A tRNA processing enzyme is a key regulator of the mitochondrial unfolded protein response
- Vanderbilt University, United States
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 discovered that the tRNA processing enzyme, homolog of ELAC2 (HOE-1), is key 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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All data generated or analyzed during this study are included in the manuscript and supporting files. Source data files have been provided for Figures 5 and 8.
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Author details
Funding
National Institute of General Medical Sciences (R01GM123260)
- James P Held
- Benjamin R Saunders
- Claudia V Pereria
- Maulik R Patel
National Institute on Aging (R00AG052666)
- Gaomin Feng
- Kristopher Burkewitz
National Institute of Environmental Health Sciences (T32ES007028)
- James P Held
National Institute of General Medical Sciences (R35GM145378)
- James P Held
- Benjamin R Saunders
- Maulik R Patel
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Copyright
© 2022, Held et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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A tRNA processing enzyme is a key regulator of the mitochondrial unfolded protein response
eLife 11:e71634.
https://doi.org/10.7554/eLife.71634
