In mammals, UPR has mostly been studied using transfection with a truncated, dysfunctional mitochondrial enzyme (OTCΔ) that does not fold correctly after translocation into the mitochondrial matrix. Using this approach, several components of the mammalian UPR have been identified including the mitochondrial chaperone heat shock protein 60 (Hsp60), the mitochondrial caseinolytic peptidase ClpP, the transcription factor Chop and the kinases c-Jun N-terminal kinase (JNK) and the interferon-induced, double-stranded RNA-activated protein kinase (Pkr).
The appropriately named activating transcription factor associated with stress (ATFS-1) is one of the primary transcription factors required for UPR activation in worms. ATFS-1 has a nuclear localization sequence that allows it to be imported into the nucleus as well as an N-terminal mitochondrial targeting sequence (MTS) that allows for import into the mitochondria.  In healthy cells, ATFS-1 is preferentially targeted to the mitochondrial matrix where it is degraded by the Lon protease. The MTS on ATFS-1 is predicted by Mitofates to be substantially weaker than most MTSs which would allow it to be sensitive to subtle mitochondrial dysfunction. Following mitochondrial stress, ATFS-1 mitochondrial import efficiency is decreased resulting in a cytoplasmic accumulation of ATFS-1.  Subsequently, ATFS-1 will enter the nucleus via its nuclear transport signal.  In the nucleus, ATFS-1 has a broad transcriptional regulation as it will: attenuate OXPHOS gene expression in both the nucleus and mitochondria, upregulate chaperones and proteases to re-establish mitochondrial proteostasis, increase ROS detoxification, and increase mitochondrial import machinery.