Interferon‐gamma contributes to disease progression in the Ndufs4(−/−) model of Leigh syndrome

Abstract Aim Leigh syndrome (LS), the most common paediatric presentation of genetic mitochondrial dysfunction, is a multi‐system disorder characterised by severe neurologic and metabolic abnormalities. Symmetric, bilateral, progressive necrotizing lesions in the brainstem are defining features of the disease. Patients are often symptom free in early life but typically develop symptoms by about 2 years of age. The mechanisms underlying disease onset and progression in LS remain obscure. Recent studies have shown that the immune system causally drives disease in the Ndufs4 (−/−) mouse model of LS: treatment of Ndufs4 (−/−) mice with the macrophage‐depleting Csf1r inhibitor pexidartinib prevents disease. While the precise mechanisms leading to immune activation and immune factors involved in disease progression have not yet been determined, interferon‐gamma (IFNγ) and interferon gamma‐induced protein 10 (IP10) were found to be significantly elevated in Ndufs4 (−/−) brainstem, implicating these factors in disease. Here, we aimed to explore the role of IFNγ and IP10 in LS. Methods To establish the role of IFNγ and IP10 in LS, we generated IFNγ and IP10 deficient Ndufs4 (−/−)/ Ifng (−/−) and Ndufs4 (−/−)/ IP10 (−/−) double knockout animals, as well as IFNγ and IP10 heterozygous, Ndufs4 (−/−)/ Ifng (+/−) and Ndufs4 (−/−)/ IP10 (+/−), animals. We monitored disease onset and progression to define the impact of heterozygous or homozygous loss of IFNγ and IP10 in LS. Results Loss of IP10 does not significantly impact the onset or progression of disease in the Ndufs4 (−/−) model. IFNγ loss significantly extends survival and delays disease progression in a gene dosage‐dependent manner, though the benefits are modest compared to Csf1r inhibition. Conclusions IFNγ contributes to disease onset and progression in LS. Our findings suggest that IFNγ targeting therapies may provide some benefits in genetic mitochondrial disease, but targeting IFNγ alone would likely yield only modest benefits in LS.