Li Yong-Xing, Cui Shu-Fang, Meng Wei, Hu Hai-Yang, Wang Chen
State Key Laboratory of Natural Medicines, School of Life Science and Technology, China Pharmaceutical University, Nanjing 210009, China.
Sichuan Da Xue Xue Bao Yi Xue Ban. 2021 May;52(3):387-395. doi: 10.12182/20210560501.
Mitochondria are important organelles that present extensively in cells, serving diverse functions. In addition to controlling cell energy production and metabolism, mitochondria are also involved in various biological processes, including anti-infection, apoptosis, and autophagy. Harmful stimuli from external environment or those generated by the cells themselves can damage mitochondria and cause mitochondrial stress response, during which the mitochondrial matrix containing mitochondrial DNA (mtDNA) can leak into the cytoplasm. Cytoplasmic mtDNA, acting as a damage-associated molecular pattern (DAMP), can activate a panel of DNA sensors and elicit innate immune response in organisms. Cyclic GMP-AMP synthase (cGAS), a key intracellular DNA sensor, can catalyze the conversion of GTP and ATP to cyclic GMP-AMP (2'3'-cGAMP), which serves as second messenger to bind and activate stimulator of interferon gene (STING), an endoplasmic adaptor protein. Beyond its critical roles in anti-microbial immunity, cGAS-STING pathway also serves important functions in many pathological and physiological processes such as autoimmunity, tumor and senescence. In this review, we focus on how the mtDNA released during mitochonrial stress response activates the cGAS-STING innate immune signaling pathway and the associated diseases, in order to help promote basic research about the role of mitochondria in innate immunity and provide new strategies for developing mitochondria-targeting drugs.
线粒体是广泛存在于细胞中的重要细胞器，具有多种功能。除了控制细胞能量产生和代谢外，线粒体还参与各种生物学过程，包括抗感染、细胞凋亡和自噬。来自外部环境的有害刺激或细胞自身产生的刺激会损伤线粒体并引发线粒体应激反应，在此过程中，包含线粒体DNA（mtDNA）的线粒体基质会泄漏到细胞质中。细胞质中的mtDNA作为一种损伤相关分子模式（DAMP），可以激活一系列DNA传感器并引发机体的固有免疫反应。环状GMP-AMP合酶（cGAS）是一种关键的细胞内DNA传感器，它可以催化GTP和ATP转化为环状GMP-AMP（2'3'-cGAMP），后者作为第二信使结合并激活内质网接头蛋白干扰素基因刺激物（STING）。除了在抗微生物免疫中的关键作用外，cGAS-STING通路在许多病理和生理过程中也发挥着重要作用，如自身免疫、肿瘤和衰老。在这篇综述中，我们重点关注线粒体应激反应过程中释放的mtDNA如何激活cGAS-STING固有免疫信号通路以及相关疾病，以促进关于线粒体在固有免疫中作用的基础研究，并为开发靶向线粒体的药物提供新策略。
