Mitochonic Acid-5 Inhibits Reactive Oxygen Species Production and Improves Human Chondrocyte Survival by Upregulating SIRT3-Mediated, Parkin-dependent Mitophagy.
Mitochonic Acid-5 Inhibits Reactive Oxygen Species Production and Improves Human Chondrocyte Survival by Upregulating SIRT3-Mediated, Parkin-dependent Mitophagy.
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Mitochonic Acid-5 通过上调 SIRT3 介导的 Parkin 依赖性线粒体自噬抑制活性氧产生并提高人类软骨细胞存活率
DOI：
10.3389/fphar.2022.911716
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发表时间：
2022
影响因子：
5.6
通讯作者：
Kang, Yan
中科院分区：
文献类型：
--
作者：
Xin, Ruobing;Xu, Yiyang;Long, Dianbo;Mao, Guping;Liao, Hongyi;Zhang, Ziji;Kang, Yan
线粒体功能障碍与骨关节炎（OA）的发病机制有关；然而，目前还没有有效的药物来治疗OA以维持线粒体稳态。研究表明，线粒体酸-5 (MA-5) 对线粒体损伤具有保护作用，并在线粒体自噬中发挥作用。然而，尚不清楚 MA-5 是否对炎症性关节软骨具有有益作用。在这里，人类骨关节炎软骨是从接受全关节置换术的患者身上获得的。白细胞介素-1β (IL-1β) 用于刺激软骨细胞并诱导炎症损伤。使用 Cell Counting Kit-8、TUNEL 和流式细胞术评估细胞凋亡。使用定量逆转录聚合酶链反应检查基因表达。使用免疫印迹、线粒体膜电位测定、JC-1染色和免疫荧光分析评估线粒体功能。使用免疫印迹和免疫荧光检测线粒体自噬。 3-(1H-1,2,3-三唑-4-基)吡啶 (3-TYP) 是 Sirtuin 3 (SIRT3) 的特异性抑制剂，用于阻断 SIRT3/Parkin 通路。通过免疫组织化学评估软骨切片中的线粒体自噬。 IL-1β被发现通过抑制SIRT3表达和线粒体自噬来诱导软骨细胞凋亡。此外，炎症损伤降低了线粒体膜电位，促进细胞内活性氧（ROS）的产生，导致线粒体分裂增加、线粒体融合抑制以及随之而来的线粒体损伤。相比之下，MA-5 治疗通过上调线粒体自噬、维持线粒体膜电位和减少线粒体凋亡来抑制过多的 ROS 产生。用 3-TYP 化学阻断 SIRT3 后，Parkin 相关的线粒体自噬也受到抑制，用 MA-5 预处理软骨细胞可以阻止这种效应，从而表明 SIRT3 是 Parkin 的上游。总体而言，MA-5被发现可以增强SIRT3的活性，促进Parkin依赖性线粒体自噬，消除软骨细胞中去极化/受损的线粒体，并保护软骨细胞。总之，MA-5 通过上调 SIRT3/Parkin 相关自噬信号通路抑制 IL-1β 诱导的氧化应激并保护软骨细胞。
Mitochondrial dysfunction is related to the pathogenesis of osteoarthritis (OA); however, there are no effective drugs to treat OA for maintaining mitochondrial homeostasis. Studies have shown that mitochonic acid-5 (MA-5) has a protective effect against mitochondrial damage and plays a role in mitophagy. However, it is not clear whether MA-5 has a beneficial effect on inflammatory articular cartilage. Here, human OA cartilage was obtained from patients undergoing total joint replacement. Interleukin-1β (IL-1β) was used to stimulate chondrocytes and induce inflammatory injury. Cell Counting Kit-8, TUNEL, and flow cytometry assays were used to assess apoptosis. Gene expression was examined using quantitative reverse transcription-polymerase chain reaction. Mitochondrial function was evaluated using immunoblotting, mitochondrial membrane potential assay, JC-1 staining, and immunofluorescence analysis. Mitophagy was detected using immunoblotting and immunofluorescence. 3-(1H-1,2,3-triazol-4-yl) pyridine (3-TYP), a specific inhibitor of Sirtuin 3 (SIRT3), was used to block the SIRT3/Parkin pathway. Mitophagy in the cartilage sections was evaluated via immunohistochemistry. IL-1β was found to induce chondrocyte apoptosis by inhibiting SIRT3 expression and mitophagy. In addition, inflammatory damage reduced the mitochondrial membrane potential and promoted the production of intracellular reactive oxygen species (ROS), leading to increased mitochondrial division, mitochondrial fusion inhibition, and the consequent mitochondrial damage. In contrast, the MA-5 treatment inhibited excessive ROS production by upregulating mitophagy, maintaining the mitochondrial membrane potential, and reducing mitochondrial apoptosis. After chemically blocking SIRT3 with 3-TYP, Parkin-related mitophagy was also inhibited, an effect that was prevented by pretreatment of the chondrocytes with MA-5, thereby suggesting that SIRT3 is upstream of Parkin. Overall, MA-5 was found to enhance the activity of SIRT3, promote Parkin-dependent mitophagy, eliminate depolarized/damaged mitochondria in chondrocytes, and protect cartilage cells. In conclusion, MA-5 inhibits IL-1β-induced oxidative stress and protects chondrocytes by upregulating the SIRT3/Parkin-related autophagy signaling pathway.
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影响因子：
8.3
作者：
Lei Q;Tan J;Yi S;Wu N;Wang Y;Wu H
通讯作者：
Wu H
影响因子：
7
作者：
Ansari MY;Khan NM;Ahmad I;Haqqi TM
通讯作者：
Haqqi TM
SIRT3 线粒体脱乙酰酶在细胞生理学、癌症和神经退行性疾病中的功能。
影响因子：
7.8
作者：
Ansari A;Rahman MS;Saha SK;Saikot FK;Deep A;Kim KH
通讯作者：
Kim KH
Sirt3 通过调节线粒体 Ca2 和线粒体生物发生来保护皮质神经元免受氧化应激
影响因子：
5.6
作者：
Dai SH;Chen T;Wang YH;Zhu J;Luo P;Rao W;Yang YF;Fei Z;Jiang XF
通讯作者：
Jiang XF
影响因子：
4.4
作者：
Blanco, FJ;López-Armada, MJ;Maneiro, E
通讯作者：
Maneiro, E