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

Stokes, Julia C., Bornstein, Rebecca L., James, Katerina, Park, Kyung Yeon, Spencer, Kira A., Vo, Katie, Snell, John C., Johnson, Brittany M., Morgan, Philip G., Sedensky, Margaret M., Baertsch, Nathan A. and Johnson, Simon (2022) Leukocytes mediate disease pathogenesis in the Ndufs4(KO) mouse model of Leigh syndrome. JCI Insight, 7 (5). e156522. ISSN 2379-3708

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Official URL: https://doi.org/10.1172/jci.insight.156522


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.

Item Type: Article
Additional Information: Funding Information: Funding: National Institutes of Health grant NIH/GM R00-126147 (SCJ). National Institutes of Health grant NIH/GM R01-133865 (MS and SCJ). Northwest Mitochondrial Research Guild (SCJ). North American Mitochondrial Disease Consortium (JS and SCJ). National Institutes of Health T32 GM086270 (KS).
Uncontrolled Keywords: Animals, Disease Models, Animal, Electron Transport Complex I, Leigh Disease/genetics, Leukocytes/metabolism, Mice, Mice, Knockout
Subjects: A300 Clinical Medicine
C400 Genetics
C700 Molecular Biology, Biophysics and Biochemistry
Department: Faculties > Health and Life Sciences > Applied Sciences
Depositing User: Rachel Branson
Date Deposited: 07 Dec 2022 09:24
Last Modified: 07 Dec 2022 09:30
URI: https://nrl.northumbria.ac.uk/id/eprint/50820

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