Signal Transducing
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Animals
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Blotting, Western
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Carrier Proteins / genetics
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Carrier Proteins / physiology*
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Cell Cycle Proteins
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Cell Line
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Cells, Cultured
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Cycloheximide / pharmacology
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DNA, Complementary / biosynthesis
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DNA, Complementary / genetics
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Eukaryotic Initiation Factors
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Hydrogen Peroxide / metabolism
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Hypoxia, Brain / metabolism*
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Hypoxia-Inducible Factor 1, alpha Subunit / biosynthesis*
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Hypoxia-Inducible Factor 1, alpha Subunit / genetics
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Immunohistochemistry
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Luciferases / genetics
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Mice
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Mice, Knockout
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Phosphoproteins / genetics
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Phosphoproteins / physiology*
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Phosphorylation
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Plasmids / genetics
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Polymerase Chain Reaction
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Protein Biosynthesis / genetics
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Protein Biosynthesis / physiology*
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Protein Kinases / genetics
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Protein Kinases / physiology*
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Protein Synthesis Inhibitors / pharmacology
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RNA Cap Analogs / metabolism
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RNA, Small Interfering / genetics
Substances
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Adaptor Proteins, Signal Transducing
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Carrier Proteins
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Cell Cycle Proteins
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DNA, Complementary
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Eif4ebp1 protein, mouse
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Eukaryotic Initiation Factors
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Hif1a protein, mouse
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Hypoxia-Inducible Factor 1, alpha Subunit
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Phosphoproteins
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Protein Synthesis Inhibitors
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RNA Cap Analogs
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RNA, Small Interfering
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7-methylguanosine triphosphate
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Cycloheximide
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Hydrogen Peroxide
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Luciferases
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Protein Kinases
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PTEN-induced putative kinase