The significance of mitochondrial DNA changes during the onset and progression of head and neck squamous cell carcinoma

Mitochondrial DNA (mtDNA) is integral to cellular function. Alterations in mtDNA can lead to significant disruptions in mitochondrial function, including cellular energy production, metabolism, and apoptosis regulation. Mitochondrial dysfunction has emerged as a crucial factor in the progression of cancer, including head and neck squamous cell carcinoma (HNSCC). Based on a literature search conducted from August 2024 to March 2025 on PubMed and Google Scholar, our review summarizes the relevance of mtDNA alterations in HNSCC development. HNSCC has been found to cause significant variations in mtDNA, including mutations, copy number variations (or known as mtDNA content) and large-scale deletions. Notably, these alterations varied by disease stage, different key aspects of mitochondrial function, such as cellular growth, senescence, metabolism and apoptosis, and cell-specific genetic context. We further suggest that drugs that modulate mitochondrial pathways, mitochondrial transplantation, and gene-editing technologies, are future treatment strategies for HNSCC. Lastly, we discuss the potential of co-roles of nuclear DNA mutations with mtDNA alterations in HNSCC to provide a holistic view of HNSCC pathogenesis and the possibility for combined therapeutic strategies in HNSCC.