Increased Drp1 promotes autophagy and ESCC progression by mtDNA stress mediated cGAS-STING pathway

Yujia Li,Dengke Bao,Hushan Yang,Yuanyuan Wu,Qi Yang,Menglan Niu,Shaogui Wan,Jing Zhao,Jiaxin Wang,Yating Yang,Hongliang Liu,Junqi Liu,Lixin Wan,Hui Chen,Yanming Wang

doi:10.1186/s13046-022-02262-z

Abstract

BackgroundMitochondrial 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 mechanism underling Drp1 to influence tumor progression is largely unknown, especially in esophageal squamous cell carcinoma (ESCC).MethodsImmunohistochemistry 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 fluorescent and confocal microscopy. Mitochondrial function was evaluated by mitochondrial membrane potential, ROS and ATP levels. Xenograft tumor model was performed in BALB/c nude mice to analyze the role of Drp1 on ESCC progression.ResultsWe 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 thereby inducing cytosolic mtDNA stress. Mechanistically, cytosolic mtDNA 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.ConclusionsOur finding reveals that Drp1 overexpression induces mitochondrial dysfunction and cytosolic mtDNA stress, which subsequently activates the cGAS-STING pathway, triggers autophagy and promotes ESCC progression.

Highlights

Mitochondrial dynamics homeostasis is important for cell metabolism, growth, proliferation, and immune responses
Li et al J Exp Clin Cancer Res (2022) 41:76 demonstrated that the critical GTPase for mitochondrial dynamics, The critical GTPase for mitochondrial dynamics (Drp1) is frequently upregulated in lung cancer and hepatocellular carcinoma (HCC), which is closely implicated in tumorigenesis [5, 6]
Drp1‐mediated mitochondrial fission promoted survival of esophageal squamous cell carcinoma (ESCC) cells in vitro and in vivo To investigate whether mitochondrial regulators Drp1 is involved in ESCC progression, we analyzed Drp1 expression in a cohort of 61 ESCC patients

Summary

Introduction

Mitochondrial dynamics homeostasis is important for cell metabolism, growth, proliferation, and immune responses. The critical GTPase for mitochondrial fission, Drp is frequently upregulated in many cancers and is closely implicated in tumorigenesis. Accumulating evidence suggests that mitochondrial mass and dynamics play a central and multi-functional role in tumor progression by modulating cell cycle, redox homeostasis, metabolism and immune signals [3, 4]. Li et al J Exp Clin Cancer Res (2022) 41:76 demonstrated that the critical GTPase for mitochondrial dynamics, Drp is frequently upregulated in lung cancer and hepatocellular carcinoma (HCC), which is closely implicated in tumorigenesis [5, 6]. We previously found that increased mitochondrial fission through upregulated Drp significantly induced cytosolic mtDNA stress and subsequent CCL2 secretion in HCC cells, leading to infiltration of tumor-associated macrophages into HCC tissues and tumor progression [12]. Whether mtDNA stress is involved in esophageal squamous cell carcinoma (ESCC) progression remains poorly understood

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Discussion

Conclusion