The UPR^mt preserves mitochondrial import to extend lifespan

The mitochondrial unfolded protein response (UPR^mt) is dedicated to promoting mitochondrial proteostasis and is linked to extreme longevity. The key regulator of this process is the transcription factor ATFS-1, which, upon UPR^mt activation, is excluded from the mitochondria and enters the nucleus to regulate UPR^mt genes. However, the repair proteins synthesized as a direct result of UPR^mt activation must be transported into damaged mitochondria that had previously excluded ATFS-1 owing to reduced import efficiency. To address this conundrum, we analyzed the role of the import machinery when the UPR^mt was induced. Using in vitro and in vivo analysis of mitochondrial proteins, we surprisingly find that mitochondrial import increases when the UPR^mt is activated in an ATFS-1–dependent manner, despite reduced mitochondrial membrane potential. The import machinery is upregulated, and an intact import machinery is essential for UPR^mt-mediated lifespan extension. ATFS-1 has a weak mitochondrial targeting sequence (MTS), allowing for dynamic subcellular localization during the initial stages of UPR^mt activation.