Abstract

Leigh syndrome (LS) is the most common pediatric presentation of genetic mitochondrial disease. LS is a multi-system disease characterized by severe neurologic and metabolic abnormalities. The defining feature of the disease is the presence of symmetric, bilateral, progressive necrotizing lesions in the brain stem, cerebellum, and basal ganglia. The pathogenic mechanisms underlying disease initiation and progression in LS have yet to be elucidated. Recent evidence demonstrates that the immune system plays a key role in LS pathogenesis. Treatment with the macrophage-depleting Csf1r inhibitor pexidartinib prevents disease in the Ndufs4(-/-) mouse model of LS, but the mechanisms leading to immune activation and governing disease progression remain to be elucidated. In recent work, the cytokines IFN{gamma} and IFN{gamma}-induced protein 10 (IP10) were found to be significantly elevated in Ndufs4(-/-) brainstem. Given their role as macrophage-activating factors, here we sought to assess the role of IFN{gamma} and IP10 in LS using by generating Ndufs4(-/-)/Ifng(-/-) and Ndufs4(-/-)/IP10(-/-) double knockout lines. We find that IP10 alone does not significantly impact the onset or progression of disease in the Ndufs4(-/-) model, while IFN{gamma} loss significantly, but modestly, improves survival. These data indicate that IFN{gamma} contributes to pathology, but that IFN{gamma} and IP10 are both dispensable for overall disease course of LS. Our findings support some role for IFN{gamma} targeting therapies in the management of mitochondrial disease, but suggest they may provide only modest benefits, at least in LS.