title: CHIP Is an Essential Determinant of Neuronal Mitochondrial Stress Signaling.
abstract: OBJECTIVE
  Determine the mechanism by which C-terminus of HSC70-interacting protein (CHIP) induction alters neuronal survival under conditions of mitochondrial stress induced by oxygen glucose deprivation.
  
  
  RESULTS
  We report that animals deficient in the E3 ubiquitin ligase, CHIP, have high baseline levels of central nervous system protein oxidation and lipid peroxidation, reduced antioxidant defenses, and decreased energetic status. Stress-associated molecules typically linked to Parkinson's disease such as the mitochondrial kinase, PTEN-inducible putative kinase 1 (PINK1), and another E3 ligase, Parkin, are upregulated in brains from CHIP knockout (KO) animals. Utilizing a novel biotin-avidin capture technique, we found that the oxidation status of Parkin and the mitochondrial fission protein, dynamin-related protein 1 (Drp1), are altered in a CHIP-dependent manner. We also found that following oxygen-glucose deprivation (OGD), the expression of CHIP, PINK1, and the autophagic marker, LC3, increase and there is activation of the redox-sensitive kinase p66(shc). Under conditions of OGD, CHIP relocalizes from the cytosol to mitochondria. Mitochondria from CHIP KO mice have profound impairments in stress response induced by calcium overload, resulting in accelerated permeability transition activity. While CHIP-deficient neurons are morphologically intact, they are more susceptible to OGD consistent with a previously unknown neuroprotective role for CHIP in maintaining mitochondrial homeostasis.
  
  
  METHODS
  CHIP relocalization to the mitochondria is essential for the regulation of mitochondrial integrity and neuronal survival following OGD.
  
  
  CONCLUSIONS
  CHIP is an essential regulator of neuronal bioenergetics and redox tone. Altering the expression of this protein has profound effects on neuronal survival when cells are exposed to OGD.
authors.affiliation: 1 Neuroscience Graduate Program, Vanderbilt Brain Institute, Vanderbilt University , Nashville, Tennessee.|2 Clinical Neuroscience Scholars Program, Vanderbilt University , Nashville, Tennessee.|3 J.B. Marshall Laboratory for Neurovascular Therapeutics, Vanderbilt University , Nashville, Tennessee.|4 Kennedy Center for Research on Human Development, Vanderbilt University , Nashville, Tennessee.
authors.forename: Amy M
authors.initials: AM
authors.lastname: Palubinsky
authors.affiliation: 1 Neuroscience Graduate Program, Vanderbilt Brain Institute, Vanderbilt University , Nashville, Tennessee.|4 Kennedy Center for Research on Human Development, Vanderbilt University , Nashville, Tennessee.|5 Department of Neuroscience, Mayo Clinic , Jacksonville, Florida.
authors.forename: Jeannette N
authors.initials: JN
authors.lastname: Stankowski
authors.affiliation: 3 J.B. Marshall Laboratory for Neurovascular Therapeutics, Vanderbilt University , Nashville, Tennessee.|4 Kennedy Center for Research on Human Development, Vanderbilt University , Nashville, Tennessee.|6 Department of Neurology, Vanderbilt University , Nashville, Tennessee.
authors.forename: Alixandra C
authors.initials: AC
authors.lastname: Kale
authors.affiliation: 7 Department of Biochemistry, Vanderbilt University , Nashville, Tennessee.|8 Department of Biomedical Informatics, Vanderbilt University , Nashville, Tennessee.
authors.forename: Simona G
authors.initials: SG
authors.lastname: Codreanu
authors.affiliation: 3 J.B. Marshall Laboratory for Neurovascular Therapeutics, Vanderbilt University , Nashville, Tennessee.|9 Vanderbilt Institute for Integrative Biosystems Research and Education, Vanderbilt University , Nashville, Tennessee.|10 Department of Neurosurgery, Dartmouth Hitchcock Hospital , Lebanon , New Hampshire.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Singer
authors.affiliation: 7 Department of Biochemistry, Vanderbilt University , Nashville, Tennessee.|8 Department of Biomedical Informatics, Vanderbilt University , Nashville, Tennessee.
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Liebler
authors.affiliation: 4 Kennedy Center for Research on Human Development, Vanderbilt University , Nashville, Tennessee.|11 Department of Pharmacology, Vanderbilt University , Nashville, Tennessee.
authors.forename: Gregg D
authors.initials: GD
authors.lastname: Stanwood
authors.affiliation: 3 J.B. Marshall Laboratory for Neurovascular Therapeutics, Vanderbilt University , Nashville, Tennessee.|4 Kennedy Center for Research on Human Development, Vanderbilt University , Nashville, Tennessee.|6 Department of Neurology, Vanderbilt University , Nashville, Tennessee.|9 Vanderbilt Institute for Integrative Biosystems Research and Education, Vanderbilt University , Nashville, Tennessee.|11 Department of Pharmacology, Vanderbilt University , Nashville, Tennessee.
authors.forename: BethAnn
authors.initials: B
authors.lastname: McLaughlin
mesh_terms: D000818:Animals; D001343:Autophagy; D015687:Cell Hypoxia; D002478:Cells, Cultured; D005947:Glucose / Q000378:metabolism; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism*; D063154:Mitochondrial Dynamics; D009474:Neurons / Q000378:metabolism*; D010084:Oxidation-Reduction; D014176:Protein Biosynthesis; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D013312:Stress, Physiological; D044767:Ubiquitin-Protein Ligases / Q000502:physiology*
chemical_list: C492951:Stub1 protein, mouse; D044767:Ubiquitin-Protein Ligases; D005947:Glucose