TY - JOUR
T1 - mTOR inhibition alleviates mitochondrial disease in a mouse model of Leigh syndrome
AU - Johnson, Simon C
AU - Yanos, Melana E
AU - Kayser, Ernst-Bernhard
AU - Quintana, Albert
AU - Sangesland, Maya
AU - Castanza, Anthony
AU - Uhde, Lauren
AU - Hui, Jessica
AU - Wall, Valerie Z
AU - Gagnidze, Arni
AU - Oh, Kelly
AU - Wasko, Brian M
AU - Ramos, Fresnida J
AU - Palmiter, Richard D
AU - Rabinovitch, Peter S
AU - Morgan, Philip G
AU - Sedensky, Margaret M
AU - Kaeberlein, Matt
PY - 2013/12/20
Y1 - 2013/12/20
N2 - 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 Ndufs4 [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.
AB - 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 Ndufs4 [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.
KW - Animals
KW - Brain/drug effects
KW - Disease Models, Animal
KW - Electron Transport Complex I/genetics
KW - Glycolysis/drug effects
KW - Leigh Disease/drug therapy
KW - Mechanistic Target of Rapamycin Complex 1
KW - Mice
KW - Mice, Knockout
KW - Mice, Mutant Strains
KW - Mitochondria/drug effects
KW - Mitochondrial Diseases/drug therapy
KW - Molecular Targeted Therapy
KW - Multiprotein Complexes/antagonists & inhibitors
KW - Neuroprotective Agents/therapeutic use
KW - Sirolimus/therapeutic use
KW - TOR Serine-Threonine Kinases/antagonists & inhibitors
U2 - 10.1126/science.1244360
DO - 10.1126/science.1244360
M3 - Article
C2 - 24231806
VL - 342
SP - 1524
EP - 1528
JO - Science
JF - Science
SN - 1095-9203
IS - 6165
ER -