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

Davide Cinat; Anna Lena De Souza; Abel Soto-Gamez; Anne L Jellema-de Bruin; Rob P Coppes; Lara Barazzuol

doi:10.1016/j.radonc.2023.110028

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

Radiother Oncol. 2024 Jan:190:110028. doi: 10.1016/j.radonc.2023.110028. Epub 2023 Nov 24.

Authors

Davide Cinat¹, Anna Lena De Souza¹, Abel Soto-Gamez¹, Anne L Jellema-de Bruin¹, Rob P Coppes¹, Lara Barazzuol²

Affiliations

¹ Department of Biomedical Sciences of Cells & Systems, Section of Molecular Cell Biology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands; Department of Radiation Oncology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
² Department of Biomedical Sciences of Cells & Systems, Section of Molecular Cell Biology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands; Department of Radiation Oncology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands. Electronic address: l.barazzuol@umcg.nl.

PMID: 38007043
DOI: 10.1016/j.radonc.2023.110028

Abstract

Background and purpose: 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: 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: 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: 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.

Keywords: Irradiation; Mitochondria; Salivary glands; Senescence; Stem cells.

MeSH terms

Animals
Cellular Senescence / radiation effects
Mice
Mitochondrial Diseases* / metabolism
Mitophagy
Quality of Life*
Salivary Glands
Stem Cells / radiation effects