Comparative Evaluation of Mitochondrial Dysfunction in Oral Leukoplakia and Associated Oral Squamous Cell Carcinoma

Abstract

Oral squamous cell carcinoma (OSCC) represents a significant global oncologic burden, particularly in regions with prevalent tobacco and areca nut exposure. A substantial proportion of OSCC arises from oral leukoplakia (OL), the most common oral potentially malignant disorder (OPMD). Although histopathological grading of epithelial dysplasia remains the principal risk assessment tool, it does not fully capture underlying metabolic and molecular instability that precedes malignant transformation. Increasing evidence suggests that mitochondrial dysfunction represents a progressive and biologically significant driver of oral carcinogenesis. Chronic carcinogen exposure induces sustained oxidative stress, leading to mitochondrial DNA (mtDNA) instability, impaired oxidative phosphorylation, altered mitochondrial dynamics, metabolic reprogramming toward glycolytic dominance, and resistance to intrinsic apoptosis. These alterations appear to evolve across the continuum from OL to invasive OSCC. This narrative review systematically evaluates contemporary evidence regarding mitochondrial alterations in oral carcinogenesis, explores diagnostic and prognostic implications, examines therapeutic targeting strategies, and highlights current limitations and future research directions. Integration of mitochondrial profiling into oral oncology may refine early risk stratification and support precision redox-based therapeutic approaches.