Selected mitochondrial DNA landscapes activate the SIRT3 axis of the UPRmt to promote metastasis

T. T. Kenny, P. Hart, M. Ragazzi, M. Sersinghe, J. Chipuk, M. A.K. Sagar, K. K. Eliceiri, T. LaFramboise, S. Grandhi, J. Santos, A. A. Riar, L. Papa, M. D'Aurello, G. Manfredi, M. M. Bonini, D. Germain*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

69 Scopus citations


By causing mitochondrial DNA (mtDNA) mutations and oxidation of mitochondrial proteins, reactive oxygen species (ROS) leads to perturbations in mitochondrial proteostasis. Several studies have linked mtDNA mutations to metastasis of cancer cells but the nature of the mtDNA species involved remains unclear. Our data suggests that no common mtDNA mutation identifies metastatic cells; rather the metastatic potential of several ROS-generating mutations is largely determined by their mtDNA genomic landscapes, which can act either as an enhancer or repressor of metastasis. However, mtDNA landscapes of all metastatic cells are characterized by activation of the SIRT/FOXO/SOD2 axis of the mitochondrial unfolded protein response (UPR(mt)). The UPR(mt) promotes a complex transcription program ultimately increasing mitochondrial integrity and fitness in response to oxidative proteotoxic stress. Using SOD2 as a surrogate marker of the UPR(mt), we found that in primary breast cancers, SOD2 is significantly increased in metastatic lesions. We propose that the ability of selected mtDNA species to activate the UPR(mt) is a process that is exploited by cancer cells to maintain mitochondrial fitness and facilitate metastasis.

Original languageEnglish (US)
Pages (from-to)4393-4404
Number of pages12
Issue number31
StatePublished - Aug 1 2017
Externally publishedYes

ASJC Scopus subject areas

  • Genetics
  • Molecular Biology
  • Cancer Research


Dive into the research topics of 'Selected mitochondrial DNA landscapes activate the SIRT3 axis of the UPRmt to promote metastasis'. Together they form a unique fingerprint.

Cite this