Feng Chaoqun, Hu Ziang, Zhao Min, Leng Chuan, Li Guangye, Yang Fei, Fan Xiaohong
Department of Orthopedics, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China.
Department of Orthopedics, The TCM Hospital of Longquanyi District, Chengdu, China.
Front Pharmacol. 2025 Apr 1;16:1579507. doi: 10.3389/fphar.2025.1579507. eCollection 2025.
Intervertebral disc degeneration (IVDD) is a prevalent condition contributing to various spinal disorders, posing a significant global health burden. Mitophagy plays a crucial role in maintaining mitochondrial quantity and quality and is closely associated with the onset and progression of IVDD. Well-documented region-specific mitophagy mechanisms in IVDD are guiding the development of therapeutic strategies. In the nucleus pulposus (NP), impaired mitochondria lead to apoptosis, oxidative stress, senescence, extracellular matrix degradation and synthesis, excessive autophagy, inflammation, mitochondrial instability, and pyroptosis, with key regulatory targets including AMPK, PGC-1α, SIRT1, SIRT3, Progerin, p65, Mfn2, FOXO3, NDUFA4L2, SLC39A7, ITGα5/β1, Nrf2, and NLRP3 inflammasome. In the annulus fibrosus (AF), mitochondrial damage induces apoptosis and oxidative stress mediated by PGC-1α, while in the cartilage endplate (CEP), mitochondrial dysfunction similarly triggers apoptosis and oxidative stress. These mechanistic insights highlight therapeutic strategies such as activating Parkin-dependent and Ub-independent mitophagy pathways for NP, enhancing Parkin-dependent mitophagy for AF, and targeting Parkin-mediated mitophagy for CEP. These strategies include the use of natural ingredients, hormonal modulation, gene editing technologies, targeted compounds, and manipulation of related proteins. This review summarizes the mechanisms of mitophagy in different regions of the intervertebral disc and highlights therapeutic approaches using mitophagy modulators to ameliorate IVDD. It discusses the complex mechanisms of mitophagy and underscores its potential as a therapeutic target. The objective is to provide valuable insights and a scientific basis for the development of mitochondrial-targeted drugs for anti-IVDD.
椎间盘退变（IVDD）是一种常见病症，可导致多种脊柱疾病，给全球健康带来重大负担。线粒体自噬在维持线粒体数量和质量方面发挥着关键作用，并且与IVDD的发生和发展密切相关。IVDD中已充分记录的区域特异性线粒体自噬机制正在指导治疗策略的开发。在髓核（NP）中，线粒体受损会导致细胞凋亡、氧化应激、衰老、细胞外基质降解与合成、过度自噬、炎症、线粒体不稳定和细胞焦亡，关键调控靶点包括AMPK、PGC-1α、SIRT1、SIRT3、早衰蛋白、p65、Mfn2、FOXO3、NDUFA4L2、SLC39A7、ITGα5/β1、Nrf2和NLRP3炎性小体。在纤维环（AF）中，线粒体损伤会诱导由PGC-1α介导的细胞凋亡和氧化应激，而在软骨终板（CEP）中，线粒体功能障碍同样会引发细胞凋亡和氧化应激。这些机制性见解突出了治疗策略，例如针对NP激活依赖Parkin和不依赖泛素的线粒体自噬途径，针对AF增强依赖Parkin的线粒体自噬，以及针对CEP靶向Parkin介导的线粒体自噬。这些策略包括使用天然成分、激素调节、基因编辑技术、靶向化合物以及操纵相关蛋白。本综述总结了椎间盘不同区域中线粒体自噬的机制，并强调了使用线粒体自噬调节剂改善IVDD的治疗方法。它讨论了线粒体自噬的复杂机制，并强调了其作为治疗靶点的潜力。目的是为开发抗IVDD的线粒体靶向药物提供有价值的见解和科学依据。
