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

Table 6 Broad spectrum of therapeutic applications of mtDNA copy number

Application	Role of mtDNAcn assessment	Therapeutic implications	Examples
Cancer prognostication	mtDNAcn serves as a biomarker for predicting cancer outcomes	Guides risk stratification and treatment intensity	Low mtDNAcn linked to poor prognosis in gastric and colorectal cancers
		Identifies patients with aggressive disease
Therapeutic targeting	Abnormal mtDNAcn highlights mitochondrial vulnerabilities	Enables development of drugs targeting mitochondrial pathways (e.g., OXPHOS inhibitors)	mtDNAcn modulation as a target in ovarian and pancreatic cancer therapies
Monitoring treatment response	Changes in mtDNAcn reflect tumor response to therapy	Serves as a real-time marker to monitor chemotherapy, radiotherapy, or immunotherapy efficacy	mtDNAcn alterations used to monitor cisplatin therapy in ovarian cancer
Personalized medicine	mtDNAcn variations help tailor therapies based on mitochondrial function	Facilitates selection of specific treatment modalities (e.g., glycolysis inhibitors vs OXPHOS inhibitors)	mtDNAcn guiding metabolic therapy choices in lung and breast cancer
Radiotherapy sensitization	Altered mtDNAcn may increase sensitivity or resistance to radiotherapy	Identifies patients who might benefit from combined mitochondrial and radiotherapy interventions	Elevated mtDNAcn linked to radio-resistance in glioblastoma
Metabolic modulation	mtDNAcn assessment reveals metabolic dependencies of tumors	Guides therapies targeting cancer metabolism (e.g., ketogenic diets, mitochondrial uncouplers)	Low mtDNAcn tumors treated with glycolysis inhibitors
Early disease detection	mtDNAcn alterations in blood or tissue serve as a non-invasive biomarker for early cancer detection	Allows early initiation of treatment, potentially improving outcomes	Reduced mtDNAcn detected in circulating cell-free DNA in lung and breast cancers
Combination therapies	mtDNAcn dynamics predict synergy between mitochondrial-targeted drugs and conventional therapies	Combines metabolic modulators with standard chemotherapy or immunotherapy for enhanced efficacy	mtDNAcn-directed combination strategies in melanoma treatment
Toxicity management	mtDNAcn levels predict susceptibility to mitochondrial toxicity from certain drugs	Assists in preemptive dose adjustments or alternative drug selection to avoid adverse effects	Monitoring mtDNAcn to prevent cardiotoxicity from anthracyclines
Rare mitochondrial disorders	mtDNAcn assessment aids in the diagnosis and management of mitochondrial diseases with cancer overlap	Develops therapies that normalize mtDNAcn or enhance mitochondrial biogenesis	mtDNAcn restoration therapies in mitochondrial depletion syndromes

mtDNAcn: Mitochondrial DNA copy number; OXPHOS: Oxidative phosphorylation.