MRNAseq and proteomic data set of one week old WT (Chop wt/wt CkmmCre wt/wt Dars2 fl/fl), Chop KO (Chop ko/ko CkmmCre wt/wt Dars2 fl/fl), Dars2 KO (Chop wt/wt CkmmCre tg/wt Dars2 fl/fl) and DKO (Chop ko/ko CkmmCre tg/wt Dars2 fl/fl) mice

ABSTRACT: Maintenance of mitochondrial homeostasis is essential for a broad spectrum of signalling, metabolic and energetic processes. Consequently, mitochondrial dysfunction is linked to the development of a wide range of myopathies and many common diseases including type 2 diabetes, Parkinson’s and Alzheimer’s diseases. In response to disturbed mitochondrial proteostasis, an organelle-specific stress response is initiated, which results in a global adaptive transcriptional response partially sharing the signature of the integrated stress response (ISR). However, the exact sequence of events of the signalling cascade resulting in the activation of the ISR remains elusive. CHOP was the first transcription factor (TF) proposed to play a role in this process, although - due to the lack of a trans-activating domain - it needs to heterodimerize with other TFs to activate or suppresses its target genes. Therefore, we decided to investigate the molecular aspects and in vivo functions of CHOP in a murine model of mitochondrial dysfunction triggered by the loss of mitochondrial translation. Disruption of mitochondrial translation by heart and skeletal muscle-specific knock-out of the mitochondrial aspartyl-tRNA synthetase DARS2 on its own results in death of the animals within 7-8 weeks. Additional deletion of CHOP even further reduces the lifespan to less than 3 weeks, suggesting an existential role of the TF within the initiated stress signalling pathway. Our recent data indicates that CHOP's impact arises from the regulation of another TF with detrimental effects when exceedingly activated under certain circumstances: ATF4.

ORGANISM(S): Mus musculus

PROVIDER: GSE149010 | GEO | 2022/04/04

REPOSITORIES: GEO