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bioRxiv · 10.1101/2021.06.22.449331

Homolog of ELAC2 is a central regulator of the mitochondrial unfolded protein response

Held, J. P.·Saunders, B. R.·Pereria, C. V.·Patel, M. R.
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Abstract

The mitochondrial unfolded protein response (UPRmt) has emerged as a predominant mechanism that preserves mitochondrial function. Consequently, multiple pathways likely exist to modulate UPRmt. We unexpectedly discovered that the tRNA processing enzyme, homolog of ELAC2 (HOE-1), is central to UPRmt regulation in Caenorhabditis elegans. We find that nuclear HOE-1 is necessary and sufficient to robustly activate UPRmt. We show that HOE-1 acts via transcription factors ATFS-1 and DVE-1 that are crucial for UPRmt. Mechanistically, we show that HOE-1 likely mediates its effects via tRNAs, as blocking tRNA export prevents HOE-1-induced UPRmt. Interestingly, we find that HOE-1 does not act via the integrated stress response, which can be activated by uncharged tRNAs, pointing towards 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 UPRmt.

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Held, J. P., Saunders, B. R., Pereria, C. V., Patel, M. R.. 2021-06-22. Homolog of ELAC2 is a central regulator of the mitochondrial unfolded protein response. https://doi.org/10.1101/2021.06.22.449331

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