Title:

Role of Mitochondrial tRNA Fragments in Metastasis

Metastasis is a process in cancer progression where cancer cells spread from the primary tumor to secondary sites. Metastasis remains a critical determinant of cancer mortality, with significant disparities in outcomes influenced by genetic and mitochondrial backgrounds. Previous research has demonstrated that maternal inheritance of mitochondrial DNA (mtDNA) influences the severity of metastasis. However, the specific element in the mitochondrial genome that contributes to these phenotypic differences remains to be discovered. Similar to the nuclear genome, single nucleotide polymorphisms (SNPs) accumulate in the mitochondrial genome as populations diverge. Different populations exhibit variable SNP frequencies, which may lead to phenotypic differences. To investigate this, mitochondrial-exchange (MNX) mice with exchanged mitochondrial genomes were created to enable comparisons of mtDNA and examination of SNP frequencies. This approach highlighted a specific polymorphic region and ultimately identified the MT-TR gene, which exhibits variable SNP frequencies among MNX strains. MT-TR encodes transfer RNA arginine (tRNA-Arg). tRNAs are continuously degraded into tRNA fragments (tRFs) that can act as growth factors influencing metastatic progression. We hypothesize that tRNA fragments derived from mitochondrial MT-TR polymorphisms affect metastatic burden. In this study, we addressed two preliminary questions integral to determining whether mitochondrial tRFs alter metastasis. Using RNA extraction and Northern blotting, we confirmed the presence of mitochondrial tRNA-Arg fragments and discovered that tRNA-Arg and its fragments are variably expressed in different tissues of MNX mice. Our findings underscore the potential of mitochondrial tRNA arginine fragments as novel targets for understanding disparities in cancer progression.

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