PACS‐2 Mitigates NPSC Apoptosis and Intervertebral Disc Degeneration by Preserving MAM Integrity via the SP1/LRRK2/Mfn2 Axis

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.