Wu Yinghao, Wu Shengting, Chen Zhiheng, Yang Erzhu, Yu Haiyue, Zhang Guowang, Lian XiaoFeng, Xu JianGuang
Department of Orthopedic Surgery, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, PR China.
Bengbu Medical University, Anhui, 233030, PR China.
Heliyon. 2024 Sep 3;10(17):e37378. doi: 10.1016/j.heliyon.2024.e37378. eCollection 2024 Sep 15.
BACKGROUND: Mitophagy selectively eliminates potentially cytotoxic and damaged mitochondria and effectively prevents excessive cytotoxicity from damaged mitochondria, thereby attenuating inflammatory and oxidative responses. However, the potential role of mitophagy in intervertebral disc degeneration remains to be elucidated. METHODS: The GSVA method, two machine learning methods (SVM-RFE algorithm and random forest), the CIBERSORT and MCPcounter methods, as well as the consensus clustering method and the WGCNA algorithm were used to analyze the involvement of mitophagy in intervertebral disc degeneration, the diagnostic value of mitophagy-associated genes in intervertebral disc degeneration, and the infiltration of immune cells, and identify the gene modules that were closely related to mitophagy. Single-cell analysis was used to detect mitophagy scores and TOMM22 expression, and pseudo-temporal analysis was used to explore the function of TOMM22 in nucleus pulposus cells. In addition, TOMM22 expression was compared between human normal and degenerated intervertebral disc tissue samples by immunohistochemistry and PCR. RESULTS: This study identified that the mitophagy pathway score was elevated in intervertebral disc degeneration compared with the normal condition. A strong link was present between mitophagy genes and immune cells, which may be used to typify intervertebral disc degeneration. The single-cell level showed that mitophagy-associated gene TOMM22 was highly expressed in medullary cells of the disease group. Further investigations indicated the upregulation of TOMM22 expression in late-stage nucleus pulposus cells and its role in cellular communication. In addition, human intervertebral disc tissue samples established that TOMM22 levels were higher in disc degeneration samples than in normal samples. CONCLUSIONS: Our findings revealed that mitophagy may be used in the diagnosis of intervertebral disc degeneration and its typing, and TOMM22 is a molecule in this regard and may act as a potential diagnostic marker in intervertebral disc degeneration.
背景：线粒体自噬可选择性清除具有潜在细胞毒性和受损的线粒体，并有效防止受损线粒体产生过度的细胞毒性，从而减轻炎症和氧化反应。然而，线粒体自噬在椎间盘退变中的潜在作用仍有待阐明。 方法：采用基因集变异分析（GSVA）方法、两种机器学习方法（支持向量机-递归特征消除算法和随机森林）、CIBERSORT和MCPcounter方法，以及共识聚类方法和加权基因共表达网络分析（WGCNA）算法，分析线粒体自噬在椎间盘退变中的参与情况、线粒体自噬相关基因在椎间盘退变中的诊断价值以及免疫细胞浸润情况，并识别与线粒体自噬密切相关的基因模块。采用单细胞分析检测线粒体自噬评分和TOMM22表达，并采用伪时间分析探讨TOMM22在髓核细胞中的功能。此外，通过免疫组织化学和聚合酶链反应比较人正常和退变椎间盘组织样本中TOMM22的表达。 结果：本研究发现，与正常情况相比，椎间盘退变中线粒体自噬途径评分升高。线粒体自噬基因与免疫细胞之间存在密切联系，这可用于对椎间盘退变进行分型。单细胞水平显示，疾病组的髓核细胞中线粒体自噬相关基因TOMM22高表达。进一步研究表明，晚期髓核细胞中TOMM22表达上调及其在细胞通讯中的作用。此外，人椎间盘组织样本证实，退变椎间盘样本中TOMM22水平高于正常样本。 结论：我们的研究结果表明，线粒体自噬可用于椎间盘退变的诊断及其分型，TOMM22在这方面是一个分子，可能作为椎间盘退变的潜在诊断标志物。
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