Impaired Integrated Stress Response and Mitochondrial Integrity Modulate Genotoxic Stress Impact and Lower the Threshold for Immune Signalling

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.

Automated summary

Mitochondria-nucleus communication during stress determines cellular fate, contributing to the development of age-related diseases. Impaired mitochondria quality control due to loss of function of the mitochondrial protease HtrA2 leads to accumulation of damaged mitochondria and triggers the integrated stress response involving the transcription factor CHOP. In this study, we examined the roles of HtrA2 and CHOP in modulating intracellular and intercellular responses by using genetic models of impaired mitochondria quality control, CHOP loss of function, and genotoxicity induced by cancer therapeutic agents. Our findings suggest that the loss of CHOP function enhances DNA damage induced by irradiation, while all transgenic cells exhibit increased DNA damage with bleomycin treatment. Genetic modifications impair the intercellular transmission of DNA damage signaling. Furthermore, RNA sequencing analysis revealed that loss of HtrA2 and CHOP function lowers the threshold for irradiation to activate innate immune responses via cGAS-STING, which may have implications for combined therapeutic approaches in various diseases.