Temelie 2023 Int J Mol Sci

From Bioblast
Publications in the MiPMap
Temelie M, Talpur R, Dominguez-Prieto M, Dantas Silva A, Cenusa C, Craciun L, Savu DI, Moisoi N (2023) Impaired integrated stress response and mitochondrial integrity modulate genotoxic stress impact and lower the threshold for immune signalling. https://doi.org/10.3390/ijms24065891

Β» Int J Mol Sci 24:5891. PMID: 36982965 Open Access

Temelie Mihaela, Talpur Rubab, Dominguez-Prieto Marta, Dantas Silva Ayanda, Cenusa Constantin, Craciun Liviu, Iulia Savu Diana Iulia, Moisoi Nicoleta (2023) Int J Mol Sci

Abstract: Mitochondria-nucleus communication during stress dictates cellular fate with consequences on the etiopathology of multiple age-related diseases. Impaired mitochondrial quality control through loss of function of the mitochondrial protease HtrA2 associates with accumulation of damaged mitochondria and triggers the integrated stress response, implicating the transcription factor CHOP. Here we have employed a combined model of impaired mitochondria quality control, namely HtrA2 loss of function, and/or integrated stress response, namely CHOP loss of function, and genotoxicity to address the distinctive roles of these cellular components in modulating intracellular and intercellular responses. The genotoxic agents employed were cancer therapeutic agents such as irradiation with X-ray and protons or treatment with the radiomimetic bleomycin. The irradiation had an enhanced effect in inducing DNA damage in cells with CHOP loss of function, while the bleomycin treatment induced more DNA damage in all the transgenic cells as compared to the control. The genetic modifications impaired the transmission of DNA damage signalling intercellularly. Furthermore, we have dissected the signalling pathways modulated by irradiation in selected genotypes with RNA sequencing analysis. We identified that loss of HtrA2 and CHOP function, respectively, lowers the threshold where irradiation may induce the activation of innate immune responses via cGAS-STING; this may have a significant impact on decisions for combined therapeutic approaches for various diseases. β€’ Keywords: DNA damage, Integrated stress response, Mitochondria function, Radioinduced signalling pathways β€’ Bioblast editor: Plangger M β€’ O2k-Network Lab: UK Leicester Moisoi N

Labels: MiParea: Respiration, Genetic knockout;overexpression 

Organism: Mouse  Tissue;cell: Fibroblast  Preparation: Intact cells 

Coupling state: LEAK, OXPHOS, ET  Pathway: N, NS  HRR: Oxygraph-2k 


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