TFAM downregulation promotes autophagy and ESCC survival through mtDNA stress-mediated STING pathway

Area of Science:

• Cellular Biology
• Cancer Research
• Immunology

Background:

• Mitochondrial biogenesis is crucial for cellular homeostasis, immune regulation, and tumor prevention.
• Dysregulation of mitochondrial function is implicated in various diseases, including cancer.

Purpose of the Study:

• To investigate the role of mitochondrial biogenesis disruption, specifically TFAM reduction, in esophageal squamous cell carcinoma (ESCC) development.
• To elucidate the molecular mechanisms linking mitochondrial dysfunction to ESCC growth.

Main Methods:

• TFAM reduction in cellular models.
• Analysis of mitochondrial DNA (mtDNA) release and cytosolic mtDNA stress.
• Assessment of the cGAS-STING signaling pathway activation.
• Evaluation of autophagy induction and its impact on ESCC growth.
• Genetic depletion of STING and enzymatic degradation of mtDNA.
• Inhibition of autophagy.

Main Results:

• TFAM reduction impairs mitochondrial function and promotes ESCC growth.
• TFAM depletion leads to cytosolic mtDNA release, inducing stress and activating the cGAS-STING pathway.
• Activation of cGAS-STING stimulates autophagy, further promoting ESCC growth.
• STING depletion or mtDNA degradation abrogates the stress response, reduces autophagy, and inhibits ESCC growth.
• Autophagy inhibition ameliorates mitochondrial dysfunction-induced cGAS-STING activation and ESCC growth.

Conclusions:

• Mitochondrial biogenesis perturbation induces mtDNA stress, activating the cGAS-STING pathway and autophagy.
• This pathway promotes esophageal squamous cell carcinoma (ESCC) growth.
• Targeting mtDNA stress, cGAS-STING, or autophagy presents a novel therapeutic strategy for ESCC.