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

Chen Xianglong, Gao H, Wu W, Shi P, Chen Yuhang, Zhang A, Cheng Z, Wu W, Yu Z, Zhang Y · 2026 · Advanced Science · Atlas ID CHEN2026C

What this study shows

Loss of chaperone-mediated autophagy lets its substrate midnolin (MIDN) accumulate; MIDN binds TSC2 and drives its proteasomal degradation independently of ubiquitination, de-repressing mTORC1 and causing senescence, SASP and matrix loss in disc cells. MIDN knockdown, LAMP2A overexpression or rapamycin each blocked the degeneration - a new upstream route to mTORC1 hyperactivation.

Abstract

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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-1beta-induced rat intervertebral disc cell models, causing cytoplasmic accumulation of a novel CMA substrate, Midnolin (MIDN).

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At a glance

Evidence type	A Animal model Marked A because it is an animal intervention or observation study measuring an organismal outcome (model: Human nucleus pulposus cells; rat caudal needle-puncture model); the code names the system studied -- animal work can be rigorous and still not be human data.
Study type	4 - Animal Study
Model system	Human nucleus pulposus cells; rat caudal needle-puncture model
Journal	Advanced Science
Year	2026
Peer reviewed	Yes
Record last updated	2026-08-22
Source	DOI 10.1002/advs.77428 · PMID 42658647

Extracted findings

Intervention	MIDN knockdown (shRNA), LAMP2A overexpression (CMA activation), rapamycin
Target	TSC2 / mTORC1 (via midnolin, MIDN)
Model	Human cells; rat
Effect	Impaired CMA -> MIDN accumulation -> TSC2 degradation -> mTORC1 hyperactivation -> senescence, SASP and matrix loss; blocked by MIDN knockdown, LAMP2A overexpression or rapamycin

Cite this paper

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Chen Xianglong, Gao, H., Wu, W., Shi, P., Chen Yuhang, Zhang, A., Cheng, Z., Wu, W., Yu, Z., & Zhang, Y. (2026). Impaired Chaperone-Mediated Autophagy Accelerates Intervertebral Disc Degeneration by Inducing MIDN Accumulation to Target TSC2 for Proteasomal Degradation. Advanced Science. https://doi.org/10.1002/advs.77428

@article{CHEN2026C,
  author       = {Chen Xianglong and Gao, H. and Wu, W. and Shi, P. and Chen Yuhang and Zhang, A. and Cheng, Z. and Wu, W. and Yu, Z. and Zhang, Y.},
  title        = {{Impaired Chaperone-Mediated Autophagy Accelerates Intervertebral Disc Degeneration by Inducing MIDN Accumulation to Target TSC2 for Proteasomal Degradation}},
  journal      = {Advanced Science},
  year         = {2026},
  doi          = {10.1002/advs.77428},
  note         = {PMID: 42658647},
}

Cite this Atlas record

The record is the Atlas's own work — the evidence label, the extracted findings and the links. It is cited as part of the dataset, not as the paper.

Barton, O. (2026). Oliver's mTOR Atlas (record CHEN2026C) [Data set]. https://mtor-atlas.org/study/CHEN2026C/ · Dataset DOI 10.5281/zenodo.22059963

@misc{atlas_CHEN2026C,
  author       = {Barton, Oliver},
  title        = {{Oliver's mTOR Atlas}, record CHEN2026C},
  howpublished = {Data set},
  year         = {2026},
  url          = {https://mtor-atlas.org/study/CHEN2026C/},
  doi          = {10.5281/zenodo.22059963}
}