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.