Reduced Cell Cleanup Speed Up Spine Disc Wear by Causing MIDN Build-Up That Breaks Down TSC2 Protein

Cohorts from patients with intervertebral disc degeneration show downregulated chaperone-mediated autophagy activity, leading to cytoplasmic accumulation of Midnolin (MIDN).

• Chaperone-mediated autophagy is associated with the regulation of cellular processes in nucleus pulposus cells.
• Accumulated Midnolin (MIDN) can bypass the normal protein degradation pathway, leading to the degradation of Tuberous Sclerosis Complex 2 (TSC2).
• Loss of TSC2 contributes to the hyperactivation of mechanistic target of rapamycin complex 1 (mTORC1), which may drive cellular senescence and extracellular matrix degradation.
• In vitro experiments and a rat intervertebral disc model indicate that targeting MIDN or modulating CMA activity can reduce signs of disc degeneration.
• The findings suggest a pathway involving impaired CMA, MIDN accumulation, TSC2 degradation, and mTORC1 activation that could be relevant to the pathogenesis of intervertebral disc degeneration.

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