Taurine can restrict mtdsRNA mediated pyroptosis by enhancing mitophagy in nucleus pulposus cells

Mitochondrial double-stranded RNA (mtdsRNA), a long-stranded RNA molecule generated by bidirectional transcription of the circular mitochondrial genome, can trigger the type 1 interferon response by activating pattern recognition receptors in the cytoplasm during mitochondrial dysfunction. However, its regulatory and pathogenic mechanisms in intervertebral disc degeneration are poorly understood. Here, we showed that mtdsRNA was abnormally elevated in degenerative nucleus pulposus tissues. Furthermore, we found that mtdsRNA leakage into the cytoplasm could cause MAVS oligomerization by binding to RLRs, and oligomerized MAVS could then promote nucleus pulposus cell pyroptosis by activating NLRP3. To further elucidate the upstream regulatory mechanism of mtdsRNA, we performed untargeted metabolomics analysis, which revealed that the downregulation of taurine under external stimuli could drive an imbalance in mtdsRNA homeostasis. RNA-seq further revealed that exogenous supplementation with taurine protected cells from mtdsRNA-induced pyroptosis by increasing mitophagy. In conclusion, our study links taurine metabolism, mitochondrial nucleic acids and pyroptosis and suggests that mtdsRNA is an important causative molecule and a potential therapeutic target in intervertebral disc degeneration.