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Carbon Monoxide Stimulates Both Mitophagy And Mitochondrial Biogenesis to Mediate Protection Against Oxidative Stress in Astrocytes

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Abstract

Astrocytes are key glial cells for the metabolic and functional support of the brain. Mitochondrial quality control (MQC), in particular the balance between mitophagy and mitochondrial biogenesis, is a major event for the maintenance of cellular homeostasis. Carbon monoxide (CO) is an endogenous gasotransmitter that inhibits cell death and inflammation by targeting mitochondria. It is well established that CO promotes cytoprotection by increasing mitochondrial population and metabolism (oxidative phosphorylation). Thus, it is hypothesized that CO-induced cytoprotection may also be mediated by the balance between mitophagy and mitochondrial biogenesis. Herein, the carbon monoxide releasing molecule-A1 (CORM-A1) was used in primary cultures of astrocytes to assess CO role on mitochondrial turnover. PINK1/Parkin-dependent mitophagy was stimulated by CORM-A1 following 1 h of treatment. While at 24 h after treatment, CORM-A1 increased mitochondrial population, which may indicate mitochondrial biogenesis. In fact, mitochondrial biogenesis was confirmed by the enhancement of PGC-1α expression that upregulates several mitochondrial transcription factors. Furthermore, inhibition of mitophagy by knocking down PINK1 expression reverted CO-induced mitochondrial biogenesis, indicating that mitochondrial turnover is dependent on modulation of mitophagy. Finally, CORM-A1 prevented astrocytic cell death induced by oxidative stress in a mitophagy-dependent manner. In fact, whenever PINK1 was knocked down, CORM-A1-induced cytoprotection was lost. In summary, CORM-A1 stimulates mitochondrial turnover, which in turn prevents astrocytic cell death. CO cytoprotection depends on increasing mitochondrial population and on eliminating dysfunctional mitochondria.

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Data Availability

The datasets generated during and/or analysed during the current study are available from the corresponding author on a reasonable request.

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Acknowledgements

We thank Ian Ganley, University of Dundee, for kindly providing the MitoQC mice. We also thank Flow Cytometry Facility of NMS-UNL, as well as UCIBIO’s BioLabs, NOVA-FCT-UNL.

Funding

The funding agency that supported the work is “Fundação para a Ciência e Tecnologia” (FCT) with 4 projects: Applied Molecular Biosciences Unit-UCIBIO (UID/Multi/04378/2020), iNOVA4Health - Programme in Translational Medicine (UID/Multi/04462/2013), LA/P/0140/2020 of the Associate Laboratory Institute for Health and Bioeconomy and PTDC/MEC-NEU/28750/2017 and the PhD scholarship for CFP with reference PD/BD/106057/2015.

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Authors and Affiliations

  1. NOVA Medical School, Universidade Nova de Lisboa, Lisbon, Portugal

    Cláudia Figueiredo-Pereira & Helena L. A. Vieira

  2. Department of Cellular and Molecular Biology, Centro de Investigaciones Biológicas Margarita Salas, CSIC, Madrid, Spain

    Beatriz Villarejo-Zori, Ignacio Ramírez-Pardo & Patricia Boya

  3. UCIBIO, Applied Molecular Biosciences Unit, Department of Chemistry, NOVA School of Science and Technology, Universidade Nova de Lisboa, Caparica, Portugal

    Pedro C. Cipriano, Diana Tavares & Helena L. A. Vieira

  4. Associate Laboratory i4HB - Institute for Health and Bioeconomy, NOVA School of Science and Technology, Universidade Nova de Lisboa, Caparica, Portugal

    Helena L. A. Vieira

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Contributions

CFP designed the study, conducted the experiments, helped with data analysis and partially wrote the manuscript, and approved the final version of the manuscript. BVZ designed the study, conducted the experiments, helped with data analysis, and approved the final version of the manuscript. PCC conducted some experiments, helped with data analysis, and approved the final version of the manuscript. DT conducted some experiments and approved the final version of the manuscript. IRP helped with mitoQC model and approved the final version of the manuscript. PB designed the study, helped with data analysis, and approved the final version of this manuscript. PJO helped with data analysis and approved the final version of the manuscript. HLAV designed the study, helped with data analysis and evaluation, wrote the manuscript, and approved the final version of this manuscript.

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Correspondence to Helena L. A. Vieira.

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Supplementary Figure 1

Purity of primary culture of astrocytes. Representative picture of immunofluorescent microscopy using anti-GFAP to verify the purity level of astrocytic primary cell culture. (PNG 953 kb)

High resolution image (TIFF 2909 kb)

Supplementary Figure 2

Control of knocking down Pink1 by siRNA transfection. Primary culture of astrocytes were transfected with Pink1 siRNA for 24 or 48h with 10 or 15 pmol of siRNA per well (24 well plates). Pink1 expression was assessed by western blot analysis. One representative membrane of 24h of transfection is presented and the respective quantification of four biological replicates and data were analysed with the Mann-Whitney test, * p<0.05 compared to control. (PNG 170 kb)

High resolution image (TIFF 4207 kb)

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Figueiredo-Pereira, C., Villarejo-Zori, B., Cipriano, P.C. et al. Carbon Monoxide Stimulates Both Mitophagy And Mitochondrial Biogenesis to Mediate Protection Against Oxidative Stress in Astrocytes. Mol Neurobiol 60, 851–863 (2023). https://doi.org/10.1007/s12035-022-03108-7

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