Melatonin Alleviates Osteoarthritis by Regulating NADPH Oxidase 4–Induced Ferroptosis and Mitigating Mitochondrial Dysfunction

IF 8.3 1区 医学 Q1 ENDOCRINOLOGY & METABOLISM Journal of Pineal Research Pub Date : 2024-09-04 DOI:10.1111/jpi.12992
Qi Wang, Beijie Qi, Shi Shi, Weihao Jiang, Dejian Li, Xinhua Jiang, Chengqing Yi
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Abstract

Recent evidence indicates that the damaged regions in osteoarthritis are accompanied by the accumulation of iron ions. Ferroptosis, as an iron-dependent form of cell death, holds significant implications in osteoarthritis. Melatonin, a natural product with strong scavenging abilities against reactive oxygen species and lipid peroxidation, plays a crucial role in the treatment of osteoarthritis. This study aims to demonstrate the existence of ferroptosis in osteoarthritis and explore the specific mechanism of melatonin in suppressing ferroptosis and alleviating osteoarthritis. Our findings reveal that melatonin reverses inflammation-induced oxidative stress and lipid peroxidation while promoting the expression of extracellular matrix components in chondrocytes, safeguarding the cells. Our research has revealed that NADPH oxidase 4 (NOX4) serves as a crucial molecule in the ferroptosis process of osteoarthritis. Specifically, NOX4 is located on mitochondria in chondrocytes, which can induce disorders in mitochondrial energy metabolism and dysfunction, thereby intensifying oxidative stress and lipid peroxidation. LC-MS analysis further uncovered that GRP78 is a downstream binding protein of NOX4. NOX4 induces ferroptosis by weakening GRP78's protective effect on GPX4 and reducing its expression. Melatonin can inhibit the upregulation of NOX4 on mitochondria and mitigate mitochondrial dysfunction, effectively suppressing ferroptosis and alleviating osteoarthritis. This suggests that melatonin therapy represents a promising new approach for the treatment of osteoarthritis.

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褪黑激素通过调节 NADPH 氧化酶 4 诱导的铁氧化作用和减轻线粒体功能障碍缓解骨关节炎。
最近的证据表明,骨关节炎的受损区域伴随着铁离子的积累。铁变态反应是一种依赖于铁的细胞死亡形式,在骨关节炎中具有重要意义。褪黑素是一种天然产物,具有很强的清除活性氧和脂质过氧化的能力,在骨关节炎的治疗中起着至关重要的作用。本研究旨在证明骨关节炎中存在铁变态反应,并探索褪黑素抑制铁变态反应、缓解骨关节炎的具体机制。我们的研究结果表明,褪黑素能逆转炎症诱导的氧化应激和脂质过氧化反应,同时促进软骨细胞细胞外基质成分的表达,保护细胞。我们的研究发现,NADPH 氧化酶 4(NOX4)是骨关节炎铁氧化过程中的一个关键分子。具体来说,NOX4 位于软骨细胞的线粒体上,可诱导线粒体能量代谢紊乱和功能障碍,从而加剧氧化应激和脂质过氧化。LC-MS分析进一步发现,GRP78是NOX4的下游结合蛋白。NOX4 通过削弱 GRP78 对 GPX4 的保护作用并减少其表达,从而诱导铁变态反应。褪黑素可抑制线粒体上NOX4的上调,缓解线粒体功能障碍,有效抑制铁变态反应,缓解骨关节炎。这表明,褪黑素疗法是治疗骨关节炎的一种很有前景的新方法。
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来源期刊
Journal of Pineal Research
Journal of Pineal Research 医学-内分泌学与代谢
CiteScore
17.70
自引率
4.90%
发文量
66
审稿时长
1 months
期刊介绍: The Journal of Pineal Research welcomes original scientific research on the pineal gland and melatonin in vertebrates, as well as the biological functions of melatonin in non-vertebrates, plants, and microorganisms. Criteria for publication include scientific importance, novelty, timeliness, and clarity of presentation. The journal considers experimental data that challenge current thinking and welcomes case reports contributing to understanding the pineal gland and melatonin research. Its aim is to serve researchers in all disciplines related to the pineal gland and melatonin.
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