Parkin and Nrf2 prevent oxidative stress-induced apoptosis in intervertebral endplate chondrocytes via inducing mitophagy and anti-oxidant defenses.

Endplate chondrocyte apoptosis is an important contributor to the pathogenesis of cartilaginous endplate (CEP) degeneration that leads to the initiation and development of intervertebral disc degeneration (IDD). In this study, we hypothesized that Parkin-mediated mitophagy and nuclear factor E2-related factor 2 (Nrf2)-mediated antioxidant system played an important role in endplate chondrocyte survival under pathological conditions.

Human endplate chondrocytes were stimulated with H₂O₂ to mimic pathological conditions. Western blotting, immunofluorescence staining, and flow cytometry were applied to detect the indicators related to mitochondrial dynamics, mitophagy, Nrf2 signaling, and apoptosis. The puncture-induced rat models were established to evaluate the changes in vivo.

Our results showed that H₂O₂ induced oxidative stress, mitochondrial dysfunction, and apoptosis in endplate chondrocytes. These H₂O₂-induced detrimental effects were inhibited by pretreatment with the mitochondria-targeted antioxidant Mito-TEMPO. In addition, mitochondrial dynamics, Parkin-mediated elimination of dysfunctional mitochondria, and Nrf2-mediated antioxidant system were promoted by H₂O₂. Knockdown of Parkin or Nrf2 increased H₂O₂-induced detrimental effects. Moreover, upregulation of Parkin and Nrf2 by polydatin protected endplate chondrocytes against H₂O₂-induced mitochondrial dysfunction, oxidative stress, and apoptosis. Finally, puncture-induced rat models showed that polydatin exerted a protective effect on CEP and disc degeneration.

Targeting Parkin and Nrf2 to improve mitochondrial homeostasis, redox balance and endplate chondrocyte survival may represent a potential therapeutic strategy for preventing IDD.