SIRT1 Activating Butein Inhibits Arecoline Induced Mitochondrial Dysfunction Through PGC1α and MTP18 in Oral Cancer

Abstract

Arecoline, the major alkaloid of areca nut, is known to induce oral carcinogenesis and is associated with mitochondrial dysfunction caused by mitochondrial DNA mutations, enzyme defects, generation of reactive oxygen species (ROS), and altered oxidative homeostasis. In this study, butein, a natural small molecule activator of SIRT1, replenishes a healthy and functional mitochondrial pool and curtails mitochondrial dysfunction. Butein, in the presence of arecoline significantly causes a decrease in mitochondrial hyperpolarisation and ROS levels in oral cancer cells. This prompts us to understand the status of functional mitochondria as such effects are possible through regulated maintenance of the mitochondrial pool. So, we studied the two possible pathways, i.e., mitochondrial biogenesis and mitochondrial dynamics, that contribute to such outcomes. Interestingly, we found increased COXIV, TOM20, and PGC1α expression during butein treatment, and it showed that inhibition of PGC1α blunt mitochondrial biogenesis and decreased the mitochondrial pool. Moreover, we also found increased expression of various mitophagy proteins, including PINK1, PARKIN, and LC3, suggesting the clearance of damaged mitochondria to maintain a healthy mitochondrial pool. Mechanistically, we studied the fission protein MTP18 and its molecular partners DRP1 and MFF and found to be dose-dependently increased during butein treatment. The activity of SIRT1 controls the functional mitochondrial pool, and inhibition of SIRT1 leads to the lowering of mitochondrial levels, as evident from the decrease in the expression of PGC1α and MTP18 in oral cancer cells. In conclusion, our study establishes that SIRT1 maintains a functional mitochondrial pool during arecoline exposure and could decrease the risk of mitochondria dysfunctionality associated onset of oral carcinogenesis