Calreticulin attenuates intervertebral disc degeneration by suppressing NLRP3 inflammasome activation through PINK1/Parkin-mediated mitophagy.

Abstract

This study investigates the role of calreticulin (CRT) in intervertebral disc degeneration (IVDD) and elucidates its underlying mechanisms. CRT expression was markedly reduced in degenerated disc tissues, implicating its involvement in IVDD pathogenesis. Both in vitro and in vivo experiments were conducted to assess the effects of CRT on nucleus pulposus cell (NPC) pyroptosis, apoptosis, and mitochondrial function. Functional analyses demonstrated that CRT overexpression alleviated disc degeneration, inhibited pyroptotic cell death, and preserved mitochondrial integrity. Mechanistically, CRT promoted the clearance of damaged mitochondria through PINK1/Parkin-mediated mitophagy, restoring mitochondrial homeostasis and suppressing ROS accumulation and NLRP3 inflammasome activation. In vivo studies using an IVDD animal model further validated these protective effects, showing reduced disc degeneration and maintenance of extracellular matrix integrity. Recent studies have demonstrated the protective effect of CRT in IVDD. This study builds on these findings and investigates a novel mechanism through which CRT mediates its protective effects in IVDD. Specifically, our study identifies the involvement of PINK1/Parkin-mediated mitophagy in CRT's ability to preserve mitochondrial function and mitigate inflammation in NPCs, offering new insights into the molecular pathways underlying CRT's protective role in IVDD.