Leukocytes mediate disease pathogenesis in the Ndufs4(KO) mouse model of Leigh syndrome

Julia C Stokes, Rebecca L Bornstein, Katerina James, Kyung Yeon Park, Kira A Spencer, Katie Vo, John C Snell, Brittany M Johnson, Philip G Morgan, Margaret M Sedensky, Nathan A Baertsch, Simon C Johnson

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21 Citations (Scopus)
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Symmetric, progressive, necrotizing lesions in the brainstem are a defining feature of Leigh syndrome (LS). A mechanistic understanding of the pathogenesis of these lesions has been elusive. Here, we report that leukocyte proliferation is causally involved in the pathogenesis of LS. Depleting leukocytes with a colony-stimulating factor 1 receptor inhibitor disrupted disease progression, including suppression of CNS lesion formation and a substantial extension of survival. Leukocyte depletion rescued diverse symptoms, including seizures, respiratory center function, hyperlactemia, and neurologic sequelae. These data reveal a mechanistic explanation for the beneficial effects of mTOR inhibition. More importantly, these findings dramatically alter our understanding of the pathogenesis of LS, demonstrating that immune involvement is causal in disease. This work has important implications for the mechanisms of mitochondrial disease and may lead to novel therapeutic strategies.

Original languageEnglish
Article numbere156522
Number of pages14
JournalJCI insight
Issue number5
Publication statusPublished - 8 Mar 2022
Externally publishedYes


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