Figure 1. UPR^mt activation via ATFS-1 regulates a broad transcriptional program.

(A) In response to mitochondrial damage or stress ATFS-1 induces genes involved in mitochondrial repair mechanisms including protein folding and protein quality control, as well as those involved in mitochondrial biogenesis, the detoxification response, metabolism and innate immune gene transcription. (B) The UPR^mt is activated during conditions such as mtDNA depletion, respiratory chain dysfunction, increased ROS or increased mitochondrial unfolded proteins, which is regulated by the mitochondrial protein-import efficiency of the transcription factor ATFS-1. In the absence of stress, ATFS-1 localizes to mitochondria via its mitochondria targeting signal (MTS), where it is degraded by the protease Lon. However, during mitochondrial dysfunction or stress, general mitochondrial protein import is attenuated, leading to the accumulation of a portion of ATFS-1 in the cytosol, followed by its translocation to the nucleus via its nuclear localization signal (NLS). In the nucleus, ATFS-1 induces the mitochondrial protective genes described in Figure 1A, which promote survival and recovery from mitochondrial stress.