Mitochondrial DNA's Interlaced Roles in Colorectal Cancer: Biomarkers, Genomic Instability, and Micropeptide Signaling

Colorectal cancer (CRC) remains a leading cause of global cancer mortality, accounting for close to 10% of all diagnosed cancers in 2020. Traditional diagnostics and research have primarily focused on nuclear genomic alterations, often overlooking the significant contributions of mitochondrial DNA (mtDNA). There's a critical gap in understanding how mtDNA's unique characteristics, including its presence in circulation, its integration into the nuclear genome, and its encoding of novel micropeptides, contribute to CRC pathogenesis and could offer new diagnostic or therapeutic avenues.

This comprehensive review synthesized recent high-impact studies to examine three interlaced aspects of mitochondrial DNA (mtDNA) in colorectal cancer (CRC). The authors explored the utility of cell-free mtDNA circulating in blood as a minimally invasive liquid biopsy biomarker. They also investigated the phenomenon of nuclear mtDNA (NUMT)-driven genomic instability, where somatic nuclear incorporation of mtDNA segments contributes to mutational burden. Finally, the review delved into mitochondria-encoded micropeptide signaling, focusing on small peptides like humanin that modulate cellular pathways and tumor behavior.

Tumor-derived cell-free mtDNA in biofluids significantly augments cancer detection sensitivity, despite ongoing technical challenges related to mtDNA fragmentation and background noise. Genomic analyses consistently reveal a significant increase in NUMT insertion events within CRC cells, directly linking mitochondrial genome escape to nuclear genome instability and identifying potential numtogenesis suppressor genes. A novel dimension of mito-nuclear interactions in cancer involves mitochondrial microproteins, such as humanin and mitochondrial open reading frame of the 12S rRNA type-c (MOTS-c).