Adenosine A2A receptor (A2AR) stimulation enhances mitochondrial metabolism and mitigates reactive oxygen species-mediated mitochondrial injury
Adenosine A2A receptor (A2AR) stimulation enhances mitochondrial metabolism and mitigates reactive oxygen species-mediated mitochondrial injury
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DOI：
10.1096/fj.201902459r
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发表时间：
2020-02-13
期刊：
影响因子：
4.8
通讯作者：
Cronstein, Bruce N.
中科院分区：
文献类型：
--
作者：
Castro, Cristina M.;Corciulo, Carmen;Cronstein, Bruce N.
在骨性关节炎软骨细胞中，线粒体产生的三磷酸腺苷和细胞外的腺苷减少，导致腺苷A2A型受体(A2AR)刺激减弱，软骨细胞动态平衡改变，参与了骨性关节炎的发病。我们验证了A2AR刺激维持或增强软骨细胞线粒体功能的假设。通过对原代小鼠软骨细胞、人软骨细胞系(T/C-28a2)、原代人软骨细胞和小鼠骨性关节炎模型的透射电子显微镜分析、线粒体应力测试、线粒体内膜极性共聚焦成像和免疫组织化学方法，研究了A2AR信号对线粒体健康和功能的影响。与来自WT动物的软骨细胞相比，来自A2AR(-/-)缺失小鼠的原代小鼠软骨细胞在16周后发展为自发性骨性关节炎，存在线粒体肿胀、功能障碍和线粒体内容减少，并增加了活性氧物种(ROS)的负担，减少了吞噬作用。用A2AR激动剂处理IL-1刺激的T/C-28a2细胞，降低了ROS负担，增加了线粒体的动态稳定性和功能，这一发现在原代人类软骨细胞中得到了概括。在肥胖诱导的骨性关节炎小鼠模型中，线粒体氧化物质显著增加，在关节内注射脂质体A2AR激动剂后显著改善。这些结果与A2AR结扎在骨性关节炎中具有丝裂保护作用的假说一致。
In OA chondrocytes, there is diminished mitochondrial production of ATP and diminished extracellular adenosine resulting in diminished adenosine A2A receptor (A2AR) stimulation and altered chondrocyte homeostasis which contributes to the pathogenesis of OA. We tested the hypothesis that A2AR stimulation maintains or enhances mitochondrial function in chondrocytes. The effect of A2AR signaling on mitochondrial health and function was determined in primary murine chondrocytes, a human chondrocytic cell line (T/C-28a2), primary human chondrocytes, and a murine model of OA by transmission electron microscopy analysis, mitochondrial stress testing, confocal live imaging for mitochondrial inner membrane polarity, and immunohistochemistry. In primary murine chondrocytes from A2AR(-/-) null mice, which develop spontaneous OA by 16 weeks, there is mitochondrial swelling, dysfunction, and reduced mitochondrial content with increased reactive oxygen species (ROS) burden and diminished mitophagy, as compared to chondrocytes from WT animals. IL-1-stimulated T/C-28a2 cells treated with an A2AR agonist had reduced ROS burden with increased mitochondrial dynamic stability and function, findings which were recapitulated in primary human chondrocytes. In an obesity-induced OA mouse model, there was a marked increase in mitochondrial oxidized material which was markedly improved after intraarticular injections of liposomal A2AR agonist. These results are consistent with the hypothesis that A2AR ligation is mitoprotective in OA.