Figure 1.

Regulation of the UPR^mt in C. elegans and mammals. A, in C. elegans, the UPR^mt is principally regulated by the bZIP transcription factor ATFS-1 that contains both mitochondrial and nuclear sorting sequences. In the absence of mitochondrial stress, ATFS-1 localizes to mitochondria and is degraded by the protease Lon. Perturbation to mitochondrial function reduces mitochondrial import efficiency causing an accumulation of cytosolic ATFS-1 and subsequent nuclear import. ATFS-1 regulates a diverse transcriptional program to recover mitochondrial function, including the attenuation of OXPHOS gene expression in both the nucleus and mitochondria. Multiple regulators of the UPR^mt have been identified, including the protease ClpP and the ABC transporter HAF-1 that control UPR^mt activity through an unidentified mechanism involving peptide efflux. B, mammalian UPR^mt is regulated by the transcription factors CHOP and ATF5 that transcriptionally regulate genes to restore mitochondrial homeostasis. CHOP is transcriptionally activated by transcription factor c-Jun during mitochondrial stress. ATF5 contains mitochondrial and nuclear localization sequences similar to ATFS-1 that regulate UPR^mt activity based on the efficiency of mitochondrial import.