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Proteotoxic stress induced by mRNA mistranslation leads to proteome aggregation and mitochondrial dysfunction in vertebrates.

ABSTRACT: Protein misfolding and aggregation deregulate the proteostasis network and are hallmarks of cell degeneration processes associated with aging and human diseases. But how proteome aggregation causes cell degeneration remains controversial due to the lack of suitable methods for controlling proteome aggregation at the cellular and organismal levels. To overcome this limitation, we have generated zebrafish embryos that exhibit protein aggregation due to misincorporation of Serine (Ser) at non-cognate protein sites on a proteome wide scale. These mistranslating embryos display up regulation of the unfolded protein response (UPR) and the ubiquitin proteasome pathway (UPP), increased protein ubiquitination and down-regulation of protein biosynthesis. Proteome damage also induces major disruption of the mitochondrial network, accompanied by mitochondrial and nuclear DNA damage and accumulation of reactive oxygen species (ROS). Taken together, our data highlight important roles of gene translational accuracy in the maintenance of ER homeostasis, DNA damage, mitochondrial function and oxidative stress. We postulate that protein biosynthesis errors (PBE) contribute to proteome aggregation and are a main cause of mitochondrial disruption.

ORGANISM(S): Danio rerio

PROVIDER: GSE50090 | GEO | 2018/01/29

REPOSITORIES: GEO

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