Mitochondrial DNA as an inflammatory mediator in cardiovascular diseases.
Mitochondrial DNA as an inflammatory mediator in cardiovascular diseases.
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DOI：
10.1042/bcj20170714
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发表时间：
2018-03-06
期刊：
影响因子：
--
通讯作者：
Otsu K
中科院分区：
文献类型：
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作者：
Nakayama H;Otsu K
线粒体在多种细胞功能中发挥核心作用，包括能量产生、钙稳态和细胞死亡。目前，越来越多的证据表明，线粒体在触发和维持炎症中的重要作用。无微生物感染的慢性炎症-称为无菌炎症-与心力衰竭的发展密切相关。无菌炎症是由模式识别受体（PRRs）的激活触发的，该受体感知内源性配体，称为损伤相关分子模式（DAMPs）。线粒体释放多种DAMPs，包括线粒体DNA、肽和脂质，通过刺激多种PRRs诱导炎症。在线粒体DAMPs中，线粒体DNA （mtDNA）目前被认为是介导多种PRRs激活的DAMP，包括toll样受体9、nod样受体和干扰素基因通路的环GMP-AMP合成酶/刺激物。这些PRR信号通路反过来导致核因子-κB和干扰素调节因子的激活，从而增强炎症细胞因子和干扰素的转录活性，诱导炎症细胞的募集。由于心脏是一个由大量线粒体组成的器官，用于消耗ATP（需要维持持续的循环收缩和舒张），因此预计会发生大量线粒体自由基氧和线粒体DAMPs的产生，并促进心脏炎症。本文将重点介绍mtDNA在心脏炎症中的作用，并对mtDNA在心脏疾病中诱导炎症反应的机制和病理意义进行综述。
Mitochondria play a central role in multiple cellular functions, including energy production, calcium homeostasis, and cell death. Currently, growing evidence indicates the vital roles of mitochondria in triggering and maintaining inflammation. Chronic inflammation without microbial infection — termed sterile inflammation — is strongly involved in the development of heart failure. Sterile inflammation is triggered by the activation of pattern recognition receptors (PRRs) that sense endogenous ligands called damage-associated molecular patterns (DAMPs). Mitochondria release multiple DAMPs including mitochondrial DNA, peptides, and lipids, which induce inflammation via the stimulation of multiple PRRs. Among the mitochondrial DAMPs, mitochondrial DNA (mtDNA) is currently highlighted as the DAMP that mediates the activation of multiple PRRs, including Toll-like receptor 9, Nod-like receptors, and cyclic GMP–AMP synthetase/stimulator of interferon gene pathways. These PRR signalling pathways, in turn, lead to the activation of nuclear factor-κB and interferon regulatory factor, which enhances the transcriptional activity of inflammatory cytokines and interferons, and induces the recruitment of inflammatory cells. As the heart is an organ comprising abundant mitochondria for its ATP consumption (needed to maintain constant cyclic contraction and relaxation), the generation of massive amounts of mitochondrial radical oxygen species and mitochondrial DAMPs are predicted to occur and promote cardiac inflammation. Here, we will focus on the role of mtDNA in cardiac inflammation and review the mechanism and pathological significance of mtDNA-induced inflammatory responses in cardiac diseases.