Mitochondrial double-stranded RNAs activates PKR to promote nucleus pulposus pyroptosis and intervertebral disc degeneration during metabolic stress

Abstract Intervertebral disc (IVD) degeneration is a common concomitant disease in obesity patients, but the mechanism remains largely unknown. Obsity is a metabolic syndrome that results in the concentrations of circulating lipids increased and metabolic stress. Therefore, pathways that integrate metabolic stress and nucleus pulposus (NP) cell death are of especially important in exploring the mechanisms of IVD degeneration. Here we present evidence that double-stranded RNA-dependent protein kinase (PKR) activates inflammasome and NP cell pyroptosis by sensing mt-dsRNA signals released by mitochondrial damage under metabolic stress, thus promoting the occurrence of IVD degeneration. And PKR deficiency alleviates IVD degeneration caused by metabolic stress in mice. Moreover, metformin prevents PKR activation and protects NP cells partly by attenuating mitochondria damage from metabolic stress. This research presents a comprehensive understanding of innate immune activation mediate by mt-dsRNA-PKR axis in NP cells that underlie the development of IVD degeneration during metabolic stress and recommends metformin as a therapeutic drug for treating IVD degeneration.