Inhibition of ETS1/DRP1 axis attenuates intervertebral disc degeneration by suppressing excessive mitochondrial fission.

Abstract

Intervertebral disc degeneration (IVDD) is a predominant contributor to low back pain, characterized by nucleus pulposus cell (NPC) senescence, extracellular matrix (ECM) metabolic dysfunction, and chronic inflammation. Excessive mitochondrial fission contributes to IVDD, yet the underlying regulatory mechanisms remain unclear. Herein, we identified ETS proto-oncogene 1 (ETS1) as a critical regulator of mitochondrial fission in human NPCs. ETS1 was upregulated in severe human IVDD and correlated with disc degeneration severity and NPC senescence. Mechanistically, inflammatory cytokines induced ETS1 upregulation, which directly bound to the dynamin 1-like (DNM1L, encoding DRP1) promoter and activated its transcription. Increased DRP1 triggered excessive mitochondrial fission, leading to reactive oxygen species accumulation, NPC senescence, and ECM catabolism. Inhibition of ETS1 via AAV5-mediated RNA interference or targeting DRP1 with CRISPR/dCas9-KRAB system or Mdivi-1 alleviated mitochondrial dysfunction, cellular senescence, ECM degradation, and attenuated IVDD progression. Collectively, our findings revealed the ETS1/DRP1 axis as a novel pathogenic mechanism and a potential therapeutic target in IVDD.