ArticleAdvanced science (Weinheim, Baden-Wurttemberg, Germany)2026
PACS-2 Mitigates NPSC Apoptosis and Intervertebral Disc Degeneration by Preserving MAM Integrity via the SP1/LRRK2/Mfn2 Axis.
Article in Advanced science (Weinheim, Baden-Wurttemberg, Germany), 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 7 papers.
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Who cites it
7 citing papers in PubMed.
- Biomaterials for intervertebral disc regeneration: Niche reprogramming, precision therapeutics, and structural reconstruction.Bioactive materials · 2027Review
- Mitochondria‑associated endoplasmic reticulum membranes in degenerative musculoskeletal disorders: Mechanistic evidence and therapeutic perspectives (Review).Molecular medicine reports · 2026Review
- MANF safeguards mitochondria-associated endoplasmic reticulum membrane integrity in nucleus pulposus-derived mesenchymal stem cells to maintain homeostasis of the intervertebral disc.Cell biology and toxicology · 2026Article
- Mitochondria-associated endoplasmic reticulum membrane (MAM): roles in innate immunity dysregulation.Cell communication and signaling : CCS · 2026Review
- Notch signaling-targeted biomimetic hydrogel constructs an anti-inflammatory "flood-control" system to alleviate pyroptosis for intervertebral disc degeneration treatment.Materials today. Bio · 2026Article
- PACS-2 Mitigates NPSC Apoptosis and Intervertebral Disc Degeneration by Preserving MAM Integrity via the SP1/LRRK2/Mfn2 Axis.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Revisiting intervertebral disc degeneration: lipid metabolism disorders as overlooked contributors to complex pathology.Frontiers in immunology · 2026Review
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Authors and funding
20 authors.
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Abstract
Intervertebral disc (IVD) degeneration (IDD) is a leading cause of lower back pain, and the application of nucleus pulposus-derived stem cells (NPSCs) holds promise for regenerative treatment. However, the harsh microenvironment of degenerative IVDs increases apoptosis in endogenous and transplanted NPSCs, limiting the effectiveness of NPSC-based therapies. Mitochondria-associated ER membrane (MAM) facilitates communication between mitochondria and ER and is critical for cellular homeostasis. PACS-2 is a central regulator of MAM homeostasis. It is found that MAM structure is disrupted in degenerative human and rat IVDs and in NPSCs exposed to an acidic environment, coinciding with reduced PACS-2 expression and increased apoptosis. In addition, Pacs-2 knockout mice with IDD displayed accelerated degeneration, accompanied by the exacerbation of ER stress, mitochondrial dysfunction, and apoptosis. Mechanistically, PACS-2 suppresses phosphorylation and nuclear translocation of the transcription factor SP1, thereby downregulating its downstream target LRRK2. This reduces LRRK2-mediated ubiquitination and degradation of Mfn2 through the JNK pathway, preserving MAM integrity and promoting NPSC survival. In vivo, transplantation of Pacs-2-overexpressing NPSCs improved cell survival and enhanced IVD repair in a degenerative model. These findings demonstrate that PACS-2 supports NPSC-mediated IVD regeneration by maintaining MAM integrity via the SP1/LRRK2/Mfn2 axis, offering potential therapeutic targets for IDD.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.