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

Publication 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.

Metrics

  • 1,628
    Page views
  • 358
    Downloads
  • 0
    Citations

Article citation count generated by polling the highest count across the following sources: Crossref, PubMed Central, Scopus.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  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
  1. Further reading

Further reading

    1. Cell Biology
    2. Neuroscience
    Damien Jullié, Camila Benitez ... Mark von Zastrow
    Research Article Updated

    Opioid tolerance is well-described physiologically but its mechanistic basis remains incompletely understood. An important site of opioid action in vivo is the presynaptic terminal, where opioids inhibit transmitter release. This response characteristically resists desensitization over minutes yet becomes gradually tolerant over hours, and how this is possible remains unknown. Here, we delineate a cellular mechanism underlying this longer-term form of opioid tolerance in cultured rat medium spiny neurons. Our results support a model in which presynaptic tolerance is mediated by a gradual depletion of cognate receptors from the axon surface through iterative rounds of receptor endocytosis and recycling. For the μ-opioid receptor (MOR), we show that the agonist-induced endocytic process which initiates iterative receptor cycling requires GRK2/3-mediated phosphorylation of the receptor’s cytoplasmic tail, and that partial or biased agonist drugs with reduced ability to drive phosphorylation-dependent endocytosis in terminals produce correspondingly less presynaptic tolerance. We then show that the δ-opioid receptor (DOR) conforms to the same general paradigm except that presynaptic endocytosis of DOR, in contrast to MOR, does not require phosphorylation of the receptor’s cytoplasmic tail. Further, we show that DOR recycles less efficiently than MOR in axons and, consistent with this, that DOR tolerance develops more strongly. Together, these results delineate a cellular basis for the development of presynaptic tolerance to opioids and describe a methodology useful for investigating presynaptic neuromodulation more broadly.

    1. Cell Biology
    Shunsuke Saito, Tokiro Ishikawa ... Kazutoshi Mori
    Research Article

    A causal relationship between endoplasmic reticulum (ER) stress and the development of neurodegenerative diseases remains controversial. Here, we focused on Seipinopathy, a dominant motor neuron disease, based on the finding that its causal gene product, Seipin, is a protein that spans the ER membrane twice. Gain-of-function mutations of Seipin produce non-glycosylated Seipin (ngSeipin), which was previously shown to induce ER stress and apoptosis at both cell and mouse levels albeit with no clarified mechanism. We found that aggregation-prone ngSeipin dominantly inactivated SERCA2b, the major calcium pump in the ER, and decreased the calcium concentration in the ER, leading to ER stress and apoptosis in human colorectal carcinoma-derived cells (HCT116). This inactivation required oligomerization of ngSeipin and direct interaction of the C-terminus of ngSeipin with SERCA2b, and was observed in Seipin-deficient neuroblastoma (SH-SY5Y) cells expressing ngSeipin at an endogenous protein level. Our results thus provide a new direction to the controversy noted above.