MTP18 inhibition triggers mitochondrial hyperfusion to induce apoptosis through ROS-mediated lysosomal membrane permeabilization-dependent pathway in oral cancer.

Debasna Pritimanjari Panigrahi, Srimanta Patra, Bishnu Prasad Behera, Pradyota Kumar Behera, Shankargouda Patil, Birija Sankar Patro, Laxmidhar Rout, Itisam Sarangi, Sujit Kumar Bhutia

Free radical biology & medicine 2022 Sep

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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. Copyright © 2022 Elsevier Inc. All rights reserved.

Citation

Debasna Pritimanjari Panigrahi, Srimanta Patra, Bishnu Prasad Behera, Pradyota Kumar Behera, Shankargouda Patil, Birija Sankar Patro, Laxmidhar Rout, Itisam Sarangi, Sujit Kumar Bhutia. MTP18 inhibition triggers mitochondrial hyperfusion to induce apoptosis through ROS-mediated lysosomal membrane permeabilization-dependent pathway in oral cancer. Free radical biology & medicine. 2022 Sep;190:307-319