RGD Reference Report - Neuronal Preconditioning Requires the Mitophagic Activity of C-terminus of HSC70-Interacting Protein. - Rat Genome Database

Send us a Message
Submit Data |  Help |  Video Tutorials |  News |  Publications |  Download |  REST API |  Citing RGD |  Contact   
Search RGD Grant Resources Citing RGD About Us Contact Us
Genes Variants Community Projects QTLs Strains Markers Genome Information Ontologies Cell Lines References Download Submit Data
OntoMate (Literature Search) JBrowse (Genome Browser) Synteny Browser (VCMap) Variant Visualizer Multi-Ontology Enrichment (MOET) Gene-Ortholog Location Finder (GOLF) InterViewer (Protein-Protein Interactions) PhenoMiner (Quatitative Phenotypes) Gene Annotator OLGA (Gene List Generator) AllianceMine GViewer (Genome Viewer)
Aging & Age-Related Disease Cancer & Neoplastic Disease Cardiovascular Disease Coronavirus Disease Developmental Disease Diabetes Hematologic Disease Immune & Inflammatory Disease Infectious Disease Liver Disease Neurological Disease Obesity & Metabolic Syndrome Renal Disease Respiratory Disease Sensory Organ Disease
Find Models Genetic Models Autism Models Rat PhenoMiner (Quantitative Phenotypes) Chinchilla PhenoMiner Expected Ranges (Quantitative Phenotype) PhenoMiner Term Comparison Hybrid Rat Diversity Panel Phenotypes Phenotypes in Other Animal Models Animal Husbandry Strain Medical Records Phylogenetics Strain Availability Calendar Rats 101 Submissions Photo Archive
Pathways
Rat Community Forum Directory of Rat Laboratories Video Tutorials News RGD Publications RGD Presentations Archive Nomenclature Guidelines Resource Links Laboratory Resources Employment Resources
Advanced Search (OLGA)

Neuronal Preconditioning Requires the Mitophagic Activity of C-terminus of HSC70-Interacting Protein.

Authors: Lizama, Britney N  Palubinsky, Amy M  Raveendran, Vineeth A  Moore, Annah M  Federspiel, Joel D  Codreanu, Simona G  Liebler, Daniel C  McLaughlin, BethAnn 
Citation: Lizama BN, etal., J Neurosci. 2018 Aug 1;38(31):6825-6840. doi: 10.1523/JNEUROSCI.0699-18.2018. Epub 2018 Jun 22.
RGD ID: 405650300
Pubmed: PMID:29934347   (View Abstract at PubMed)
PMCID: PMC6070662   (View Article at PubMed Central)
DOI: DOI:10.1523/JNEUROSCI.0699-18.2018   (Journal Full-text)

The C terminus of HSC70-interacting protein (CHIP, STUB1) is a ubiquitously expressed cytosolic E3-ubiquitin ligase. CHIP-deficient mice exhibit cardiovascular stress and motor dysfunction before premature death. This phenotype is more consistent with animal models in which master regulators of autophagy are affected rather than with the mild phenotype of classic E3-ubiquitin ligase mutants. The cellular and biochemical events that contribute to neurodegeneration and premature aging in CHIP KO models remain poorly understood. Electron and fluorescent microscopy demonstrates that CHIP deficiency is associated with greater numbers of mitochondria, but these organelles are swollen and misshapen. Acute bioenergetic stress triggers CHIP induction and relocalization to mitochondria, where it plays a role in the removal of damaged organelles. This mitochondrial clearance is required for protection following low-level bioenergetic stress in neurons. CHIP expression overlaps with stabilization of the redox stress sensor PTEN-inducible kinase 1 (PINK1) and is associated with increased LC3-mediated mitophagy. Introducing human promoter-driven vectors with mutations in either the E3 ligase or tetracopeptide repeat domains of CHIP in primary neurons derived from CHIP-null animals enhances CHIP accumulation at mitochondria. Exposure to autophagy inhibitors suggests that the increase in mitochondrial CHIP is likely due to diminished clearance of these CHIP-tagged organelles. Proteomic analysis of WT and CHIP KO mouse brains (four male, four female per genotype) reveals proteins essential for maintaining energetic, redox, and mitochondrial homeostasis undergo significant genotype-dependent expression changes. Together, these data support the use of CHIP-deficient animals as a predictive model of age-related degeneration with selective neuronal proteotoxicity and mitochondrial failure.SIGNIFICANCE STATEMENT Mitochondria are recognized as central determinants of neuronal function and survival. We demonstrate that C terminus of HSC70-Interacting Protein (CHIP) is critical for neuronal responses to stress. CHIP upregulation and localization to mitochondria is required for mitochondrial autophagy (mitophagy). Unlike other disease-associated E3 ligases such as Parkin and Mahogunin, CHIP controls homeostatic and stress-induced removal of mitochondria. Although CHIP deletion results in greater numbers of mitochondria, these organelles have distorted inner membranes without clear cristae. Neuronal cultures derived from animals lacking CHIP are more vulnerable to acute injuries and transient loss of CHIP renders neurons incapable of mounting a protective response after low-level stress. Together, these data suggest that CHIP is an essential regulator of mitochondrial number, cell signaling, and survival.



Gene Ontology Annotations    Click to see Annotation Detail View

Biological Process

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
Stub1Ratpositive regulation of mitophagy involved_inIMP PMID:29934347UniProt 

Cellular Component

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
Stub1Ratmitochondrion located_inIDA PMID:29934347UniProt 

Objects Annotated

Genes (Rattus norvegicus)
Stub1  (STIP1 homology and U-box containing protein 1)


Additional Information