SP1/CTR1 介导的氧化应激诱导椎间盘退变中的杯突症

IF 5 3区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
BioFactors Pub Date : 2024-04-10 DOI:10.1002/biof.2052
Xuanzuo Chen, Kanglu Li, Yan Xiao, Wei Wu, Hui Lin, Xiangcheng Qing, Shuo Tian, Sheng Liu, Shiqing Feng, Baichuan Wang, Zengwu Shao, Yizhong Peng
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引用次数: 0

摘要

椎间盘退行性变(IDD)是一种与年龄有关的疾病,也是腰痛的罪魁祸首。氧化应激诱导的细胞死亡在椎间盘退行性变的发病机制中扮演着重要角色。铜中毒是最近发现的一种程序性细胞死亡形式,依赖于铜的可用性。铜氧化酶是否参与了IDD的进展仍是未知数。在此,我们建立了体外和体内模型来研究 IDD 中的杯突症以及氧化应激与髓核细胞(NPCs)中铜敏感性相互作用的机制。我们发现,大鼠和人类退化的椎间盘中铁氧还蛋白-1(FDX1)的含量都有所增加。在生理浓度的 Cu2+ 存在下,NPCs 的亚致死氧化应激导致 FDX1 表达增加、三羧酸(TCA)循环相关蛋白脂酰化和聚集以及细胞死亡,而 FDX1 基因敲除可抑制细胞死亡。由于铜稳态参与了铜诱导的细胞毒性,我们研究了铜转运相关蛋白的作用,包括输入蛋白(CTR1)和外流泵(ATPase 转运体、ATP7A 和 ATP7B)。在氧化应激下,CTR1 和 ATP7A 的含量增加,阻断 CTR1 可减少氧化应激/铜诱导的 TCA 相关蛋白聚集和细胞死亡。此外,氧化应激促进了特异性蛋白 1(SP1)的表达和 SP1 介导的 CTR1 转录。抑制 SP1 可降低细胞死亡率,保持椎间盘水合状态,减轻组织变性。这表明氧化应激通过促进 SP1 介导的 CTR1 转录上调 FDX1 的表达和铜通量,从而导致 TCA 循环相关蛋白聚集和杯突症的增加。这项研究强调了杯突症在IDD进展过程中的重要性,并为IDD治疗提供了一个很有前景的治疗靶点。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

SP1/CTR1-mediated oxidative stress-induced cuproptosis in intervertebral disc degeneration

SP1/CTR1-mediated oxidative stress-induced cuproptosis in intervertebral disc degeneration

SP1/CTR1-mediated oxidative stress-induced cuproptosis in intervertebral disc degeneration

Intervertebral disc degeneration (IDD) is an age-related disease and is responsible for low back pain. Oxidative stress-induced cell death plays a fundamental role in IDD pathogenesis. Cuproptosis is a recently discovered form of programmed cell death dependent on copper availability. Whether cuproptosis is involved in IDD progression remains unknown. Herein, we established in vitro and in vivo models to investigate cuproptosis in IDD and the mechanisms by which oxidative stress interacts with copper sensitivity in nucleus pulposus cells (NPCs). We found that ferredoxin-1 (FDX1) content increased in both rat and human degenerated discs. Sublethal oxidative stress on NPCs led to increased FDX1 expression, tricarboxylic acid (TCA) cycle-related proteins lipoylation and aggregation, and cell death in the presence of Cu2+ at physiological concentrations, while FDX1 knockdown inhibited cell death. Since copper homeostasis is involved in copper-induced cytotoxicity, we investigated the role of copper transport-related proteins, including importer (CTR1) and efflux pumps (ATPase transporter, ATP7A, and ATP7B). CTR1 and ATP7A content increased under oxidative stress, and blocking CTR1 reduced oxidative stress/copper-induced TCA-related protein aggregation and cell death. Moreover, oxidative stress promoted the expression of specific protein 1 (SP1) and SP1-mediated CTR1 transcription. SP1 inhibition decreased cell death rates, preserved disc hydration, and alleviated tissue degeneration. This suggests that oxidative stress upregulates FDX1 expression and copper flux through promoting SP1-mediated CTR1 transcription, leading to increased TCA cycle-related protein aggregation and cuproptosis. This study highlights the importance of cuproptosis in IDD progression and provides a promising therapeutic target for IDD treatment.

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来源期刊
BioFactors
BioFactors 生物-内分泌学与代谢
CiteScore
11.50
自引率
3.30%
发文量
96
审稿时长
6-12 weeks
期刊介绍: BioFactors, a journal of the International Union of Biochemistry and Molecular Biology, is devoted to the rapid publication of highly significant original research articles and reviews in experimental biology in health and disease. The word “biofactors” refers to the many compounds that regulate biological functions. Biological factors comprise many molecules produced or modified by living organisms, and present in many essential systems like the blood, the nervous or immunological systems. A non-exhaustive list of biological factors includes neurotransmitters, cytokines, chemokines, hormones, coagulation factors, transcription factors, signaling molecules, receptor ligands and many more. In the group of biofactors we can accommodate several classical molecules not synthetized in the body such as vitamins, micronutrients or essential trace elements. In keeping with this unified view of biochemistry, BioFactors publishes research dealing with the identification of new substances and the elucidation of their functions at the biophysical, biochemical, cellular and human level as well as studies revealing novel functions of already known biofactors. The journal encourages the submission of studies that use biochemistry, biophysics, cell and molecular biology and/or cell signaling approaches.
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