Mitohormesis Primes Tumor Invasion and Metastasis

Moderate mitochondrial stress can lead to persistent activation of cytoprotective mechanisms – a phenomenon termed mitohormesis. Here, we show that mitohormesis primes a subpopulation of cancer cells to basally upregulate mitochondrial stress responses, such as the mitochondrial unfolded protein response (UPR mt ) providing an adaptive metastatic advantage. In this subpopulation, UPR mt activation persists in the absence of stress, resulting in reduced oxidative stress indicative of mitohormesis. Mechanistically, we showed that the SIRT3 axis of UPR mt is necessary for invasion and metastasis. In breast cancer patients, a 7-gene UPR mt signature demonstrated that UPR mt-HIGH patients have significantly worse clinical outcomes, including metastasis. Transcriptomic analyses revealed that UPR mt-HIGH patients have expression profiles characterized by metastatic programs and the cytoprotective outcomes of mitohormesis. While mitohormesis is associated with health and longevity in non-pathological settings, these results indicate that it is perniciously used by cancer cells to promote tumor progression.