mTOR Inhibition by Rapamycin Alleviates Mitochondrial Disease in the Ndufs4-Mouse Model of Leigh Syndrome




Wasko, Brian

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Mitochondrial dysfunction contributes to numerous health problems, including neurological and muscular degeneration, cardiomyopathies, cancer, diabetes, and pathologies of aging. Severe mitochondrial defects can result in childhood disorders such as Leigh syndrome, for which there are no effective therapies. We found that rapamycin, a specific inhibitor of the mechanistic target of rapamycin (mTOR) signaling pathway, robustly enhances survival and attenuates disease progression in a mouse model of Leigh syndrome. Administration of rapamycin to these mice, which are deficient in the mitochondrial respiratory chain subunit Ndufsf [NADH dehydrogenase (ubiquinone) FE-S protein 4], delays onset of neurological symptoms, reduces neuroinflammation, and prevents brain lesions. Although the precise mechanism of rescue remains to be determined, rapamycin induces a metabolic shift toward amino acid catabolism and away from glycolysis, alleviating the buildup of glycolytic intermediates. This therapeutic strategy may prove relevant for a broad range of mitochondrial diseases.



Animals, Brain/drug effects, Brain/enzymology, Brain/pathology, Disease Models, Animal Electron Transport Complex I/genetics, Electron Transport Complex I/metabolism, Glycolysis/drug effects, Leigh Disease/drug therapy, Leigh Disease/genetics, Leigh Disease/pathology, Mechanistic Target of Rapamycin Complex 1, Mice Mice, Knockout Mice, Mutant Strains Mitochondria/drug effects, Mitochondria/enzymology, Mitochondrial Diseases/drug therapy, Mitochondrial Diseases/genetics, Mitochondrial Diseases/pathology, Molecular Targeted Therapy, Multiprotein Complexes/antagonists & inhibitors, Neuroprotective Agents/therapeutic use, Sirolimus/therapeutic use, TOR Serine-Threonine Kinases/antagonists & inhibitors


Johnson SC, Yanos ME, Kayser E, Quintana A, Sangesland M, Castanza A, Uhde L, Hui J, Wall JZ, Gagnidze A, Oh K, Wasko BM, Ramos FJ, Palmiter R, Rabinovitch P, Morgan PJ, Sedensky MM, Kaeberlein M. mTOR inhibition by rapamycin alleviates mitochondrial disease in the Ndufs4 - mouse model of leigh syndrome. Science. 2013. Dec 20;342(6165):1524-8.