Mitochondrial dysfunction in intervertebral disc degeneration: Linking oxidative stress, altered cell fate, and Matrix degeneration.

Intervertebral disc degeneration (IVDD) is a major pathological basis of chronic low back pain and is closely associated with disrupted cellular homeostasis, extracellular matrix (ECM) imbalance, and chronic inflammation. In recent years, mitochondrial dysfunction(definition) has emerged as a key upstream event linking multiple degenerative changes in the disc. Impaired mitochondrial homeostasis, characterized by energy metabolism disorder, mitochondrial membrane potential loss, excessive mitochondrial reactive oxygen species (mtROS) production, Ca²⁺ imbalance, and mitochondrial DNA damage, can promote abnormal cell fate decisions, suppress ECM synthesis, and enhance matrix catabolism. In parallel, mechanical overload, inflammatory stimulation, hypoxia, nutrient deprivation, acidic stress, aging, and oxidative stress further aggravate mitochondrial injury, forming a self-amplifying cycle of microenvironmental stress, mitochondrial dysfunction, oxidative damage, cell fate dysregulation, and ECM degeneration. Although previous reviews have discussed mitochondrial dysfunction in IVDD from the perspectives of small-molecule interventions, ER stress-mitochondrial crosstalk, mitochondrial quality control (MQC), or mitophagy, a unified framework connecting mitochondrial injury with oxidative stress, regulated cell fate programs, inflammatory amplification, and ECM degeneration remains insufficiently defined. By integrating mitochondrial pathology, cell fate regulation, biomarker development, and therapeutic implications, this review provides a systematic framework for understanding IVDD pathogenesis and developing future disease-modifying treatments.