Ouqiang Wu, Yuxin Jin, Shoutao Weng, Zhiguang Zhang, Keyu Tu, Jing Sun, Linjie Chen, Qizhu Chen, Zhihua Chen, Morgan Jones, Wang Xinzhou, Zhenyu Guo, Yan Michael Li, Yangli Xie, Min Wu, Shuying Shen, Aimin Wu
Alpha-ketoglutarate (α-KG), a key intermediate in the tricarboxylic acid (TCA) cycle, was found to be significantly decreased in nucleus pulposus (NP) tissues of patients with intervertebral disc degeneration (IVDD). Supplementation with α-KG restored nucleus pulposus cell (NPC) proliferation, reduced apoptosis, and reestablished extracellular matrix (ECM) metabolic homeostasis. Mechanistically, α-KG enhanced mitophagy and suppressed reactive oxygen species (ROS) accumulation, effects that were abolished by the mitophagy inhibitor Mdivi-1. Further investigation identified isocitrate dehydrogenase 1 (IDH1) as essential for α-KG production and mitochondrial maintenance, with its expression controlled by the METTL3/MALAT1/miR-23c axis. Specifically, METTL3-mediated m 6 A modification destabilized MALAT1, attenuating its sponging of miR-23c and ultimately leading to IDH1 suppression. These findings reveal a novel regulatory pathway governing mitophagy and oxidative stress in NPCs, highlighting potential therapeutic targets for IVDD.