DRP1-mediated mitophagy facilitates oral squamous cell carcinoma tumor cell survival under glucose restriction

Oral squamous cell carcinoma (OSCC) can progress within a nutrient-limited microenvironment, especially under low-glucose conditions. However, the mechanisms enabling tumor cells to cope with glucose limitation, particularly those that counteract Reactive Oxygen Species (ROS) accumulation, remain largely unknown. Here, we showed that dynamin-related protein 1 (DRP1)-mediated Mitophagy promoted OSCC cell survival under glucose restriction. High expression of DRP1 was observed in OSCC tumor cells and identified as an indicator of poor prognosis. Either expression knockdown or pharmacological inhibition of DRP1 significantly reduced tumor cell Mitophagy, leading to increased ROS production and consequently accelerating OSCC tumor cell death. The promoting effect of DRP1 on OSCC tumor growth, alongside its inhibitory effect on ROS production, was also confirmed in vivo. Furthermore, as a key nutrient stress sensor, AMP-activated protein kinase (AMPK) was activated upon glucose restriction. Pharmacological inhibition of AMPK was associated with reduced DRP1 mitochondrial translocation and diminished Mitophagy. These findings collectively uncover that DRP1 contributes to Mitophagy and allows OSCC cells to adapt to glucose limitation and overcome associated ROS stress, providing potential mechanistic insights for enhancing the efficiency of targeted therapies strategies.