mTOR Inhibition Alleviates Mitochondrial Disease in a Mouse Model of Leigh Syndrome

Abstract

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.

Mitochondrial Complex I Deficiency Enhances Skeletal Myogenesis but Impairs Insulin Signaling through SIRT1 Inactivation

“…muscles and lactic acidosis, which leads to Leigh's disease with symptoms of encephalomyopathy and cardiomyopathy (10,11). In particular, many mutations have been found in the catalytic subunits of CI in Leigh's disease patients (12).…”

Correction

“…Long-term treatment with rapamycin, a molecule that inhibits mTOR signalling, reduces the accumulation of DNA damage in another genomic-instability disorder, Werner syndrome 7 . There have been other examples of daily rapamycin treatments causing substantial extensions in lifespan -for instance, rapamycin approximately triples the lifespan of mice that lack a mitochondrial protein called Ndufs4, which is involved in energy production 8 .…”

Lifespan extension and cancer prevention in HER-2/neu transgenic mice treated with low intermittent doses of rapamycin

“…1 Rapamycin extends life span in mice. [2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20] Furthermore, rapamycin delays the onset of cancer in mice. [3][4][5][6][7][9][10][11][12][13]15,18 Rapamycin and everolimus (a rapamycin analog) decrease the risk of cancer in humans, who receive these rapalogs to prevent transplant rejection.…”

“…Importantly, the clearance of rapamycin is much faster in mice than in humans. For example, in mice levels of rapamycin drop 20-folds the next day after injection, 14 whereas in humans its terminal half-life is about 2.5 d. 38,39 It was estimated that a 1.5 mg/kg injection in mice corresponds to the therapeutic oral dose in humans. 40 Every other day (e.o.d.)…”