MTP18 Promotes mtDNA Stress-Mediated Inflammation and Autophagy to Confer Drug Resistance in Oral Cancer

Abstract

Emerging evidences highlight a significant association of aberrant mitochondrial function with drug resistance and increased proliferation in cancer. Cancer cells modulate mitochondrial dynamics to counteract chemotherapy stress. Excessive stress causes mtDNA to leak out and drive an inflammatory response. The inner mitochondrial protein MTP18 executes mitochondrial fission and has an LIR motif that interacts with LC3 and promotes mitophagy. This study explores the role of an inner mitochondrial membrane protein, MTP18, in oral cancer survival and proliferation under therapeutic stress. Cisplatin treatment enhances the expression of mitochondrial fission proteins MTP18, pDRP1, and consequently mtDNA release into the cytosol. MTP18 overexpression promotes mitochondrial fission and mitochondrial fission-mediated mtDNA-stress that induces inflammasome activation through cGAS-STING and NLRP3 pathways. Activation of these inflammation-inducing pathways promotes cancer cell proliferation and progression. However, DRP1 knockdown in MTP18 overexpressing cells reduces the cGAS and NLRP3 activation, indicating the significant role of DRP1 and MTP18 complex in mediating mitochondrial fission-induced mtDNA stress. Moreover, it has elucidated the underlying mechanism by which MTP18 protects cancer cells from apoptosis by activating autophagy. Increased colocalization of LC3 and LAMP1 in MTP18 overexpressed cells shows increased autolysosome formation, and inhibition of autophagy in MTP18 overexpression cells further increases type-I interferon and inflammasome signaling. MTP18-mediated autophagy activation protects oral cancer cells from excessive inflammation and cell death. This study also proposes the cytotoxic role of methyl gallate, a natural compound, in suppressing mitochondrial fission-mediated oral cancer cell proliferation. Moreover, it induces apoptosis, increases cellular ROS production, and inhibits autophagy flux.