1. Academic Validation
  2. Mitochondrial DNA release mediated by TFAM deficiency promotes copper-induced mitochondrial innate immune response via cGAS-STING signalling in chicken hepatocytes

Mitochondrial DNA release mediated by TFAM deficiency promotes copper-induced mitochondrial innate immune response via cGAS-STING signalling in chicken hepatocytes

  • Sci Total Environ. 2023 Sep 22;167315. doi: 10.1016/j.scitotenv.2023.167315.
Quanwei Li 1 Shaofeng Wang 1 Pan Guo 1 Yuanhong Feng 1 Wenlan Yu 1 Hui Zhang 1 Jianying Guo 1 Ying Li 1 Lianmei Hu 1 Jiaqiang Pan 1 Jianzhao Liao 1 Zhaoxin Tang 2
Affiliations

Affiliations

  • 1 College of Veterinary Medicine, South China Agricultural University, Guangzhou 510642, Guangdong, PR China.
  • 2 College of Veterinary Medicine, South China Agricultural University, Guangzhou 510642, Guangdong, PR China. Electronic address: tangzx@scau.edu.cn.
Abstract

Copper (Cu) is pollution metal that is a global concern due to its toxic effects. A recent study found that the release of mitochondrial DNA (mtDNA) into the cytoplasm can activate the innate immune response, but the exact mechanisms underlying the effect of Cu exposure remains unknown. In this study, we identified that the reduction in transcription Factor A (TFAM) led to mtDNA leakage into the cytoplasm under Cu exposure in hepatocytes, accompanied by the activation of the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway-mediated innate immunity (increased expression of cGAS, STING, TANK-binding kinase-1 (TBK1), and interferon regulatory factor-3 (IRF3)) genes and proteins, and enhanced phosphorylation levels of TBK1 and IRF3). Subsequently, silencing TFAM (siTFAM) significantly aggravated mtDNA release and the innate immune response under Cu treatment. Mitochondrial DNA depletion alleviated Cu-induced innate immunity in hepatocytes, while mtDNA transfection further enhanced the innate immune response. Notably, the inhibition of STING effectively alleviated the phosphorylation levels of the TBK1 and IRF3 proteins induced by Cu, while the upregulation of STING aggravated the Cu-induced innate immunity. Furthermore, EtBr and H-151(a STING Inhibitor) treatment dramatically reversed the effect of TFAM depletion on the sharpened innate immune response induced by Cu via the cGAS-STING pathway. In general, these findings demonstrated the TFAM deficiency promotes innate immunity by activating the mtDNA-cGAS-STING signalling pathway under Cu exposure in hepatocytes, providing new insight into Cu toxicology.

Keywords

Copper; Innate immune response; Mitochondrial DNA; TFAM; cGAS-STING pathway.

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