TY - JOUR
T1 - Leukocytes mediate disease pathogenesis in the Ndufs4(KO) mouse model of Leigh syndrome
AU - Stokes, Julia C.
AU - Bornstein, Rebecca L.
AU - James, Katerina
AU - Park, Kyung Yeon
AU - Spencer, Kira A.
AU - Vo, Katie
AU - Snell, John C.
AU - Johnson, Brittany M.
AU - Morgan, Philip G.
AU - Sedensky, Margaret M.
AU - Baertsch, Nathan A
AU - Johnson, Simon C
N1 - 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).
PY - 2022/3/8
Y1 - 2022/3/8
N2 - 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.
AB - 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.
KW - Animals
KW - Disease Models, Animal
KW - Electron Transport Complex I
KW - Leigh Disease/genetics
KW - Leukocytes/metabolism
KW - Mice
KW - Mice, Knockout
UR - http://www.scopus.com/inward/record.url?scp=85125891731&partnerID=8YFLogxK
U2 - 10.1172/jci.insight.156522
DO - 10.1172/jci.insight.156522
M3 - Article
C2 - 35050903
SN - 2379-3708
VL - 7
JO - JCI insight
JF - JCI insight
IS - 5
M1 - e156522
ER -