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

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.

Roles of the mitochondrial genetics in cancer metastasis: not to be ignored any longer

“…The authors attributed the variability to levels of mtDNA heteroplasmy, most notably in the MDA-MB-157 human breast carcinoma cell line. However, on average the invasive cell lines had an increase in a shift toward a more glycolytic phenotype [73]. Other papers report the ratio of oxidative phosphorylation to glycolysis to either increase [74] or decrease [75] as invasion and metastasis increases.…”

“…Taking this into consideration Kenny et al . analyzed the role of the mitochondrial unfolded protein response (UPR MT ) [73] and found that activation of SOD2 through a SIRT3/FOXO3a/SOD2 axis downstream of the UPR MT may increase mitochondrial biogenesis and the antioxidant response in aggressive disease. Furthermore, the authors demonstrated that SOD2 expression is an important component in the regulation of the invasion, but is not sufficient to drive the invasive phenotype.…”

“…Furthermore, the authors demonstrated that SOD2 expression is an important component in the regulation of the invasion, but is not sufficient to drive the invasive phenotype. They also found a significant association between SOD2 expression and metastatic lesions, and by using cybrids were able to demonstrate that the expression of the SIRT3/FOXO3a/SOD2 signaling axis proteins were elevated in the presence of mtDNA from invasive cell lines [73]. However, SOD2 was not found to be a regulator of metastasis in other studies [147,148].…”

Understanding Mitochondrial Polymorphisms in Cancer

“…Kenny and colleagues discovered that the activation of SIRT/FOXO/SOD2 axis of the mitochondrial unfolded protein response (UPR mt ) is a common feature of the mtDNA of metastatic cells (25). In particular, super-oxide dismutase 2 (SOD2) was found to be substantially increased in more highly metastatic human breast cancer cell lines (MDA-MB-231, MDA-MB-361, and MDA-MB-157) compared with less metastatic cell lines MCF-7 and ZR-75-1.…”

“…In particular, super-oxide dismutase 2 (SOD2) was found to be substantially increased in more highly metastatic human breast cancer cell lines (MDA-MB-231, MDA-MB-361, and MDA-MB-157) compared with less metastatic cell lines MCF-7 and ZR-75-1. Interestingly, Kenny and colleagues found that there was no one specific mtDNA mutation that drove metastasis in the cancer cells, but rather the composition of the mtDNA genome [i.e., presence or absence of reactive oxygen species (ROS); activation of the SIRT/FOXO/SOD2 axis of the UPR mt ] dictated either promotion or repression of cancer cell metastasis (25). In comparison with Kenny and colleagues, Arnold and colleagues sequenced the mitochondrial genome of 10 prostate cancer patients with bone metastases (26).…”