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

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.

Data availability

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.

Article and author information

Author details

  1. James P Held

    Department of Biological Sciences, Vanderbilt University, Nashville, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Gaomin Feng

    Department of Cell and Developmental Biology, Vanderbilt University, Nashville, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Benjamin R Saunders

    Department of Biological Sciences, Vanderbilt University, Nashville, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Claudia V Pereria

    Department of Biological Sciences, Vanderbilt University, Nashville, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Kristopher Burkewitz

    Department of Cell and Developmental Biology, Vanderbilt University, Nashville, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Maulik R Patel

    Department of Biological Sciences, Vanderbilt University, Nashville, United States
    For correspondence
    maulik.r.patel@vanderbilt.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3749-0122

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.

Reviewing Editor

  1. Xiaochen Wang, Institute of Biophysics Chinese Academy of Sciences, China

Version history

  1. Preprint posted: June 22, 2021 (view preprint)
  2. Received: June 25, 2021
  3. Accepted: April 21, 2022
  4. Accepted Manuscript published: April 22, 2022 (version 1)
  5. Version of Record published: May 3, 2022 (version 2)
  6. Version of Record updated: May 17, 2022 (version 3)

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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  1. James P Held
  2. Gaomin Feng
  3. Benjamin R Saunders
  4. Claudia V Pereria
  5. Kristopher Burkewitz
  6. Maulik R Patel
(2022)
A tRNA processing enzyme is a key regulator of the mitochondrial unfolded protein response
eLife 11:e71634.
https://doi.org/10.7554/eLife.71634

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https://doi.org/10.7554/eLife.71634

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