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

Table 1 Summary of liquid-biopsy and mitochondrial pathways in colorectal cancer: From biomarkers to therapy

Theme	Scope	Key finding	Mechanism	Clinical implication
Liquid biopsy: Cf-mtDNA for detection and monitoring	CRC cohorts (supported by pan-cancer WGS including CRC)	Adding cf-mtDNA fraction features to standard ctDNA models improves CRC detection (AUC: 0.73 to 0.81)[12]	Because cells harbor thousands of mtDNA genomes, apoptosis/necrosis releases abundant yet highly short circulating fragments that require short-amplicon or deep-sequencing assays[6,10,11]	Quantifying cf-mtDNA fractions can serve as early-warning or pharmacodynamic markers and should be integrated with nuclear features for best performance[12]
cf-mtDNA variability and pre-analytics	CRC (assay/stage-dependent)	Direction of change differs by method/cohort: Pan-cancer WGS shows elevated cf-mtDNA fraction in CRC, yet a CRC dPCR study found lower pre-treatment plasma mtDNA in patients vs controls (approximately 684 copies/mL vs approximately 1081 copies/mL)[6]	Differences likely reflect disease stage, tumor mtDNA content, patient physiology, and pre-analytical/assay factors[6,12]	Pre-analytical standardization coupled with multi-analyte panels - such as combining mtDNA abundance with nuclear mutation/protein markers or augmenting protein panels with mtDNA quantitation - can enhance early detection and follow-up surveillance[12]
NUMTs burden in CRC	CRC tissue	Tumors show approximately 4.2-fold higher mtDNA-derived nuclear reads than matched normals (proxy for somatic NUMTs); higher burden associates with worse survival[14]	New NUMTs integrate at nuclear DSBs via error-prone MMEJ, with > 90% involving non-coding mtDNA (often D-loop)[13]	Evaluation of NUMT burden as a prognostic biomarker since higher NUMT levels associate with worse survival and reflect increased genomic instability[14,26]
NUMT suppressor (YME1 L1)	CRC tissue	YME1 L1 acts as a human NUMT-suppressor; 16% of CRC tumors harbored YME1 L1 mutations and knockout increased nuclear mtDNA[14,26]	Loss of the mitochondrial protease YME1 L1 relaxes mitochondrial quality control, permitting mtDNA leakage and nuclear integration[26]	YME1 L1-deficient tumors may represent a subset with unique vulnerabilities and higher numtogenesis, suggesting potential prognostic value and therapeutic angles[14,26]
HN/GP130 chemoresistance axis	Pan-cancer/GBMs evidence	HN promotes chemoresistance and growth via GP130-ERK signaling, promotes blood-tumor barrier formation and gp130 antagonists abrogate these effects in GBMs models[18,29,37-39]	HN signals via a gp130-containing receptor complex and triggers pro-survival cascades (STAT3/MAPK/PI3K-Akt); it inhibits Bax-mediated mitochondrial apoptosis[18]; in GBMs, HN → gp130 → ERK → DDR drives chemoresistance[29]	Identify HN-high subsets and test gp130-pathway blockade to re-sensitise tumors to chemotherapy (evidence in GBMs models)[29]
MOTS-c (MDPs) tumor-suppressive signaling	Preclinical/pan-cancer	There is decline in MOTS-c levels in aggressive disease and exogenous MOTS-c suppresses growth and dissemination in vivo[43]	MOTS-c is to the nucleus under stress, activates AMPK, and inhibits mTORC1 by interfering with USP7-mediated LARS1 deubiquitination[15,30-34,43,44]	Evaluate MOTS-c in CRC as a biomarker and therapeutic candidate: In MOTS-c-low settings, consider recombinant MOTS-c/analogs[43] or targeting downstream AMPK-mTOR axis (via AMPK activation and/or direct mTORC1 inhibition)[15,30-34]

cf-mtDNA: Cell-free mitochondrial DNA; CRC: Colorectal cancer; AUC: Area under the curve; mtDNA: Mitochondrial DNA; WGS: Whole genome sequencing; dPCR: Digital polymerase chain reaction; NUMTs: Nuclear mtDNAs; DSB: Double-strand break; MMEJ: Microhomology-mediated end-joining; YME1: Yeast mitochondrial escape-1; HN: Humanin; GBMs: Glioblastoma; ERK: Extracellular signal-regulated kinase; STAT3: Signal transducer and activator of transcription 3; MAPK: Mitogen-activated protein kinase; PI3K: Phosphatidylinositol 3-kinase; Akt: Protein kinase B; DDR: DNA damage response; MDPs: Mitochondria-derived peptides; MOTS-c: Mitochondrial open reading frame of the 12S rRNA type-c; AMPK: AMP-activated protein kinase; mTORC1: Mammalian target of rapamycin complex 1; LARS1: Leucyl-tRNA synthetase 1.