TDP43 cytoplasmic mislocalization initiates mitochondrial dysfunction and intercellular senescence propagation in...

Intervertebral disc degeneration (IDD), a leading cause of low back pain, involves progressive dysfunction of nucleus pulposus (NP) cells and extracellular matrix degradation. The pathological mechanisms underlying IDD remain complex and lack comprehensive elucidation. This study identifies the RNA-binding protein TDP43 as a central driver of IDD pathogenesis through analysis of human clinical specimens and rodent models. We demonstrate that TDP43 expression escalates proportionally with disc degeneration severity and aberrantly accumulates in the mitochondria of degenerative NP cells. This mitochondrial mislocalization triggers nuclear pore complex impairment, mitochondrial membrane potential collapse, and irreversible cellular senescence. Critically, TDP43 is secreted within mitochondrial-derived vesicles, which function as intercellular mediators that propagate pro-inflammatory cytokines and senescence phenotypes to neighboring NP cells. Both genetic and pharmacological inhibition of vesicular TDP43 effectively attenuated mitochondrial dysfunction and reduced cellular senescence and ultimately decelerated IDD progression in vivo and in vitro. Our findings establish TDP43-loaded mitochondrial-derived vesicles as novel mediators of intercellular pathology and nominate TDP43 as a therapeutic target for IDD intervention.