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

  • Radiother Oncol. 2023 Nov 23:110028. doi: 10.1016/j.radonc.2023.110028.
Davide Cinat  1 ,  Anna Lena De Souza  1 ,  Abel Soto-Gamez  1 ,  Anne L Jellema-de Bruin  1 ,  Rob P Coppes  1 ,  Lara Barazzuol  2
Affiliations
  • 1. 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.
  • 2. 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: [email protected].
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.
Products