Compression-induced senescence of nucleus pulposus cells by promoting mitophagy activation via the PINK1/PARKIN pathway.

ABSTRACT

The current research aimed to explore the possible relationship between PINK1/PARKIN-mediated mitophagy and the compression-induced senescence of nucleus pulposus cells (NPCs). Therefore, the stages of senescence in NPCs were measured under compression lasting 0, 24 and 48 hours. The mitophagy-related markers, autophagosomes and mitochondrial membrane potential were tested to determine the levels of PINK1/PARKIN-mediated mitophagy under compression. The PINK1 and PARKIN levels were also measured by immunohistochemistry of human and rat intervertebral disc (IVD) tissues taken at different degenerative stages. A specific mitophagy inhibitor, cyclosporine A (CSA) and a constructed PINK1-shRNA were used to explore the relationship between mitophagy and senescence by down-regulating the PINK1/PARKIN-mediated mitophagy levels. Our results indicated that compression significantly enhanced the senescence of NPCs in a time-dependent manner. Also, PINK1/PARKIN-mediated mitophagy was found to be activated by the extended duration of compression on NPCs as well as the increased degenerative stages of IVD tissues. After inhibition of PINK1/PARKIN-mediated mitophagy by CSA and PINK1-shRNA, the senescence of NPCs induced by compression was strongly rescued. Hence, the excessive degradation of mitochondria in NPCs by mitophagy under continuous compression may accelerate the senescence of NPCs. Regulating PINK1/PARKIN-mediated mitophagy might be a potential therapeutic treatment for IVD degeneration.