Impaired Chaperone‐Mediated Autophagy Accelerates Intervertebral Disc Degeneration by Inducing MIDN Accumulation to Target TSC2 for Proteasomal Degradation

Abstract

ABSTRACT Intervertebral disc degeneration (IDD) is a leading cause of low back pain with incompletely understood mechanisms. Although autophagy dysfunction is a documented contributor to IDD, the precise pathobiological role of chaperone‐mediated autophagy (CMA) remains poorly understood. Here, we demonstrate that CMA activity is downregulated in nucleus pulposus cells (NPCs) from IDD patients and IL‐1β‐induced rat intervertebral disc cell models, causing cytoplasmic accumulation of a novel CMA substrate, Midnolin (MIDN). Accumulated MIDN bypasses the ubiquitin‐proteasome system and directly binds to Tuberous Sclerosis Complex 2 (TSC2), mediating its degradation. TSC2 loss relieves mechanistic target of rapamycin complex 1 (mTORC1) inhibition, resulting in mTORC1 hyperactivation, which drives cellular senescence, senescence‐associated secretory phenotype (SASP), and extracellular matrix (ECM) degradation in NPCs. In vitro and in a rat caudal needle puncture model, MIDN knockdown (shRNA), CMA activation (LAMP2A overexpression), or mTORC1 inhibition (Rapamycin) significantly attenuated IL‐1β or MIDN overexpression‐induced senescence and disc degeneration. Our findings reveal an “Impaired CMA–MIDN accumulation–TSC2 degradation–mTORC1 activation” axis central to IDD pathogenesis, offering potential therapeutic targets.