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METTL3 regulates α-KG-dependent mitophagy and apoptosis in nucleus pulposus cells through the MALAT1/miR-23c/IDH1
Ouqiang Wu1, Yuxin Jin2, Shoutao Weng2
1Department of Orthopaedics, Key Laboratory of Structural Malformations in Children of Zhejiang Province, Key Laboratory of Orthopaedics of Zhejiang Province, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, China; Department of Orthopaedics, Key Laboratory of Musculoskeletal System Degeneration and Regeneration Translational Research of Zhejiang Province, Sir Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310000, China.
Abstract:
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 m6A 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.
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