mtDNA, Metastasis, and the Mitochondrial Unfolded Protein Response (UPRmt)

Kenny, Timothy; Germain, Doris

doi:10.3389/fcell.2017.00037

Cited by 31 publications

(28 citation statements)

References 39 publications

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“…Having previously demonstrated that nuclear (34) and mitochondrial (11,16) genetics could alter the efficiency of mammary tumor development and metastasis, we sought to distinguish the impact of stromal contributions in metastatic colonization. Accumulating data implicate mitochondrial function (9,27,(35)(36)(37) and localization (38) in the metastatic process. Because metastasis involves a complex interplay between tumor cells and stroma, including bidirectional signaling and recognition between cells, matrices, and soluble factors, our experimental design kept nuclear and mitochondrial genomes constant between tumor cells and mice, while changing the mitochondria only in the stroma.…”

Section: Discussionmentioning

confidence: 99%

Mitochondrial Haplotype of the Host Stromal Microenvironment Alters Metastasis in a Non-cell Autonomous Manner

et al. 2020

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Mitochondria contribute to tumor growth through multiple metabolic pathways, regulation of extracellular pH, calcium signaling, and apoptosis. Using the Mitochondrial Nuclear Exchange (MNX) mouse models, which pair nuclear genomes with different mitochondrial genomes, we previously showed that mitochondrial SNPs regulate mammary carcinoma tumorigenicity and metastatic potential in genetic crosses. Here, we tested the hypothesis that polymorphisms in stroma significantly affect tumorigenicity and experimental lung metastasis. Using syngeneic cancer cells (EO771 mammary carcinoma and B16-F10 melanoma cells) injected into wild-type and MNX mice (i.e., same nuclear DNA but different mitochondrial DNA), we showed mt-SNP-dependent increases (C3H/HeN) or decreases (C57BL/6J) in experimental metastasis. Superoxide scavenging reduced experimental metastasis. In addition, expression of lung nuclear-encoded genes changed specifically with mt-SNP. Thus, mitochondrial-nuclear cross-talk alters nuclear-encoded signaling pathways that mediate metastasis via both intrinsic and extrinsic mechanisms. Significance: Stromal mitochondrial polymorphisms affect metastatic colonization through reactive oxygen species and mitochondrial-nuclear cross-talk.

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Section: Discussionmentioning

confidence: 99%

Mitochondrial Haplotype of the Host Stromal Microenvironment Alters Metastasis in a Non-cell Autonomous Manner

et al. 2020

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“…To date, there is no solid evidence implicating mutations in mtDNA as drivers of tumor formation; however, there are some nonrandom tumor progression-associated changes in mtDNA reported for some tumor types (26, 45, 46). Thus, mtDNA is more likely a contributor to controlling tumor latency or metastasis predicated on active mitochondrial-nuclear cross-talk.…”

Section: Discussionmentioning

confidence: 99%

Mitochondrial Haplotype Alters Mammary Cancer Tumorigenicity and Metastasis in an Oncogenic Driver–Dependent Manner

et al. 2017

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Using a novel mouse model, a mitochondrial-nuclear exchange model termed MNX, we tested the hypothesis that inherited mitochondrial haplotypes alter primary tumor latency and metastatic efficiency. Male FVB/N-Tg(MMTVneu)202Mul/J (Her2) transgenic mice were bred to female MNX mice having FVB/NJ nuclear DNA with either FVB/NJ, C57BL/6J, or BALB/cJ mtDNA. Pups receiving the C57BL/6J or BALB/cJ mitochondrial genome (i.e., females crossed with Her2 males) showed significantly (P < 0.001) longer tumor latency (262 vs. 293 vs. 225 days), fewer pulmonary metastases (5 vs. 7 vs. 15), and differences in size of lung metastases (1.2 vs. 1.4 vs. 1.0 mm diameter) compared with FVB/NJ mtDNA. Although polyoma virus middle T–driven tumors showed altered primary and metastatic profiles in previous studies, depending upon nuclear and mtDNA haplotype, the magnitude and direction of changes were not the same in the HER2-driven mammary carcinomas. Collectively, these results establish mitochondrial polymorphisms as quantitative trait loci in mammary carcinogenesis, and they implicate distinct interactions between tumor drivers and mitochondria as critical modifiers of tumorigenicity and metastasis.

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“…Another important observation is that mutations in OXPHOS genes and accumulation of ROS can lead to the oxidation of proteins and their missfolding. To balance this, metastatic cells show high expression of the unfolded protein response (UPR mt ), which allows them to survive in this highly stressed environment (45,52).…”

Section: Mitochondria Variants and Cancermentioning

confidence: 99%

“…The overexpression of genes involved in the activation of the UPR mt has also been observed in metastatic cells. The UPR mt system protects from protein misfolding and oxidation; however, it might also maintain deleterious mtDNA mutations conferring advantages that facilitate cancer cell metastasis (52,82).…”

Section: Mitochondria Variants and Cancermentioning

confidence: 99%

Overview of mitochondrial germline variants and mutations in human disease: Focus on breast cancer (Review)

et al. 2018

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High lactate production in cells during growth under oxygen-rich conditions (aerobic glycolysis) is a hallmark of tumor cells, indicating the role of mitochondrial function in tumorigenesis. In fact, enhanced mitochondrial biogenesis and impaired quality control are frequently observed in cancer cells. Mitochondrial DNA (mtDNA) encodes 13 subunits of oxidative phosphorylation (OXPHOS), is present in thousands of copies per cell, and has a very high mutation rate. Mutations in mtDNA and nuclear DNA (nDNA) genes encoding proteins that are important players in mitochondrial biogenesis and function are involved in oncogenic processes. A wide range of germline mtDNA polymorphisms, as well as tumor mtDNA somatic mutations have been identified in diverse cancer types. Approximately 72% of supposed tumor-specific somatic mtDNA mutations reported, have also been found as polymorphisms in the general population. The ATPase 6 and NADH dehydrogenase subunit genes of mtDNA are the most commonly mutated genes in breast cancer (BC). Furthermore, nuclear genes playing a role in mitochondrial biogenesis and function, such as peroxisome proliferators-activated receptor gamma coactivator-1 (PGC-1), fumarate hydratase (FH) and succinate dehydrogenase (SDH) are frequently mutated in cancer. In this review, we provide an overview of the mitochondrial germline variants and mutations in cancer, with particular focus on those found in BC.

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mtDNA, Metastasis, and the Mitochondrial Unfolded Protein Response (UPRmt)

Cited by 31 publications

References 39 publications

Mitochondrial Haplotype of the Host Stromal Microenvironment Alters Metastasis in a Non-cell Autonomous Manner

Mitochondrial Haplotype of the Host Stromal Microenvironment Alters Metastasis in a Non-cell Autonomous Manner

Mitochondrial Haplotype Alters Mammary Cancer Tumorigenicity and Metastasis in an Oncogenic Driver–Dependent Manner

Overview of mitochondrial germline variants and mutations in human disease: Focus on breast cancer (Review)

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