PKR drives neuropathology in a mouse model of Leigh syndrome

PKR is a critical mediator of mitochondrial neuropathology in Ndufs4-deficient mice, where its deletion or silencing delays neurological decline, attenuates neuroinflammation, and extends survival.

• Why it matters: Mitochondrial dysfunction can trigger innate antiviral programs, but it is unclear which immune pathways actually drive neurodegeneration in Leigh syndrome models.
• What they did: The study mapped a cell-type-specific type I interferon program in vulnerable GABAergic neurons of Ndufs4-deficient mice and Leigh syndrome brain organoids, then tested innate immune mediator ablation (Ifnar1 or Sting1) versus PKR deletion or silencing.
• The result: While Ifnar1 or Sting1 loss did not ameliorate progression, PKR deletion delayed decline, reduced neuroinflammation, extended survival, and normalized JNK signaling without restoring mitochondrial respiration.

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