The UPRmt Preserves Mitochondrial Import to Extend Lifespan

Authors

Nan Xin
Jenni Durieux
Chunxia Yang
Suzanne Wolff
Hyun-Eui Kim
Andrew Dillin

Publication Date

7-4-2022

Journal

Journal of Cell Biology

Abstract

The mitochondrial unfolded protein response (UPRmt) 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 UPRmt activation, is excluded from the mitochondria and enters the nucleus to regulate UPRmt genes. However, the repair proteins synthesized as a direct result of UPRmt 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 UPRmt was induced. Using in vitro and in vivo analysis of mitochondrial proteins, we surprisingly find that mitochondrial import increases when the UPRmt 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 UPRmt-mediated lifespan extension. ATFS-1 has a weak mitochondrial targeting sequence (MTS), allowing for dynamic subcellular localization during the initial stages of UPRmt activation.

Keywords

Animals, Caenorhabditis elegans, Caenorhabditis elegans Proteins, Longevity, Mitochondria, Mitochondrial Proteins, Transcription Factors, Unfolded Protein Response