Mistargeted mitochondrial proteins activate a proteostatic response in the cytosol

ABSTRACT: The vast majority of the mitochondrial proteome originates from nuclear genes and is transported into the organelle after synthesis in the cytosol. Complex machineries, which maintain the specificity of protein import and sorting, include the TIM23 translocase responsible for the transfer of precursor proteins into the matrix and the MIA machinery required for the biogenesis of intermembrane space proteins. Dysfunctions of mitochondrial protein sorting pathways result in diminishing specific substrate proteins, followed by systemic pathology of the organelle and organismal death1-4. Cellular responses that are caused by accumulation of mitochondrial precursor proteins in the cytosol are largely unknown. Here we show a comprehensive picture of the changes in the cellular transcriptome and proteome in response to the stress associated with protein import dysfunction. We identify pathways that protect the cell against mitochondrial biogenesis defects by inhibiting protein synthesis and by activation of the proteasome, a major machine for cellular protein clearance. The proteasomal activity is modulated in proportion to the quantity of mislocalized mitochondrial precursor proteins in the cytosol. We propose that this type of unfolded protein response activated by mistargeting of proteins (UPRam) is beneficial for the cells. UPRam provides a means for buffering the consequences of physiological slowdown in mitochondrial protein import and for counteracting pathologies that are caused or contributed by mitochondrial dysfunction.

INSTRUMENT(S): LTQ Orbitrap, LTQ Orbitrap Elite

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

SUBMITTER: Friedel Drepper  

LAB HEAD: Bettina Warscheid

PROVIDER: PXD001495 | Pride | 2015-07-31

REPOSITORIES: Pride