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

Area of Science:

• Biochemistry
• Molecular Biology
• Orthopedics

Background:

• Intervertebral disc degeneration (IVDD) is a primary cause of low back pain and spinal disorders.
• The molecular mechanisms underlying IVDD remain largely unknown.
• The role of basic leucine zipper ATF-like transcription factor 2 (BATF2) in IVDD has not been previously elucidated.

Purpose of the Study:

• To investigate the role and molecular mechanisms of BATF2 in the pathogenesis of IVDD.
• To explore the potential of targeting the BATF2-activating transcription factor 3 (ATF3) axis for IVDD treatment.

Main Methods:

• Analysis of BATF2 expression in degenerated nucleus pulposus (NP) tissues.
• In vitro and in vivo functional assays to assess the effects of BATF2 overexpression on NP cells (NPCs) and IVDD progression.
• Investigation of mitochondrial function and redox homeostasis.
• Exploration of the interaction between BATF2 and ATF3, including ubiquitination.
• Assessment of ATF3 knockdown effects on BATF2-induced pathologies.

Main Results:

• BATF2 expression was significantly upregulated in degenerated NP tissues.
• BATF2 overexpression promoted NPC apoptosis and extracellular matrix (ECM) catabolism.
• BATF2 impaired mitochondrial function by disrupting redox homeostasis.
• BATF2 stabilized ATF3 by inhibiting its ubiquitination.
• ATF3 overexpression mimicked BATF2's effects, and ATF3 knockdown reversed BATF2-induced mitochondrial dysfunction and IVDD progression.

Conclusions:

• The BATF2-ATF3 axis exacerbates IVDD by disrupting mitochondrial redox homeostasis and impairing mitochondrial function.
• Targeting the BATF2-ATF3 pathway presents a potential therapeutic strategy for IVDD.