Fig. 1.

Overview of the mitochondrial unfolded protein response (UPR^mt) signaling in Caenorhabditis elegans. Chaperones heat shock protein (HSP)-6, HSP-60 and the protease CLPP-1 perform protein quality control in the mitochondria. When unfolded, misfolded or unassembled proteins accumulate in the matrix, CLPP-1 cleaves the proteins into short peptides, which are exported by the transporter HAF-1 into the cytoplasm and thereby inhibit mitochondrial protein import. As a result, the transcription factor ATFS-1 cannot be imported into mitochondria for degradation, and therefore translocates to the nucleus, where, presumably in a complex with small ubiquitin-like protein UBL-5 and homeodomain-containing transcription factor DVE-1, it activates the transcription of stress response genes, which reconstitute mitochondrial homeostasis. In a complementary pathway, reactive oxygen species (ROS), generated by oxidative phosphorylation (OXPHOS) complexes (I–V) under stress, activate GCN-2 kinase, which inhibits cytosolic protein translation by phosphorylation of eukaryotic translation initiation factor 2α (eIF2α), thus reducing the protein-folding load in the mitochondria. TIM, translocase of inner membrane complex; TOM, translocase of outer membrane complex; NLS, nuclear localization/export sequence; MTS, mitochondrial targeting sequence; mt, mitochondria.