FIGURE 2.

The mitochondrial unfolded protein response. (A) ATFS-1 is a unique protein that can serve as a sensor for mitochondrial health and fitness. It contains both a nuclear localization signal (NLS) and a mitochondrial localization signal (MLS). Under basal, unstressed conditions, ATFS-1 is imported into the mitochondria where it is degraded by LON protease. Under conditions of mitochondrial stress or damage, mitochondrial import decreases, allowing ATFS-1 to instead accumulate in the mitochondria where it can activate UPR^MT with additional transcriptional regulators including DVE-1 and chromatin regulator JMJD-1.2. (B) Similar to the HSR, UPR^MT can also be communicated in a nonautonomous manner. Neurons that experience mitochondrial stress can signal to the peripheral tissue, including the intestine, through serotonin and WNT signaling to result in systemic activation of UPR^MT, increased stress resilience, and increased lifespan.