A tRNA processing enzyme is a key regulator of the mitochondrial unfolded protein response.

The mitochondrial unfolded protein response (UPR mt ) has emerged as a predominant mechanism that preserves mitochondrial function. Consequently, multiple pathways likely exist to modulate UPR mt . We discovered that the tRNA processing enzyme, homolog of ELAC2 (HOE-1), is key to UPR mt regulation in Caenorhabditis elegans . We find that nuclear HOE-1 is necessary and sufficient to robustly activate UPR mt . We show that HOE-1 acts via transcription factors ATFS-1 and DVE-1 that are crucial for UPR mt . Mechanistically, we show that HOE-1 likely mediates its effects via tRNAs, as blocking tRNA export prevents HOE-1-induced UPR mt . Interestingly, we find that HOE-1 does not act via the integrated stress response, which can be activated by uncharged tRNAs, pointing toward its reliance on a new mechanism. Finally, we show that the subcellular localization of HOE-1 is responsive to mitochondrial stress and is subject to negative regulation via ATFS-1. Together, we have discovered a novel RNA-based cellular pathway that modulates UPR mt .