Mitohormesis Primes Tumor Invasion and Metastasis

Cell Rep. 2019 May 21;27(8):2292-2303.e6. doi: 10.1016/j.celrep.2019.04.095.


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.

Keywords: HSP60; SIRT3; SOD2; UPR(mt); breast cancer; metastasis; mitochondria; mitohormesis; reactive oxygen species; unfolded protein response.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Breast Neoplasms / drug therapy*
  • Breast Neoplasms / genetics*
  • Female
  • Humans
  • Mice
  • Mitochondrial Proteins / metabolism*
  • Neoplasm Metastasis
  • Reactive Oxygen Species
  • Unfolded Protein Response / genetics*


  • Mitochondrial Proteins
  • Reactive Oxygen Species