Succinate dehydrogenase mediated ROS production contributes to ASIC1a-induced chondrocyte pyroptosis in rheumatoid arthritis

IF 4.2 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular basis of disease Pub Date : 2024-11-23 DOI:10.1016/j.bbadis.2024.167585

Wenqiang Liu , Yayun Xu , Weirong Hu , Longbiao Zhang , Cheng Wang , Fengshuo Wang , Zhuoyan Zai , Xuewen Qian , Xiaoqing Peng , Feihu Chen

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Abstract

Our previous study showed that acidic stimuli activate acid-sensitive ion channel 1a (ASIC1a), resulting in chondrocyte destruction associated with rheumatoid arthritis (RA). However, the exact underlying processes remain unclear. Recent evidence suggests that the production of reactive oxygen species (ROS) mediated by succinate dehydrogenase (SDH), contributes to chondrocyte damage. The objective of this study was to investigate the involvement of SDH in ASIC1a-induced chondrocyte destruction in RA and to explore the associated mechanisms both in vivo and in vitro. Our findings revealed that the cartilage of mice with collagen-induced arthritis (CIA) and acid-treated chondrocytes exhibited a substantial increase in SDH expression. Furthermore, SDH inhibition attenuates acidosis-induced pyroptosis in chondrocytes. Notably, ASIC1a activation through acid stimuli increases SDH activity and pyroptosis through the Ca²⁺/CaMKK2/AMPK pathway in chondrocytes. Mechanistically, SDH assembly factor 2 (SDHAF2) was identified as a key modulator of SDH activity induced by ASIC1a in acid-stressed chondrocytes. Moreover, the expression of SDH in CIA mouse chondrocytes decreased and the histological characteristics of ankle joint damage were reduced by the ASIC1a-particular blocker PcTx-1. Overall, these observations suggest that ASIC1a activation under acidic conditions increases SDH activity and modulates SDHAF2, thereby promoting chondrocyte pyroptosis through the Ca²⁺/CaMKK2/AMPK pathway.

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琥珀酸脱氢酶介导的 ROS 生成有助于 ASIC1a 在类风湿性关节炎中诱导软骨细胞热解。

我们之前的研究表明，酸性刺激会激活酸敏感离子通道 1a（ASIC1a），导致与类风湿性关节炎（RA）相关的软骨细胞破坏。然而，确切的基本过程仍不清楚。最近的证据表明，由琥珀酸脱氢酶（SDH）介导的活性氧（ROS）的产生导致了软骨细胞的损伤。本研究的目的是调查SDH在ASIC1a诱导的RA软骨细胞破坏中的参与情况，并探讨体内和体外的相关机制。我们的研究结果表明，胶原诱导的关节炎（CIA）小鼠的软骨和酸处理的软骨细胞显示出 SDH 表达的大幅增加。此外，SDH抑制可减轻酸中毒诱导的软骨细胞热休克。值得注意的是，通过酸刺激激活 ASIC1a 可提高软骨细胞中 SDH 的活性，并通过 Ca2+/CaMKK2/AMPK 途径增加软骨细胞中的热休克。从机理上讲，SDH组装因子2（SDHAF2）被确定为酸应激软骨细胞中由ASIC1a诱导的SDH活性的关键调节因子。此外，在 ASIC1a 特定阻断剂 PcTx-1 的作用下，CIA 小鼠软骨细胞中 SDH 的表达减少，踝关节损伤的组织学特征减轻。总之，这些观察结果表明，ASIC1a 在酸性条件下被激活会增加 SDH 的活性并调节 SDHAF2，从而通过 Ca2+/CaMKK2/AMPK 途径促进软骨细胞的热凋亡。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Biochimica et biophysica acta. Molecular basis of disease 生物-生化与分子生物学

CiteScore

12.30

自引率

0.00%

发文量

218

审稿时长

32 days

期刊介绍： BBA Molecular Basis of Disease addresses the biochemistry and molecular genetics of disease processes and models of human disease. This journal covers aspects of aging, cancer, metabolic-, neurological-, and immunological-based disease. Manuscripts focused on using animal models to elucidate biochemical and mechanistic insight in each of these conditions, are particularly encouraged. Manuscripts should emphasize the underlying mechanisms of disease pathways and provide novel contributions to the understanding and/or treatment of these disorders. Highly descriptive and method development submissions may be declined without full review. The submission of uninvited reviews to BBA - Molecular Basis of Disease is strongly discouraged, and any such uninvited review should be accompanied by a coverletter outlining the compelling reasons why the review should be considered.