In this study, we found that OPA1 protein, which regulates IMM events, is downregulated in in vitro and in vivo prion disease models, and overexpression of OPA1 blocked prion-induced mitochondrial network fragmentation and mitochondrial dysfunction, loss of mtDNA, and neuronal apoptosis, suggesting that OPA1 could be an effective therapeutic target for the treatment of early-stage prion diseases. The gene discussed is OPA1; the disease is prion disease.