The BATF2-ATF3 axis exacerbates intervertebral disc degeneration via inducing mitochondrial dysfunction.

Intervertebral disc degeneration (IVDD) is the leading cause of low back pain, spinal instability, disc herniation and spinal stenosis, which is a serious risk to human health, yet its molecular mechanisms remain unknown. The basic leucine zipper ATF-like transcription factor 2 (BATF2) has been reported to play important roles in regulating cell proliferation, apoptosis, and inflammatory responses; however, its specific role in IVDD remains unknown. We firstly demonstrated BATF2 expression was significantly upregulated in degenerated nucleus pulposus (NP) tissues. Functional assays demonstrated that BATF2 overexpression promoted nucleus pulposus cell (NPC) apoptosis and extracellular matrix (ECM) catabolism in vitro and vivo. It is further demonstrated that BATF2 impairs mitochondrial function by disturbing mitochondrial redox homeostasis. Mechanistically, BATF2 stabilizes the activating transcription factor 3 (ATF3) by inhibiting the ubiquitination modification of ATF3. Notably, ATF3 overexpression accelerated NPC apoptosis and ECM degradation. More importantly, ATF3 knockdown reversed the effects of BATF2-induced mitochondrial dysfunction and IVDD progression. These results suggest that BATF2-ATF3 axis disrupts mitochondrial redox homeostasis to impair mitochondrial function, thereby exacerbating the progression of IVDD. Targeting BATF2-ATF3 axis could provide a potential strategy for IVDD treatment.