Genetically controlled mtDNA deletions prevent ROS damage by arresting oxidative phosphorylation

  1. Simon Stenberg
  2. Jing Li
  3. Arne B Gjuvsland
  4. Karl Persson
  5. Erik Demitz-Helin
  6. Carles González Peña
  7. Jia-Xing Yue
  8. Ciaran Gilchrist
  9. Timmy Ärengård
  10. Payam Ghiaci
  11. Lisa Larsson-Berghund
  12. Martin Zackrisson
  13. Silvana Smits
  14. Johan Hallin
  15. Johanna L Höög
  16. Mikael Molin
  17. Gianni Liti
  18. Stig W Omholt  Is a corresponding author
  19. Jonas Warringer  Is a corresponding author
  1. University of Gothenburg, Sweden
  2. Sun Yat-sen University Cancer Center, China
  3. Norwegian University of Life Sciences, Norway
  4. University of Gothenburg, Spain
  5. Chalmers University of Technology, Sweden
  6. Université Côte d'Azur, CNRS, INSERM, IRCAN, France

Abstract

Deletion of mitochondrial DNA in eukaryotes is currently attributed to rare accidental events associated with mitochondrial replication or repair of double-strand breaks. We report the discovery that yeast cells arrest harmful intramitochondrial superoxide production by shutting down respiration through genetically controlled deletion of mitochondrial oxidative phosphorylation genes. We show that this process critically involves the antioxidant enzyme superoxide dismutase 2 and two-way mitochondrial-nuclear communication through Rtg2 and Rtg3. While mitochondrial DNA homeostasis is rapidly restored after cessation of a short-term superoxide stress, long-term stress causes maladaptive persistence of the deletion process, leading to complete annihilation of the cellular pool of intact mitochondrial genomes and irrevocable loss of respiratory ability. This shows that oxidative stress-induced mitochondrial impairment may be under strict regulatory control. If the results extend to human cells, the results may prove to be of etiological as well as therapeutic importance with regard to age-related mitochondrial impairment and disease.

Data availability

Sequence data that support the findings of this study have been deposited in Sequencing Read Archive (SRA) with the accession codes PRJNA622836.The growth phenotyping code can be found at https://github.com/Scan-o-Matic/scanomatic.git, the simulation code at https://github.com/HelstVadsom/GenomeAdaptation.git and the imaging code at https://github.com/CamachoDejay/SStenberg_3Dyeast_tools.The authors declare that all other data supporting the findings of this study are available within the paper as Supplemental Information Data S1-S30, which can be previewed at https://data.mendeley.com/datasets/mvx7t7rw2d/draft?a=95381e47-dc80-47af-85ab-e0478912a209.

The following data sets were generated

Article and author information

Author details

  1. Simon Stenberg

    Department of Chemistry and Molecular Biology, University of Gothenburg, Gothenburg, Sweden
    Competing interests
    The authors declare that no competing interests exist.
  2. Jing Li

    State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, China
    Competing interests
    The authors declare that no competing interests exist.
  3. Arne B Gjuvsland

    Department of Animal and Aquacultural Sciences, Norwegian University of Life Sciences, Ås, Norway
    Competing interests
    The authors declare that no competing interests exist.
  4. Karl Persson

    Department of Chemistry and Molecular Biology, University of Gothenburg, Gothenburg, Sweden
    Competing interests
    The authors declare that no competing interests exist.
  5. Erik Demitz-Helin

    Department of Chemistry and Molecular Biology, University of Gothenburg, erikdemitzhelin, Sweden
    Competing interests
    The authors declare that no competing interests exist.
  6. Carles González Peña

    Department of Chemistry and Molecular Biology, University of Gothenburg, Argentona, Spain
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7771-7988
  7. Jia-Xing Yue

    State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, China
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2122-9221
  8. Ciaran Gilchrist

    Department of Chemistry and Molecular Biology, University of Gothenburg, Gothenburg, Sweden
    Competing interests
    The authors declare that no competing interests exist.
  9. Timmy Ärengård

    Department of Chemistry and Molecular Biology, University of Gothenburg, Gothenburg, Sweden
    Competing interests
    The authors declare that no competing interests exist.
  10. Payam Ghiaci

    Department of Chemistry and Molecular Biology, University of Gothenburg, Gothenburg, Sweden
    Competing interests
    The authors declare that no competing interests exist.
  11. Lisa Larsson-Berghund

    Department of Chemistry and Molecular Biology, University of Gothenburg, Gothenburg, Sweden
    Competing interests
    The authors declare that no competing interests exist.
  12. Martin Zackrisson

    Department of Chemistry and Molecular Biology, University of Gothenburg, Gothenburg, Sweden
    Competing interests
    The authors declare that no competing interests exist.
  13. Silvana Smits

    Department of Chemistry and Molecular Biology, University of Gothenburg, Gothenburg, Sweden
    Competing interests
    The authors declare that no competing interests exist.
  14. Johan Hallin

    Department of Chemistry and Molecular Biology, University of Gothenburg, Gothenburg, Sweden
    Competing interests
    The authors declare that no competing interests exist.
  15. Johanna L Höög

    Department of Chemistry and Molecular Biology, University of Gothenburg, Gothenburg, Sweden
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-2162-3816
  16. Mikael Molin

    Department of Biology and Biological Engineering, Chalmers University of Technology, Gothenburg, Sweden
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3903-8503
  17. Gianni Liti

