Chowdhury Arpita, Witte Steffen, Aich Abhishek
Department of Cellular Biochemistry, University Medical Center, Göttingen, Germany.
Cluster of Excellence "Multiscale Bioimaging, from Molecular Machines to Networks of Excitable Cells" (MBExC), University of Göttingen, Göttingen, Germany.
Front Cell Dev Biol. 2022 Feb 11;10:796066. doi: 10.3389/fcell.2022.796066. eCollection 2022.
Mitochondria, in symbiosis with the host cell, carry out a wide variety of functions from generating energy, regulating the metabolic processes, cell death to inflammation. The most prominent function of mitochondria relies on the oxidative phosphorylation (OXPHOS) system. OXPHOS heavily influences the mitochondrial-nuclear communication through a plethora of interconnected signaling pathways. Additionally, owing to the bacterial ancestry, mitochondria also harbor a large number of Damage Associated Molecular Patterns (DAMPs). These molecules relay the information about the state of the mitochondrial health and dysfunction to the innate immune system. Consequently, depending on the intracellular or extracellular nature of detection, different inflammatory pathways are elicited. One group of DAMPs, the mitochondrial nucleic acids, hijack the antiviral DNA or RNA sensing mechanisms such as the cGAS/STING and RIG-1/MAVS pathways. A pro-inflammatory response is invoked by these signals predominantly through type I interferon (T1-IFN) cytokines. This affects a wide range of organ systems which exhibit clinical presentations of auto-immune disorders. Interestingly, tumor cells too, have devised ingenious ways to use the mitochondrial DNA mediated cGAS-STING-IRF3 response to promote neoplastic transformations and develop tumor micro-environments. Thus, mitochondrial nucleic acid-sensing pathways are fundamental in understanding the source and nature of disease initiation and development. Apart from the pathological interest, recent studies also attempt to delineate the structural considerations for the release of nucleic acids across the mitochondrial membranes. Hence, this review presents a comprehensive overview of the different aspects of mitochondrial nucleic acid-sensing. It attempts to summarize the nature of the molecular patterns involved, their release and recognition in the cytoplasm and signaling. Finally, a major emphasis is given to elaborate the resulting patho-physiologies.
线粒体与宿主细胞共生，执行从产生能量、调节代谢过程、细胞死亡到炎症等各种各样的功能。线粒体最突出的功能依赖于氧化磷酸化（OXPHOS）系统。氧化磷酸化通过大量相互关联的信号通路严重影响线粒体与细胞核之间的通讯。此外，由于线粒体起源于细菌，它还含有大量的损伤相关分子模式（DAMPs）。这些分子将线粒体健康和功能障碍状态的信息传递给先天免疫系统。因此，根据检测的细胞内或细胞外性质，会引发不同的炎症途径。一类DAMPs，即线粒体核酸，劫持抗病毒DNA或RNA传感机制，如cGAS/STING和RIG-1/MAVS途径。这些信号主要通过I型干扰素（T1-IFN）细胞因子引发促炎反应。这会影响广泛的器官系统，这些系统表现出自身免疫性疾病的临床表现。有趣的是，肿瘤细胞也设计出巧妙的方法来利用线粒体DNA介导的cGAS-STING-IRF3反应来促进肿瘤转化和发展肿瘤微环境。因此，线粒体核酸传感途径对于理解疾病发生和发展的根源及性质至关重要。除了病理方面的兴趣外，最近的研究还试图阐明核酸跨线粒体外膜释放的结构因素。因此，本综述全面概述了线粒体核酸传感的不同方面。它试图总结所涉及分子模式的性质、它们在细胞质中的释放和识别以及信号传导。最后，重点阐述了由此产生的病理生理学。
