The UPR^mtPreserves Mitochondrial Import to Extend Lifespan

SummaryThe mitochondrial unfolded protein response (UPRmt) is dedicated to promote mitochondrial proteostasis and is linked to extreme longevity in worms, flies, and mice. The key regulator of this process is the transcription factor, ATFS-1. In the absence of mitochondrial stress, ATFS-1 is transported to the mitochondria and degraded. During conditions of mitochondrial stress, ATFS-1 is excluded from the mitochondria and enters the nucleus to regulate the expression of UPRmtgenes. However, there exists a dichotomy in regards to induction of the UPRmtand mitochondrial import. The repair proteins synthesized as a direct result of UPRmtactivation must be transported into damaged mitochondria that had previously excluded ATFS-1 due to reduced import efficiency. To address this conundrum, we analyzed the role of the import machinery under conditions where the UPRmtwas induced. Usingin vitrobiochemical assays of mitochondrial import andin vivoanalysis of mitochondrial proteins, we surprisingly find that the efficiency of mitochondrial import increases when the UPRmtis activated in an ATFS-1 dependent manner, even though membrane potential is reduced. The import machinery is upregulated at the transcription and translation level, and intact import machinery is essential for UPRmt-mediated increase and lifespan extension. With age, import capacity decreases, and activation of the UPRmtdelays this decline and increases longevity. Finally, we find that ATFS-1 has a significantly weaker mitochondrial targeting sequence (MTS), allowing for dynamic subcellular localization during the initial stages of UPRmtactivation.