    Institute for Research on Cancer and Aging, Université Côte d'Azur, CNRS, INSERM, IRCAN, Nice, France
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2318-0775
  18. Stig W Omholt

    Department of Animal and Aquacultural Sciences, Norwegian University of Life Sciences, Ås, Norway
    For correspondence
    Stig.omholt@ntnu.no
    Competing interests
    The authors declare that no competing interests exist.
  19. Jonas Warringer

    Department of Chemistry and Molecular Biology, University of Gothenburg, Gothenburg, Sweden
    For correspondence
    jonas.warringer@cmb.gu.se
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6144-2740

Funding

Vetenskapsrådet (2014-6547)

  • Jonas Warringer

Agence Nationale de la Recherche (ANR-13-BSV6-0006-01)

  • Gianni Liti

Agence Nationale de la Recherche (ANR-15-IDEX-01)

  • Gianni Liti

Agence Nationale de la Recherche (ANR-16-CE12-0019)

  • Gianni Liti

Agence Nationale de la Recherche (ANR-18-CE12-0004)

  • Gianni Liti

Human Frontiers Science Program (LT000182/2019-L)

  • Johan Hallin

Vetenskapsrådet (2014-4605)

  • Jonas Warringer

Vetenskapsrådet (2015-05427)

  • Mikael Molin

Vetenskapsrådet (2018-03638)

  • Mikael Molin

Vetenskapsrådet (2018-03453)

  • Johanna L Höög

Cancerfonden (2017-778)

  • Mikael Molin

Norges Forskningsråd (178901/V30)

  • Stig W Omholt

Norges Forskningsråd (222364/F20)

  • Stig W Omholt

Agence Nationale de la Recherche (ANR-11-LABX-0028-01)

  • Gianni Liti

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

Reviewing Editor

  1. Jan Gruber, Yale-NUS College, Singapore

Publication history

  1. Received: December 3, 2021
  2. Accepted: July 7, 2022
  3. Accepted Manuscript published: July 8, 2022 (version 1)

Copyright

© 2022, Stenberg 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

  • 874
    Page views
  • 387
    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. Simon Stenberg
  2. Jing Li
  3. Arne B Gjuvsland
  4. Karl Persson
  5. Erik Demitz-Helin
  6. Carles González Peña
  7. Jia-Xing Yue
  8. Ciaran Gilchrist
  9. Timmy Ärengård
  10. Payam Ghiaci
  11. Lisa Larsson-Berghund
  12. Martin Zackrisson
  13. Silvana Smits
  14. Johan Hallin
  15. Johanna L Höög
  16. Mikael Molin
  17. Gianni Liti
  18. Stig W Omholt
  19. Jonas Warringer
(2022)
Genetically controlled mtDNA deletions prevent ROS damage by arresting oxidative phosphorylation
eLife 11:e76095.
https://doi.org/10.7554/eLife.76095

Further reading

    1. Cell Biology
    2. Neuroscience
    Lauritz Kennedy et al.
    Research Article

    Neonatal cerebral hypoxia-ischemia (HI) is the leading cause of death and disability in newborns with the only current treatment being hypothermia. An increased understanding of the pathways that facilitate tissue repair after HI may aid the development of better treatments. Here, we study the role of lactate receptor HCAR1 in tissue repair after neonatal HI in mice. We show that HCAR1 knockout mice have reduced tissue regeneration compared with wildtype mice. Furthermore, proliferation of neural progenitor cells and glial cells, as well as microglial activation was impaired. Transcriptome analysis showed a strong transcriptional response to HI in the subventricular zone of wildtype mice involving about 7300 genes. In contrast, the HCAR1 knockout mice showed a modest response, involving about 750 genes. Notably, fundamental processes in tissue repair such as cell cycle and innate immunity were dysregulated in HCAR1 knockout. Our data suggest that HCAR1 is a key transcriptional regulator of pathways that promote tissue regeneration after HI.

    1. Cell Biology
    2. Developmental Biology
    Swathy Babu et al.
    Research Article

    Btg3-associated nuclear protein (Banp) was originally identified as a nuclear matrix-associated region (MAR)-binding protein and it functions as a tumor suppressor. At the molecular level, Banp regulates transcription of metabolic genes via a CGCG-containing motif called the Banp motif. However, its physiological roles in embryonic development are unknown. Here, we report that Banp is indispensable for the DNA damage response and chromosome segregation during mitosis. Zebrafish banp mutants show mitotic cell accumulation and apoptosis in developing retina. We found that DNA replication stress and tp53-dependent DNA damage responses were activated to induce apoptosis in banp mutants, suggesting that Banp is required for regulation of DNA replication and DNA damage repair. Furthermore, consistent with mitotic cell accumulation, chromosome segregation was not smoothly processed from prometaphase to anaphase in banp morphants, leading to a prolonged M-phase. Our RNA- and ATAC-sequencing identified 31 candidates for direct Banp target genes that carry the Banp motif. Interestingly, a DNA replication fork regulator, wrnip1, and two chromosome segregation regulators, cenpt and ncapg, are included in this list. Thus, Banp directly regulates transcription of wrnip1 for recovery from DNA replication stress, and cenpt and ncapg for chromosome segregation during mitosis. Our findings provide the first in vivo evidence that Banp is required for cell-cycle progression and cell survival by regulating DNA damage responses and chromosome segregation during mitosis.