Although stress-induced mitochondrial hyperfusion (SIMH) exerts a protective role in aiding cell survival, in the absence of mitochondrial fission, SIMH drives oxidative stress-related induction of apoptosis. In this study, our data showed that MTP18, a mitochondrial fission-promoting protein expression, was increased in oral cancer. We have screened and identified S28, a novel inhibitor of MTP18, which was found to induce SIMH and subsequently trigger apoptosis. Interestingly, it inhibited MTP18-mediated mitochondrial fission, as shown by a decrease in p-Drp1 along with increased Mfn1 expression in oral cancer cells. Moreover, S28 induced autophagy but not mitophagy due to the trouble in engulfment of hypoperf... More
Although stress-induced mitochondrial hyperfusion (SIMH) exerts a protective role in aiding cell survival, in the absence of mitochondrial fission, SIMH drives oxidative stress-related induction of apoptosis. In this study, our data showed that MTP18, a mitochondrial fission-promoting protein expression, was increased in oral cancer. We have screened and identified S28, a novel inhibitor of MTP18, which was found to induce SIMH and subsequently trigger apoptosis. Interestingly, it inhibited MTP18-mediated mitochondrial fission, as shown by a decrease in p-Drp1 along with increased Mfn1 expression in oral cancer cells. Moreover, S28 induced autophagy but not mitophagy due to the trouble in engulfment of hypoperfused mitochondria. Interestingly, S28-mediated SIMH resulted in the loss of mitochondrial membrane potential, leading to the consequent generation of mitochondrial superoxide to induce intrinsic apoptosis. Mechanistically, S28-induced mitochondrial superoxide caused lysosomal membrane permeabilization (LMP), resulting in decreased lysosomal pH, which impaired autophagosome-lysosome fusion. In this setting, it showed that overexpression of MTP18 resulted in mitochondrial fission leading to mitophagy and inhibition of superoxide-mediated LMP and apoptosis. Further, S28, in combination with FDA-approved anticancer drugs, exhibited higher apoptotic activity and decreased cell viability, suggesting the MTP18 inhibition combined with the anticancer drug could have greater efficacy against cancer.
