Faculty Collaboration Database

Selected mitochondrial DNA landscapes activate the SIRT3 axis of the UPR^mt to promote metastasis. Oncogene 2017 Aug;36(31):4393-4404

Date

04/04/2017

Pubmed ID

28368421

Pubmed Central ID

PMC5542861

DOI

10.1038/onc.2017.52

Scopus ID

2-s2.0-85016955700 (requires institutional sign-in at Scopus site)   81 Citations

Abstract

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.

Author List

Kenny TC, Hart P, Ragazzi M, Sersinghe M, Chipuk J, Sagar MAK, Eliceiri KW, LaFramboise T, Grandhi S, Santos J, Riar AK, Papa L, D'Aurello M, Manfredi G, Bonini MG, Germain D

MESH terms used to index this publication - Major topics in bold

Breast Neoplasms
Cell Line, Tumor
DNA, Mitochondrial
Female
Forkhead Box Protein O3
Humans
Mitochondria
Neoplasm Metastasis
Sirtuin 3
Superoxide Dismutase
Unfolded Protein Response