Mitochondrial genomic backgrounds affect nuclear DNA methylation and gene expression

Mitochondrial DNA (mtDNA) mutations and polymorphisms contribute to many complex diseases, including cancer. Using a unique mouse model that contains nuclear DNA (nDNA) from one mouse strain and homoplasmic mitochondrial haplotypes from different mouse strain(s) - designated Mitochondrial Nuclear Exchange (MNX) - we show that mtDNA can alter mammary tumor metastasis. Since retrograde and anterograde communication exist between the nuclear and mitochondrial genomes, we hypothesized that there are differential mtDNA-driven changes in nDNA expression and DNA methylation. Genome-wide nDNA methylation and gene expression were measured in harvested brain tissue from paired wild-type and MNX mice. Selective differential DNA methylation and gene expression were observed between strains having identical nDNA, but different mtDNA. These observations provide insights into how mtDNA might alter epigenetic regulation and thereby contribute to the pathogenesis of metastasis.

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