Mitochondrial dysfunction is increasingly recognized as a trigger of innate immune responses, yet whether these responses contribute to neurodegeneration remains poorly understood. Here, we uncover a cell-type-specific antiviral program in vulnerable GABAergic neurons of Ndufs4-deficient mice and human brain organoids modeling Leigh syndrome. Despite robust type I interferon responses, genetic ablation of innate immune mediators Ifnar1 or Sting1 fails to ameliorate disease progression. Instead, we identify the double-stranded RNA sensor protein kinase R (PKR) as a critical mediator of mitochondrial neuropathology. PKR associates with mitochondrial RNA, while its genetic deletion or silencing delays neurological decline, attenuates neuroinflammation, and extends survival without restoring mitochondrial respiration. PKR deletion also normalizes JNK signaling without detectable global translational repression, suggesting a noncanonical contribution to disease. Together, our findings reveal PKR-mediated antiviral RNA sensing as a pathogenic mechanism in mitochondrial complex I deficiency and highlight PKR as a candidate target for mitochondrial encephalopathies.