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.