We found that NF-κB nuclear translocation was disturbed in prion-infected cells after IAV/WSN infection, resulting in suppression of the Sod2 gene expression and elevation of mtROS levels, and that the elevated mtROS in turn activated NLRP3 inflammasomes and eventually suppressed necroptotic cell death in prion-infected cells after IAV/WSN infection. Here, NFKB1 is linked to early-onset parkinsonism-intellectual disability syndrome.