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.