Butein, a Polyphenol Phytocompound in MPTP Opening Mediated Apoptosis and Mitochondrial Quality Control by Modulating Mitophagy

Abstract

Mitochondria are the key players in maintaining cellular health by critically regulating metabolic processes, stress adaptation through cellular survival, and redox balance. They govern these by a synchronized process of mitochondrial homeostasis through fission and fusion cycles, facilitating a segregation of dysfunctional mitochondria from a healthy population and enabling either their repair or destruction by targeting them through the mitophagy pathway. However, excessive stress also leads to their clearance through mitochondrial apoptosis and an alteration in mitochondrial potential, leading to their removal. In this study, we explored the mechanistic modulation of these phenomena through a therapeutic compound, Butein, a flavonoid phytochemical found in the plant Butea monosperma, which is well-known to show anti-inflammatory properties. We found significantly upregulated MTP18 and DRP1 mediated mitochondrial fission along with an augmentation of the PINK1-PARKIN-dependent mitophagy pathway. This finding was integrated with the previously reported cytotoxic effect of Butein as it triggered a caspase-dependent increase of apoptosis and cytochrome c release. We further explored the role of Butein to escalate the opening of mitochondrial membrane permeability pore (MPTP) by inducing oxidative stress and altering the levels of its component Cyclophilin D, with a concomitant decrease of mitochondrial calcium levels, pointing to its role in aiding cell death. Contrastingly, we found a simultaneous inhibition of apoptotic cell death by fission and mitophagy, indicating its dual role in the clearance of impaired cellular populations. At the same time, it maintains a pro-survival advantage for healthy mitochondria. Thus, this balance was found to be a major driver for restraining oral cancer progression by a compromised environment of mitochondrial health.