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.
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
Further reading
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- Cell Biology
- Stem Cells and Regenerative Medicine
Conjugated linoleic acids (CLAs) can serve as a nutritional intervention to regulate quality, function, and fat infiltration in skeletal muscles, but the specific cytological mechanisms remain unknown. Here, we applied single-nucleus RNA-sequencing (snRNA-seq) to characterize the cytological mechanism of CLAs regulates fat infiltration in skeletal muscles based on pig models. We investigated the regulatory effects of CLAs on cell populations and molecular characteristics in pig muscles and found CLAs could promote the transformation of fast glycolytic myofibers into slow oxidative myofibers. We also observed three subpopulations including SCD+/DGAT2+, FABP5+/SIAH1+, and PDE4D+/PDE7B+ subclusters in adipocytes and CLAs could increase the percentage of SCD+/DGAT2+ adipocytes. RNA velocity analysis showed FABP5+/SIAH1+ and PDE4D+/PDE7B+ adipocytes could differentiate into SCD+/DGAT2+ adipocytes. We further verified the differentiated trajectory of mature adipocytes and identified PDE4D+/PDE7B+ adipocytes could differentiate into SCD+/DGAT2+ and FABP5+/SIAH1+ adipocytes by using high intramuscular fat (IMF) content Laiwu pig models. The cell-cell communication analysis identified the interaction network between adipocytes and other subclusters such as fibro/adipogenic progenitors (FAPs). Pseudotemporal trajectory analysis and RNA velocity analysis also showed FAPs could differentiate into PDE4D+/PDE7B+ preadipocytes and we discovered the differentiated trajectory of preadipocytes into mature adipocytes. Besides, we found CLAs could promote FAPs differentiate into SCD+/DGAT2+ adipocytes via inhibiting c-Jun N-terminal kinase (JNK) signaling pathway in vitro. This study provides a foundation for regulating fat infiltration in skeletal muscles by using nutritional strategies and provides potential opportunities to serve pig as an animal model to study human fat infiltrated diseases.
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- Cell Biology
- Medicine
Background:
It has been reported that loss of PCBP2 led to increased reactive oxygen species (ROS) production and accelerated cell aging. Knockdown of PCBP2 in HCT116 cells leads to significant downregulation of fibroblast growth factor 2 (FGF2). Here, we tried to elucidate the intrinsic factors and potential mechanisms of bone marrow mesenchymal stromal cells (BMSCs) aging from the interactions among PCBP2, ROS, and FGF2.
Methods:
Unlabeled quantitative proteomics were performed to show differentially expressed proteins in the replicative senescent human bone marrow mesenchymal stromal cells (RS-hBMSCs). ROS and FGF2 were detected in the loss-and-gain cell function experiments of PCBP2. The functional recovery experiments were performed to verify whether PCBP2 regulates cell function through ROS/FGF2-dependent ways.
Results:
PCBP2 expression was significantly lower in P10-hBMSCs. Knocking down the expression of PCBP2 inhibited the proliferation while accentuated the apoptosis and cell arrest of RS-hBMSCs. PCBP2 silence could increase the production of ROS. On the contrary, overexpression of PCBP2 increased the viability of both P3-hBMSCs and P10-hBMSCs significantly. Meanwhile, overexpression of PCBP2 led to significantly reduced expression of FGF2. Overexpression of FGF2 significantly offset the effect of PCBP2 overexpression in P10-hBMSCs, leading to decreased cell proliferation, increased apoptosis, and reduced G0/G1 phase ratio of the cells.
Conclusions:
This study initially elucidates that PCBP2 as an intrinsic aging factor regulates the replicative senescence of hBMSCs through the ROS-FGF2 signaling axis.
Funding:
This study was supported by the National Natural Science Foundation of China (82172474).
