Mitochondrial dysfunction as a key mediator of endplate chondrocyte senescence: emerging insights and targeted interventions.

Abstract

Intervertebral disc degeneration (IVDD) is a leading global cause of chronic pain and functional impairment. The senescence of endplate chondrocytes (EPCs) associated with the IVDD cascade, with mitochondrial homeostatic imbalance serving as the central pathological key mediator. EPCs inhabit a physiological niche defined by hypoxia, limited nutrients, and high mechanical loads, requiring precise metabolic regulation and mitochondrial quality control. This review integrates recent advances in mitochondrial biology to clarify how organelle dysfunction promotes EPC senescence. We first analyze the metabolic shift from oxidative phosphorylation to glycolysis and its impact on extracellular matrix stability. We then examine the mechanisms by which mitochondrial reactive oxygen species activate the NLRP3 inflammasome and NF-κB pathways to drive the senescence-associated secretory phenotype. Furthermore, the review discusses how fusion-fission imbalance and mitophagy failure lead to the accumulation of damaged mitochondria, and how mito-nuclear communication facilitates epigenetic remodeling to sustain senescent transcriptional programs. Finally, we evaluate therapeutic interventions targeting mitochondrial homeostasis, including targeted antioxidants, NAD+ precursors, and mitochondrial transplantation. To address the delivery challenges of avascular cartilage, the potential of cartilage-penetrating nanocarriers and gene-editing technologies is also discussed. This review establishes a theoretical framework for developing etiology-based precision therapies for IVDD.