Mitophagy induction improves salivary gland stem/progenitor cell function by reducing senescence after irradiation.

irradiation mitochondria salivary glands senescence stem cells

Journal

Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology
ISSN: 1879-0887
Titre abrégé: Radiother Oncol
Pays: Ireland
ID NLM: 8407192

Informations de publication

Date de publication:
23 Nov 2023
Historique:
received: 15 06 2023
revised: 15 11 2023
accepted: 19 11 2023
medline: 26 11 2023
pubmed: 26 11 2023
entrez: 25 11 2023
Statut: aheadofprint

Résumé

Patients undergoing radiotherapy for head and neck cancer often experience a decline in their quality of life due to the co-irradiation of salivary glands. Radiation-induced cellular senescence is a key factor contributing to salivary gland dysfunction. Interestingly, mitochondrial dysfunction and cellular senescence have been reported to be strongly interconnected and thus implicated in several aging-related diseases. This study aims to investigate the role of mitochondrial dysfunction in senescence induction in salivary gland stem/progenitor cells after irradiation. A dose of 7 Gy photons was used to irradiate mouse salivary gland organoids. Senescent markers and mitochondrial function were assessed using rt-qPCR, western blot analysis, SA-β-Gal staining and flow cytometry analysis. Mitochondrial dynamics-related proteins were detected by western blot analysis while Mdivi-1 and MFI8 were used to modulate the mitochondrial fission process. To induce mitophagy, organoids were treated with Urolithin A and PMI and subsequently stem/progenitor cell self-renewal capacity was assessed as organoid forming efficiency. Irradiation led to increased senescence and accumulation of dysfunctional mitochondria. This was accompanied by a strong downregulation of mitochondrial fission-related proteins and mitophagy-related genes. After irradiation, treatment with the mitophagy inducer Urolithin A attenuated the senescent phenotype and improved organoid growth and stem/progenitor cell self-renewal capacity. This study shows the important interplay between senescence and mitochondrial dysfunction after irradiation. Importantly, activation of mitophagy improved salivary gland stem/progenitor cell function thereby providing a novel therapeutic strategy to restore the regenerative capacity of salivary glands following irradiation.

Sections du résumé

BACKGROUND AND PURPOSE OBJECTIVE
Patients undergoing radiotherapy for head and neck cancer often experience a decline in their quality of life due to the co-irradiation of salivary glands. Radiation-induced cellular senescence is a key factor contributing to salivary gland dysfunction. Interestingly, mitochondrial dysfunction and cellular senescence have been reported to be strongly interconnected and thus implicated in several aging-related diseases. This study aims to investigate the role of mitochondrial dysfunction in senescence induction in salivary gland stem/progenitor cells after irradiation.
MATERIALS AND METHODS METHODS
A dose of 7 Gy photons was used to irradiate mouse salivary gland organoids. Senescent markers and mitochondrial function were assessed using rt-qPCR, western blot analysis, SA-β-Gal staining and flow cytometry analysis. Mitochondrial dynamics-related proteins were detected by western blot analysis while Mdivi-1 and MFI8 were used to modulate the mitochondrial fission process. To induce mitophagy, organoids were treated with Urolithin A and PMI and subsequently stem/progenitor cell self-renewal capacity was assessed as organoid forming efficiency.
RESULTS RESULTS
Irradiation led to increased senescence and accumulation of dysfunctional mitochondria. This was accompanied by a strong downregulation of mitochondrial fission-related proteins and mitophagy-related genes. After irradiation, treatment with the mitophagy inducer Urolithin A attenuated the senescent phenotype and improved organoid growth and stem/progenitor cell self-renewal capacity.
CONCLUSION CONCLUSIONS
This study shows the important interplay between senescence and mitochondrial dysfunction after irradiation. Importantly, activation of mitophagy improved salivary gland stem/progenitor cell function thereby providing a novel therapeutic strategy to restore the regenerative capacity of salivary glands following irradiation.

Identifiants

DOI: 10.1016/j.radonc.2023.110028 PMID: 38007043
pubmed: 38007043
pii: S0167-8140(23)09335-0
doi: 10.1016/j.radonc.2023.110028
pii:
doi:

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Pagination

110028

Informations de copyright

Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.

Auteurs

Davide Cinat (D)

Department of Biomedical Sciences of Cells & Systems, Section of Molecular Cell Biology, University Medical Center Groningen, University of Groningen, Groningen, 9713 GZ, The Netherlands; Department of Radiation Oncology, University Medical Center Groningen, University of Groningen, Groningen, 9713 GZ, The Netherlands.

Anna Lena De Souza (A)

Department of Biomedical Sciences of Cells & Systems, Section of Molecular Cell Biology, University Medical Center Groningen, University of Groningen, Groningen, 9713 GZ, The Netherlands; Department of Radiation Oncology, University Medical Center Groningen, University of Groningen, Groningen, 9713 GZ, The Netherlands.

Abel Soto-Gamez (A)

Department of Biomedical Sciences of Cells & Systems, Section of Molecular Cell Biology, University Medical Center Groningen, University of Groningen, Groningen, 9713 GZ, The Netherlands; Department of Radiation Oncology, University Medical Center Groningen, University of Groningen, Groningen, 9713 GZ, The Netherlands.

Anne L Jellema-de Bruin (AL)

Department of Biomedical Sciences of Cells & Systems, Section of Molecular Cell Biology, University Medical Center Groningen, University of Groningen, Groningen, 9713 GZ, The Netherlands; Department of Radiation Oncology, University Medical Center Groningen, University of Groningen, Groningen, 9713 GZ, The Netherlands.

Rob P Coppes (RP)

Department of Biomedical Sciences of Cells & Systems, Section of Molecular Cell Biology, University Medical Center Groningen, University of Groningen, Groningen, 9713 GZ, The Netherlands; Department of Radiation Oncology, University Medical Center Groningen, University of Groningen, Groningen, 9713 GZ, The Netherlands.

Lara Barazzuol (L)

Department of Biomedical Sciences of Cells & Systems, Section of Molecular Cell Biology, University Medical Center Groningen, University of Groningen, Groningen, 9713 GZ, The Netherlands; Department of Radiation Oncology, University Medical Center Groningen, University of Groningen, Groningen, 9713 GZ, The Netherlands. Electronic address: l.barazzuol@umcg.nl.

Classifications MeSH