{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Stokes JC"],"funding":["North American Mitochondrial Disease Consortium","Northwest Mitochondrial Research Guild","NIH Office of the Director","NHLBI NIH HHS","NINDS NIH HHS","NIGMS NIH HHS"],"pagination":["e156522"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC8983133"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["7(5)"],"pubmed_abstract":["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."],"journal":["JCI insight"],"pubmed_title":["Leukocytes mediate disease pathogenesis in the Ndufs4(KO) mouse model of Leigh syndrome."],"pmcid":["PMC8983133"],"funding_grant_id":["F31 NS120442","n/a","K99 GM126147","R01 GM133865","R00 GM126147","NIH/GM R01 133865","R00 HL145004","T32 GM086270","R00 126147"],"pubmed_authors":["Baertsch NA","Johnson SC","Park KY","Snell JC","Bornstein RL","Stokes JC","Morgan PG","Spencer KA","Vo K","James K","Sedensky MM","Johnson BM"],"additional_accession":[]},"is_claimable":false,"name":"Leukocytes mediate disease pathogenesis in the Ndufs4(KO) mouse model of Leigh syndrome.","description":"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.","dates":{"release":"2022-01-01T00:00:00Z","publication":"2022 Mar","modification":"2025-04-05T00:27:53.082Z","creation":"2025-04-05T00:27:53.082Z"},"accession":"S-EPMC8983133","cross_references":{"pubmed":["35050903"],"doi":["10.1172/jci.insight.156522"]}}