Format

Send to

Choose Destination
Antioxid Redox Signal. 2015 Aug 20;23(6):535-49. doi: 10.1089/ars.2014.6102. Epub 2015 Mar 18.

CHIP Is an Essential Determinant of Neuronal Mitochondrial Stress Signaling.

Palubinsky AM1,2,3,4, Stankowski JN1,4,5, Kale AC3,4,6, Codreanu SG7,8, Singer RJ3,9,10, Liebler DC7,8, Stanwood GD4,11, McLaughlin B3,4,6,9,11.

Author information

1
1 Neuroscience Graduate Program, Vanderbilt Brain Institute, Vanderbilt University , Nashville, Tennessee.
2
2 Clinical Neuroscience Scholars Program, Vanderbilt University , Nashville, Tennessee.
3
3 J.B. Marshall Laboratory for Neurovascular Therapeutics, Vanderbilt University , Nashville, Tennessee.
4
4 Kennedy Center for Research on Human Development, Vanderbilt University , Nashville, Tennessee.
5
5 Department of Neuroscience, Mayo Clinic , Jacksonville, Florida.
6
6 Department of Neurology, Vanderbilt University , Nashville, Tennessee.
7
7 Department of Biochemistry, Vanderbilt University , Nashville, Tennessee.
8
8 Department of Biomedical Informatics, Vanderbilt University , Nashville, Tennessee.
9
9 Vanderbilt Institute for Integrative Biosystems Research and Education, Vanderbilt University , Nashville, Tennessee.
10
10 Department of Neurosurgery, Dartmouth Hitchcock Hospital , Lebanon , New Hampshire.
11
11 Department of Pharmacology, Vanderbilt University , Nashville, Tennessee.

Abstract

AIMS:

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.

INNOVATION:

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.

PMID:
25602369
PMCID:
PMC4544748
DOI:
10.1089/ars.2014.6102
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Atypon Icon for PubMed Central
Loading ...
Support Center