Inner mitochondrial membrane fission protein, MTP18, serves as a mitophagy receptor to prevent apoptosis in oral cancer

Abstract

MTP18, an inner mitochondrial membrane protein, plays a vital role in maintaining mitochondrial morphology. Furthermore, MTP18 induces mitochondrial fission with subsequent mitophagy, functioning as a mitophagy receptor that targets dysfunctional mitochondria into autophagosomes for elimination. Interestingly, MTP18 interacts with LC3 through its LC3 interacting region (LIR) to induce mitochondrial autophagy. Mutation in the LIR motif (mLIR) inhibits that interaction, thus suppressing mitophagy. Moreover, Parkin/PINK1 deficiency abrogates mitophagy in MTP18-overexpressing FaDu cells. Upon exposure to CCCP, MTP18[mLIR]-FaDu cells show decreased TOM20 expression without affecting COX IV expression. Conversely, loss of Parkin/PINK1 results in inhibition of TOM20 and COX IV degradation in MTP18[mLIR]-FaDu cells exposed to CCCP, establishing Parkin-mediated proteasomal degradation of outer mitochondrial membrane as essential for effective mitophagy. We found that MTP18 provides a survival advantage to oral cancer cells exposed to cellular stress and that inhibition of MTP18-dependent mitophagy induced cell death in oral cancer cells. The findings demonstrate that MTP18 is a novel mitophagy receptor and that MTP18-dependent mitophagy has pathophysiologic implications for oral cancer progression, indicating inhibition of MTP18-mitophagy could thus be a promising cancer therapy strategy.