USP19 restores mitochondrial function in neurons by deubiquitinating FUS to alleviate trigeminal neuralgia

Deubiquitinating enzymes of the ubiquitin-specific peptidase (USP) family have been increasingly recognized for their roles in modulating neuropathic pain. In this study, bioinformatic analysis identified USP19 as a downregulated gene in trigeminal neuralgia (TN). Using a mouse model of TN induced by foramen lacerum impingement of the trigeminal nerve (FLIT), we demonstrated that adeno-associated virus-mediated overexpression of USP19 in the cerebral cortex significantly alleviated anxiety-like and pain-like behaviors. USP19 overexpression promoted deubiquitination and stabilization of fused in sarcoma (FUS), as confirmed by Western blotting, actinomycin D treatment, and ubiquitination assays. In HT22 and SH-SY5Y cells exposed to lipopolysaccharide to induce mitochondrial dysfunction, USP19 restored mitochondrial membrane potential, reduced mitochondrial reactive oxygen species, suppressed DRP1 phosphorylation, and upregulated CYTB and ND4 levels. These effects were reversed by FUS knockdown, both in vitro and in vivo. Moreover, FUS silencing abolished USP19-mediated improvements in NAD⁺/NADH ratio and mitochondrial function, as well as its analgesic and anxiolytic benefits in TN mice. These findings suggest that USP19 alleviates TN by enhancing FUS deubiquitination and preserving mitochondrial integrity in neurons. This study reveals a novel USP19/FUS signaling axis in the regulation of mitochondrial homeostasis and provides a promising therapeutic target for the treatment of TN.