Mitoprotein-induced stress launches a global transcriptional fail-safe program

ABSTRACT: Most mitochondrial proteins are synthesized as cytosolic precursor proteins before being imported into mitochondria. Cytosolic accumulation of mitochondrial precursors hazards cellular fitness and is associated with a growing number of diseases, but is not observed under physiological conditions. Individual mechanisms that allow cells to avoid cytosolic accumulation of mitochondrial precursors have recently been discovered, but their interplay and regulation remain elusive. Here we show that cells rapidly launch a global transcriptional program to restore cellular proteostasis after induction of a “clogger” protein that reduces the number of available mitochondrial import sites. Cells upregulate the protein folding and proteolytic systems in the cytosol and downregulate both the cytosolic translation machinery and many mitochondrial metabolic enzymes, presumably to relieve the workload of the overstrained mitochondrial import system. We show that this transcriptional remodeling is a combination of a “wideband” core response regulated by the transcription factors Hsf1 and Rpn4 and a unique mitoprotein-induced downregulation of the oxidative phosphorylation components, the most abundant group of precursorsmediated by an inactivation of the Hap2/3/4/5 complex. These findings depict the first comprehensive, time-resolved model of adaptations to mitochondrial import impairment. This reveals the regulation of previously described reactions and combines them with a so far unidentified mitochondrion-specific arm into an overarching coordinated network of the cellular mitoprotein-induced stress response.

OTHER RELATED OMICS DATASETS IN: GSE116749

INSTRUMENT(S): Q Exactive

ORGANISM(S): Saccharomyces Cerevisiae (baker's Yeast)

TISSUE(S): Cell Culture

SUBMITTER: Felix Boos  

LAB HEAD: Johannes M. Herrmann

PROVIDER: PXD011789 | Pride | 2019-01-14

REPOSITORIES: Pride