Mitochondrial RNA modifications in gene expression and cancer biology

Abstract RNA modifications are essential in regulating gene expression at the post-transcriptional level. Recent studies, including our own, have highlighted that RNA modifications, such as N 6 -methyladenosine (m 6 A) and methyl-5-cytosine (m 5 C), play a crucial role in tumorigenesis, metabolism, and anti-tumor immunity. Targeting RNA modification machinery may represent a promising therapeutic strategy in cancer. Intriguingly, emerging evidence reveals numerous modifications in mitochondrial RNA (mt-RNA), expanding the concept of epitranscriptomics to mitochondria. The mammalian mitochondrion possesses its own genome, which encodes 22 transfer RNAs (tRNAs), 2 ribosomal RNAs (rRNAs), and 13 proteins necessary for energy production via oxidative phosphorylation (OxPhos). The mitochondrial transcriptome is produced from large polycistronic transcripts, implying that mitochondrial gene expression is predominantly regulated post-transcriptionally. In this review, we summarize all currently known mt-RNA modifications, their potential regulatory machinery, as well as their biological functions in tumorigenesis and metabolism. Additionally, given that this field is still in its infancy, we discuss several critical knowledge gaps and propose future research directions to clarify the mechanistic and clinical significance in the study of mt-RNA modifications.