Ubiquitination-mediated degradation of NLRX1 drives metabolic vulnerability and accelerates intervertebral disc degeneration.

Intervertebral disc degeneration (IVDD) is driven in part by senescence of nucleus pulposus (NP) cells, yet the metabolic defects underlying this process remain incompletely defined. Although NLRX1 has been implicated in mitochondrial quality control, the mechanisms governing its stability and its role in OXPHOS regulation during IVDD remain unclear. Here, we show that oxidative phosphorylation (OXPHOS) progressively declines with increasing IVDD severity and that loss of NLRX1 contributes to this defect by disrupting mitochondrial respiration and redox homeostasis in NP cells. Nlrx1-/- mice exhibited accelerated age-related IVDD, accompanied by reduced abundance of OXPHOS markers and increased senescence markers. Mechanistically, RNF126 promotes K48-linked polyubiquitination of NLRX1 at K520, leading to its degradation and consequent impairment of OXPHOS and redox balance in NP cells. A degradation-resistant NLRX1K520R mutant restored OXPHOS function, reduced mitochondrial fragmentation, and attenuated oxidative stress under senescence-inducing conditions. Engineered exosomes delivering NLRX1K520R alleviated IVDD-related phenotypes in vivo. These findings identify the RNF126-NLRX1 axis as a critical checkpoint of metabolic vulnerability that couples mitochondrial stress to senescence in NP cells during IVDD and highlight NLRX1 stabilization as a proof-of-concept therapeutic strategy.