In the most conserved branch of the UPR ER, IRE1 is activated by its dissociation from BiP this results in IRE1 oligomerization and activation of its cytosolic domain, which contains a sequence-specific RNase activity that splices the X-box binding protein 1 ( XBP1) mRNA. Inositol-requiring 1 (IRE1), protein-kinase-like endoplasmic reticulum kinase (PERK) and activating transcription factor 6 (ATF6) all monitor the protein-folding status in the ER lumen through direct interactions with the ER chaperone-binding immunoglobulin protein (BiP) ( Ma and Hendershot, 2001 Ron and Walter, 2007). The UPR ER is a tripartite signaling pathway that is regulated by three ER-localized transmembrane proteins. Signaling within the UPR ER is significantly complicated by the need to transduce the signal across the ER membrane to the nucleus ( Fig. The subsequent increase in chaperones re-establishes protein-folding homeostasis and the excess of free DnaK is able to interact with σ32 to repress the response ( Straus et al., 1990 Tilly et al., 1983). Upon accumulation of unfolded proteins, DnaK preferentially interacts with clients and releases σ32 to activate transcription of the heat-shock operon. For example, in Escherichia coli, the transcription factor σ32 is repressed by the Hsp70 chaperone DnaK ( Guisbert et al., 2004). Studies of chaperone expression in response to unfolded protein accumulation have revealed a conserved signaling paradigm, where signaling is repressed by free chaperones that are not engaged by client proteins. Maintenance of protein-folding homeostasis is essential for all organisms and requires molecular chaperones, which promote a functional protein-folding environment by preventing the aggregation of newly synthesized, newly imported or stress-denatured proteins, as well as by facilitating efficient folding and complex assembly of nascent polypeptides. Here, we review the current knowledge of this mitochondrial unfolded protein response (UPR mt), compare it with the better understood UPR of the endoplasmic reticulum and highlight its potential impact on development and disease. ![]() Work in cultured mammalian cells and Caenorhabditis elegans has yielded clues to the mechanisms linking perturbations in the protein-folding environment in the mitochondrial matrix to the expression of nuclear genes encoding mitochondrial proteins. Mitochondria have dedicated molecular chaperones and proteases that promote proper protein folding, complex assembly and quality control. The protein-folding environment in mitochondria is challenged by organelle architecture, the presence of reactive oxygen species and the difficulties associated with assembly of the electron transport chain, which consists of components encoded by both the mitochondrial and the nuclear genomes. Mitochondria are required for numerous essential metabolic processes including the regulation of apoptosis therefore, proper maintenance of the mitochondrial proteome is crucial.
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