METTL3 regulates α-KG-dependent mitophagy and apoptosis in nucleus pulposus cells through the MALAT1/miR-23c/IDH1 axis.

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.