Interlaced roles of mitochondrial DNA in colorectal cancer: Liquid-biopsy biomarkers, nuclear mtDNA-driven genomic instability, and mito-encoded micro peptide signaling.

Colorectal cancer (CRC) is a widely occurring malignancy with significant mortality on a global scale, making up close to 10% of all diagnosed cancers in 2020. While traditional CRC diagnostics and research have focused on nuclear genomic alterations, emerging evidence has highlighted the multifaceted roles of mitochondrial DNA (mtDNA) in the pathogenesis and clinical management of CRC. In this review, we examine three interlaced aspects of mtDNA in CRC: (1) Liquid biopsy biomarkers: Cell-free mtDNA circulating in the blood serving as a minimally invasive diagnostic and monitoring tool; (2) Nuclear mtDNA (NUMT)-driven genomic instability: The somatic nuclear incorporation of mtDNA (NUMT segments, or NUMT), contributing to mutational burden and chromosomal disruption in tumours; and (3) Mitochondria-encoded micropeptide signaling - small peptides encoded by the mtDNA that modulate cellular pathways and tumour behaviour. Recent high-impact studies have demonstrated that tumour-derived mtDNA in biofluids can augment cancer detection sensitivity, although technical challenges remain due to mtDNA fragmentation and background noise. Meanwhile, genomic analyses have uncovered a significant increase in NUMT insertion events in CRC cells, linking mitochondrial genome escape to nuclear genome instability and identifying potential numtogenesis suppressor genes. A novel dimension of mito-nuclear interactions in cancer was discovered in mitochondrial microproteins, such as humanin and mitochondrial open reading frame of the 12S rRNA type-c. Humanin exhibits both tumour-promoting and cytoprotective properties under specific conditions, while mitochondrial open reading frame of the 12S rRNA type-c possesses tumour-suppressive activities under other conditions. The outcomes of clinical, mechanistic, and translational research, revealing how mtDNA-based biomarkers and involvement contribute towards early detection, prognostication, and treatment of CRC, are presented.