Mitohormesis Primes Tumor Invasion and Metastasis

Abstract

Summary: 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 (UPRmt) providing an adaptive metastatic advantage. In this subpopulation, UPRmt activation persists in the absence of stress, resulting in reduced oxidative stress indicative of mitohormesis. Mechanistically, we showed that the SIRT3 axis of UPRmt is necessary for invasion and metastasis. In breast cancer patients, a 7-gene UPRmt signature demonstrated that UPRmt-HIGH patients have significantly worse clinical outcomes, including metastasis. Transcriptomic analyses revealed that UPRmt-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. : Mitohormesis, a phenomenon resulting in persistent activation of cytoprotective mechanisms, has been studied in the context of aging and longevity. Kenny et al. demonstrate that breast cancer cells co-opt mitohormesis to promote their invasion and metastasis via activation of the mitochondrial unfolded protein response (UPRmt). Keywords: mitohormesis, reactive oxygen species, SOD2, SIRT3, mitochondria, breast cancer, UPRmt, metastasis, HSP60, unfolded protein response