CHIP Is an Essential Determinant of Neuronal Mitochondrial Stress Signaling

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, PTENinducible 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 p66shc . 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. Antioxid. Redox Signal. 23, 535-549.

Sphingosine kinase 2 activates autophagy and protects neurons against ischemic injury through interaction with Bcl-2 via its putative BH3 domain

“…The LC3II was increased after SPK2 overexpression compared with LV-vector-infected neurons. OGD upregulated LC3II, in agreement with published results, 16 , 27 , 28 , 29 , 30 , 31 while SPK2 overexpression further increased LC3II after OGD treatment ( Figure 2a ). We then examined the autophagic flux in SPK2-overexpressing neurons using ammonium chloride (NH 4 Cl), an inhibitor of lysosome-phagosome fusion.…”

The complex phenotype of spinocerebellar ataxia type 48 in eight unrelated Italian families

“…Therefore, in the absence of functional studies, it can only be hypothesized that the novel STUB1 variants identified in the present study may be detrimental for neuronal function, by either impairing protein ubiquitination or affecting the activities of HSP70 and HSP90 chaperones . Experimental data also suggest that stress‐associated molecules typically linked to parkinsonism, such as the PTEN‐inducible putative kinase 1 (PINK1) and Parkin, are upregulated in the brains of CHIP knockout mice , but further studies are needed to clarify if this issue might contribute to the pathogenesis of SCA48 and SCAR16.…”

rAAV8-733-Mediated Gene Transfer of CHIP/Stub-1 Prevents Hippocampal Neuronal Death in Experimental Brain Ischemia

“…Furthermore, the same group has reported the role of CHIP in the maintenance of mitochondria homeostasis, hence regulating neuronal survival following OGD. 25 Results of experiments in both in vivo and in vitro models of brain ischemia have disclosed an increased level of clustered ubiquitinated proteins that may lead to protein aggregates in neurons of the hippocampal CA1 region and ensuing cell death. 10 It has been suggested that irreversible aggregation of translational complex components, chaperones, and protein folding enzymes following brain ischemia lead to inhibition of translation and subsequent neuron death.…”