A nuclear-based quality control pathway for non-imported mitochondrial proteins

  1. Viplendra PS Shakya
  2. William A Barbeau
  3. Tianyao Xiao
  4. Christina S Knutson
  5. Max H Schuler
  6. Adam L Hughes  Is a corresponding author
  1. University of Utah School of Medicine, United States

Abstract

Mitochondrial import deficiency causes cellular toxicity due to the accumulation of non-imported mitochondrial precursor proteins, termed mitoprotein-induced stress. Despite the burden mis-localized mitochondrial precursors place on cells, our understanding of the systems that dispose of these proteins is incomplete. Here, we cataloged the location and steady-state abundance of mitochondrial precursor proteins during mitochondrial impairment in S. cerevisiae. We found that a number of non-imported mitochondrial proteins localize to the nucleus, where they are subjected to proteasome-dependent degradation through a process we term nuclear-associated mitoprotein degradation (mitoNUC). Recognition and destruction of mitochondrial precursors by the mitoNUC pathway requires the presence of an N-terminal mitochondrial targeting sequence (MTS) and is mediated by combined action of the E3 ubiquitin ligases San1, Ubr1, and Doa10. Impaired breakdown of precursors leads to alternative sequestration in nuclear-associated foci. These results identify the nucleus as an important destination for the disposal of non-imported mitochondrial precursors.

Data availability

All data generated or analyzed during this study are included in the manuscript and supporting files.

Article and author information

Author details

  1. Viplendra PS Shakya

    Biochemistry, University of Utah School of Medicine, Salt Lake City, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6429-8692
  2. William A Barbeau

    Biochemistry, University of Utah School of Medicine, Salt Lake City, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6056-7231
  3. Tianyao Xiao

    Biochemistry, University of Utah School of Medicine, Salt Lake City, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-2571-167X
  4. Christina S Knutson

    Biochemistry, University of Utah School of Medicine, Salt Lake City, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Max H Schuler

    Biochemistry, University of Utah School of Medicine, Salt Lake City, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Adam L Hughes

    Biochemistry, University of Utah School of Medicine, Salt Lake City, United States
    For correspondence
    hughes@biochem.utah.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7095-3793

Funding

National Institute on Aging (AG043095)

  • Adam L Hughes

National Institute of General Medical Sciences (GM119694)

  • Adam L Hughes

American Federation for Aging Research

  • Adam L Hughes

United Mitochondrial Disease Foundation

  • Adam L Hughes

Kinship Foundation

  • Adam L Hughes

Glenn Foundation for Medical Research

  • Adam L Hughes

American Heart Association

  • Max H Schuler

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Maya Schuldiner, Weizmann Institute, Israel

Publication history

  1. Received: July 19, 2020
  2. Accepted: March 17, 2021
  3. Accepted Manuscript published: March 18, 2021 (version 1)
  4. Version of Record published: March 25, 2021 (version 2)

Copyright

© 2021, Shakya 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. Viplendra PS Shakya
  2. William A Barbeau
  3. Tianyao Xiao
  4. Christina S Knutson
  5. Max H Schuler
  6. Adam L Hughes
(2021)
A nuclear-based quality control pathway for non-imported mitochondrial proteins
eLife 10:e61230.
https://doi.org/10.7554/eLife.61230
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