Harnessing mitophagy for intervertebral disc degeneration: a paradigm shift in targeted therapeutics

• Mitochondrial quality control via mitophagy is pivotal in maintaining intervertebral disc homeostasis and preventing oxidative, inflammatory, and metabolic stress–induced degeneration • Dysregulated mitophagy contributes to apoptosis, ferroptosis, and calcification across nucleus pulposus, annulus fibrosus, and cartilage endplate cells, accelerating intervertebral disc degeneration • Key signaling pathways including PINK1–Parkin, BNIP3/NIX, FUNDC1, PHB2, and cardiolipin orchestrate both canonical and non-canonical mitophagy in disc cells. • Therapeutic modulation of mitophagy —through small molecules (urolithin A, metformin, resveratrol, MitoQ), gene therapy, and stem-cell-derived exosomes—offers a promising strategy to restore mitochondrial function in IDD • Future directions emphasize integrating multi-omics, spatial transcriptomics, and large-animal models to achieve precise, stage-specific mitophagy targeting for clinical translation. Intervertebral disc degeneration (IDD) is a leading cause of chronic low back pain worldwide. It involves degenerative changes in nucleus pulposus, annulus fibrosus, and cartilage endplate cells, driven by factors such as oxidative stress, inflammation, mechanical imbalance, and apoptosis. Mitochondrial dysfunction lies at the heart of IDD progression, marked by excessive reactive oxygen species, reduced ATP production, and compromised cellular homeostasis. Mitophagy, the selective autophagic clearance of damaged mitochondria, emerges as a key regulator of mitochondrial quality control. Canonical pathways including those involving PINK1–PRKN/Parkin, BNIP3 and BNIP3L/NIX, as well as non-canonical mechanisms involving PHB2 and cardiolipin, coordinate the removal of dysfunctional mitochondria. However, dysregulated mitophagy in IDD can spur persistent oxidative stress, chronic inflammation, and cell death in different disc cell types, thereby hastening tissue degeneration. Therapeutic strategies focusing on mitophagy modulation include small-molecule agents, gene therapy targeting key mitophagy regulators, and stem cell treatments that restore mitochondrial function. Despite promising preclinical findings, challenges remain, particularly in achieving specificity and safety, as well as translating these approaches into effective clinical interventions. Future efforts integrating multi-omics analyses, refined animal models, and gene-editing tools may deepen our understanding of mitophagy’s role in IDD and pave the way for novel, targeted therapies aimed at improving patient outcomes.