Mitochondrial Fission-Induced mtDNA Stress Promotes ESCC Progression by cGAS-STING Mediated Autophagy

Abstract Background Mitochondrial dynamics homeostasis is important for cell metabolism, growth, proliferation, and immune responses. The critical GTPase for mitochondrial fission, Drp1 is frequently upregulated in many cancers and is closely implicated in tumorigenesis. However, the underling mechanism by Drp1 influence tumor progression is largely unknown, especially in esophageal squamous cell carcinoma (ESCC). Methods Immunohistochemistry was used to examine Drp1 and LC3B expression in tissues of ESCC patients. Autophagic vesicles were investigated by transmission electron microscopy. Fluorescent LC3B puncta and mitochondrial nucleoid were observed by microscope and confocal microscopy. Mitochondrial function was evaluated by mitochondrial membrane potential, ROS and ATP measurement. Xenograft nude mice model was performed in BALB/c nude mice to confirm the role of Drp1 on ESCC progression. Results We found that Drp1 high expression is correlated with poor overall survival of ESCC patients. Drp1 overexpression promotes cell proliferation and xenograft ESCC tumor growth by triggering autophagy. Furthermore, we demonstrated that Drp1 overexpression disturbs mitochondrial function and subsequent induces mitochondrial DNA (mtDNA) released into the cytosol, which is recognized as cytosolic mtDNA stress. Mechanistically, cytosolic mtDNA stress activates the cGAS-STING pathway and facilitates autophagy, which promotes ESCC cancer growth. Moreover, mtDNA digestion with DNase I and autophagy inhibition with chloroquine attenuates the cGAS-STING pathway activation and ESCC cancer growth. Conclusions Our finding reveals that Drp1 overexpression induces mitochondrial dysfunction and cytosolic mitochondrial DNA stress, which subsequently activates the cGAS-STING pathway, triggers autophagy and promotes ESCC progression.