Biological and translational attributes of mitochondrial DNA copy number: Laboratory perspective to clinical relevance

Table 4 Role of mtDNA copy number in various stages of cancer development and progression

Aspect	Role of mtDNAcn	Mechanism/impact	Examples
Cancer risk	Altered mtDNAcn (increase or decrease) may predispose individuals to cancer development	Imbalance in ROS production	Decreased mtDNAcn linked to breast cancer risk
		Compromised cellular energy metabolism	Increased mtDNAcn linked to lung cancer risk
Tumor initiation	Changes in mtDNAcn can affect mitochondrial biogenesis and metabolic reprogramming	Promotes a shift to aerobic glycolysis (Warburg effect)	Low mtDNAcn observed in colorectal cancer tissues
		Increases ROS, leading to genomic instability
Tumor progression	Dynamic changes in mtDNAcn support adaptation to tumor microenvironment	High mtDNAcn enables oxidative metabolism in hypoxic conditions	Elevated mtDNAcn associated with metastatic breast cancer
		Supports invasive and metastatic properties
Therapeutic resistance	Altered mtDNAcn contributes to drug resistance	High mtDNAcn enhances oxidative phosphorylation, reducing sensitivity to certain chemotherapies	Increased mtDNAcn linked to resistance in lung cancer treatments
Prognostic biomarker	mtDNAcn alterations can predict cancer outcomes	Low mtDNAcn correlates with poor prognosis in many cancers	Reduced mtDNAcn in gastric cancer linked to poor survival
		High mtDNAcn may predict aggressive tumor behavior
Immune evasion	Changes in mtDNAcn influence immune responses within the tumor microenvironment	mtDNA release into the cytoplasm activates inflammatory pathways	mtDNA-derived DAMPs in melanoma
		Alters immune surveillance mechanisms
Angiogenesis	mtDNAcn modulates energy demand and oxidative stress, indirectly affecting vascular growth	High mtDNAcn supports angiogenic signaling	Increased angiogenesis in glioblastoma with altered mtDNAcn
Metastasis	Altered mtDNAcn facilitates energy supply for metastatic spread	Provides metabolic flexibility for survival in secondary sites	Elevated mtDNAcn in metastatic colorectal cancer

mtDNAcn: Mitochondrial DNA copy number; ROS: Reactive oxygen species; DAMPs: Damage-associated molecular patterns.