Doolittle, Woo Kyung LeePark, SunmiLee, Seul GiJeong, SeonhyangLee, GibbeumRyu, DongryeolSchoonjans, KristinaAuwerx, JohanLee, JandeeJo, Young Suk2022-10-242022-10-242022-10-242022-10-0410.1038/s41388-022-02484-7https://infoscience.epfl.ch/handle/20.500.14299/191625WOS:000864233500001Cancer progression is associated with metabolic reprogramming and causes significant intracellular stress; however, the mechanisms that link cellular stress and growth signalling are not fully understood. Here, we identified a mechanism that couples the mitochondrial stress response (MSR) with tumour progression. We demonstrated that the MSR is activated in a significant proportion of human thyroid cancers via the upregulation of heat shock protein D family members and the mitokine, growth differentiation factor 15. Our study also revealed that MSR triggered AKT/S6K signalling by activating mTORC2 via activating transcription factor 4/sestrin 2 activation whilst promoting leucine transporter and nutrient-induced mTORC1 activation. Importantly, we found that an increase in (mt)DNA played an essential role in MSR-induced mTOR activation and that crosstalk between MYC and MSR potentiated mTOR activation. Together, these findings suggest that the MSR could be a predictive marker for aggressive human thyroid cancer as well as a useful therapeutic target.Biochemistry & Molecular BiologyOncologyCell BiologyGenetics & HeredityBiochemistry & Molecular BiologyOncologyCell BiologyGenetics & Hereditygene-expressionmetabolismphosphorylationperspectivesurvivalwarburgproteostasissuppressionhomeostasisresistancetext::journal::journal article::research article