Genetically controlled mtDNA deletions prevent ROS damage by arresting oxidative phosphorylation
- University of Gothenburg, Sweden
- Sun Yat-sen University Cancer Center, China
- Norwegian University of Life Sciences, Norway
- University of Gothenburg, Spain
- Chalmers University of Technology, Sweden
- 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.
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Chronic superoxide distress causes irreversible loss of mtDNA segmentsNCBI BioProject, PRJNA622836.
Article and author information
Author details
Carles González Peña
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
- Jan Gruber, Yale-NUS College, Singapore
Publication history
- Preprint posted: November 20, 2020 (view preprint)
- Received: December 3, 2021
- Accepted: July 7, 2022
- Accepted Manuscript published: July 8, 2022 (version 1)
- Version of Record published: August 30, 2022 (version 2)
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.
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Genetically controlled mtDNA deletions prevent ROS damage by arresting oxidative phosphorylation
eLife 11:e76095.
https://doi.org/10.7554/eLife.76095
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