Cigarette smoke induces mitochondrial DNA damage and activates cGAS-STING pathway: application to a biomarker for atherosclerosis

• DOI: 10.1042/cs20220525
• Publication Date: 2023-01-04T16:30:58Z
• Authors: Keitaro Ueda; Chiemi Sakai; Takafumi Ishida; Kosuke Morita; Yusuke Kobayashi; Yasunori Horikoshi; Akiko Baba; Yuma Okazaki; Masao Yoshizumi; Satoshi Tashiro; Mari Ishida
• Keywords: 0303 health sciences; Endothelial Cells; Atherosclerosis; DNA, Mitochondrial; Nucleotidyltransferases; Cigarette Smoking; Mitochondria; 3. Good health; 03 medical and health sciences; Cardiovascular System & Vascular Biology; Humans; Cell-Free Nucleic Acids; DNA Damage

Abstract Cigarette smoking is a major risk factor for atherosclerosis. We previously reported that DNA damage was accumulated in atherosclerotic plaque, and increased human mononuclear cells by smoking. As vascular endothelial are known to modulate inflammation, we investigated the mechanism which activates innate immunity focusing on damage. Furthermore, sought characterize plasma level of cell-free (cfDNA), result mitochondrial and/or genomic damage, as biomarker smoke extract (CSE) nucleus mitochondria cells. Mitochondrial induced minority outer membrane permeabilization, insufficient cell death but instead led nuclear fragments, derived from mitochondria, were cytosol, caused persistent increase IL-6 mRNA expression via cyclic GMP-AMP synthase (cGAS)-stimulator interferon genes (STING) pathway. cfDNA, quantified with quantitative PCR culture medium CSE. Consistent vitro results, cfDNA (mt-cfDNA) (n-cfDNA) young healthy smokers compared age-matched nonsmokers. Additionally, both mt-cfDNA n-cfDNA significantly patients atherosclerosis normal controls. Our multivariate analysis revealed only predicted In conclusion, cytosolic cigarette resultant activation cGAS-STING pathway may be development. The mt-cfDNA, possibly useful