Koo TH, Leong XB, Lee YL, Hayati F, Zakaria AD. Interlaced roles of mitochondrial DNA in colorectal cancer: Liquid-biopsy biomarkers, nuclear mtDNA-driven genomic instability, and mito-encoded micro peptide signaling. World J Gastrointest Oncol 2025; 17(12): 112753 [DOI: 10.4251/wjgo.v17.i12.112753]
Corresponding Author of This Article
Andee Dzulkarnaen Zakaria, Department of Surgery, Hospital Pakar Universiti Sains Malaysia, School of Medical Sciences, Jalan Raja Perempuan Zainab 2, Kubang Kerian 16150, Kelantan, Malaysia. andee@usm.my
Research Domain of This Article
Oncology
Article-Type of This Article
Minireviews
Open-Access Policy of This Article
This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
World J Gastrointest Oncol. Dec 15, 2025; 17(12): 112753 Published online Dec 15, 2025. doi: 10.4251/wjgo.v17.i12.112753
Interlaced roles of mitochondrial DNA in colorectal cancer: Liquid-biopsy biomarkers, nuclear mtDNA-driven genomic instability, and mito-encoded micro peptide signaling
Thai-Hau Koo, Andee Dzulkarnaen Zakaria, Department of Surgery, Hospital Pakar Universiti Sains Malaysia, School of Medical Sciences, Kubang Kerian 16150, Kelantan, Malaysia
Xue-Bin Leong, Yi-Lin Lee, Universiti Sains Malaysia, School of Medical Sciences, Health Campus, Kubang Kerian 16150, Kelantan, Malaysia
Firdaus Hayati, Department of Surgery, Faculty of Medicine and Health Sciences, University Malaysia Sabah, Kota Kinabalu 88400, Sabah, Malaysia
Co-first authors: Thai-Hau Koo and Xue-Bin Leong.
Author contributions: Koo TH and Leong XB contributed equally as co-first authors. Koo TH, Hayati F, and Zakaria AD designed the overall concept and outline of the manuscript; Leong XB and Lee YL contributed to the discussion and design of the manuscript; Koo TH, Leong XB, Lee YL, and Zakaria AD contributed to the writing and editing of the manuscript, illustrations, and review of literature. All authors have read and approved the final manuscript.
Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.
Open Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Andee Dzulkarnaen Zakaria, Department of Surgery, Hospital Pakar Universiti Sains Malaysia, School of Medical Sciences, Jalan Raja Perempuan Zainab 2, Kubang Kerian 16150, Kelantan, Malaysia. andee@usm.my
Received: August 5, 2025 Revised: September 28, 2025 Accepted: November 12, 2025 Published online: December 15, 2025 Processing time: 128 Days and 17.2 Hours
Abstract
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.
Core Tip: This minireviews highlights the emerging roles of mitochondrial DNA (mtDNA) in colorectal cancer beyond its role in energy metabolism. Three interrelated domains are focused on in this paper: (1) Cell-free mtDNA as a liquid biopsy biomarker of exceptional sensitivity; (2) Nuclear mtDNA fragments as a component of genomic instability; and (3) Mitochondria-derived peptides, such as humanin and mitochondrial open reading frame of the 12S rRNA type-c, as regulators of tumour behaviour. These insights reveal novel diagnostic and therapeutic potential by targeting mitochondrial-nuclear cross-talk in colorectal cancer.
