Mitochondrial fission dictates pro-survival adaptation and irreversible demise in oral cancer

Mitochondrial fission is dynamically balanced with fusion, which is essential for maintaining cellular energy homeostasis and metabolic plasticity. In oral cancer, (of which over 90% is oral squamous cell carcinoma; OSCC) accumulating evidence highlights that dysregulated mitochondrial fission is intimately linked to high-grade malignancy, metastatic propensity, and acquired chemoresistance. Notably, mitochondrial fission exhibits a striking functional dichotomy in this context. On the one hand, oncogenic sustained excessive fragmentation supports elevated metabolic demands and facilitates tumor progression by coupling fission to protective mitophagy and cellular motility. Conversely, under therapeutic pressure from genotoxic agents, the same fission machinery can be exploited to trigger lethal mitophagy and intrinsic apoptosis. However, the precise molecular mechanisms by which the fission machinery deciphers distinct upstream signals dictates these divergent pro-survival versus pro-death outcomes remain insufficiently understood. Moreover, the impact of spatial heterogeneity of fission events, specifically the distinction between proliferative midzone fission and degradative peripheral fission, on therapeutic response is largely unexplored. This review systematically dissects the context-dependent plasticity of mitochondrial fission in oral cancer and provides a unified mechanistic framework to reconcile existing contradictions. We further propose that strategically disrupting the dynamic equilibrium of mitochondria may overcome drug resistance and reshape therapeutic outcomes in OSCC, with potential extrapolation to other oral cancer subtypes.