LAUSR

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 single nucleotide polymorphisms (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 (mtDNA], we showed mt-SNP-dependent increase (C3H/HeN) or decrease (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 which mediate metastasis via both intrinsic and extrinsic mechanisms.