sirolimus and Leigh-Disease

Mitochondrial diseases represent a spectrum of disorders caused by impaired mitochondrial function, ranging in severity from mortality during infancy to progressive adult-onset disease. Mitochondrial dysfunction is also recognized as a molecular hallmark of the biological ageing process. Rapamycin, a drug that increases lifespan and health during normative ageing, also increases survival and reduces neurological symptoms in a mouse model of the severe mitochondrial disease Leigh syndrome. The Ndufs4 knockout (Ndufs4

Topics: Acarbose; Animals; Disease Models, Animal; Electron Transport Complex I; Leigh Disease; Mice; Mitochondria; Mitochondrial Diseases; Sirolimus

Genetic mitochondrial diseases are the most frequent cause of inherited metabolic disorders and one of the most prevalent causes of heritable neurological disease. Leigh syndrome is the most common clinical presentation of pediatric mitochondrial disease, typically appearing in the first few years of life, and involving severe multisystem pathologies. Clinical care for Leigh syndrome patients is difficult, complicated by the wide range of symptoms including characteristic progressive CNS lesion, metabolic sequelae, and epileptic seizures, which can be intractable to standard management. While no proven therapies yet exist for the underlying mitochondrial disease, a ketogenic diet has led to some reports of success in managing mitochondrial epilepsies, with ketosis reducing seizure risk and severity. The impact of ketosis on other aspects of disease progression in Leigh syndrome has not been studied, however, and a rigorous study of the impact of ketosis on seizures in mitochondrial disease is lacking. Conversely, preclinical efforts have identified the intracellular nutrient signaling regulator mTOR as a promising therapeutic target, with data suggesting the benefits are mediated by metabolic changes. mTOR inhibition alleviates epilepsies arising from defects in TSC, an mTOR regulator, but the therapeutic potential of mTOR inhibition in seizures related to primary mitochondrial dysfunction is unknown. Given that ketogenic diet is used clinically in the setting of mitochondrial disease, and mTOR inhibition is in clinical trials for intractable pediatric epilepsies of diverse causal origins, a direct experimental assessment of their effects is imperative. Here, we define the impact of dietary ketosis on survival and CNS disease in the Ndufs4(KO) mouse model of Leigh syndrome and the therapeutic potential of both dietary ketosis and mTOR inhibition on seizures in this model. These data provide timely insight into two important clinical interventions.

Topics: Animals; Diet, Ketogenic; Disease Models, Animal; Electron Transport Complex I; Leigh Disease; Mice; Mice, Knockout; Sirolimus; TOR Serine-Threonine Kinases; Treatment Outcome

Mice missing the Complex I subunit NADH:Ubiquinone Oxidoreductase Fe-S Protein 4 (NDUFS4) of the electron transport chain are a leading model of the severe mitochondrial disease Leigh syndrome. These mice have enabled a better understanding of mitochondrial dysfunction in human disease, as well as in the discovery of interventions that can potentially suppress mitochondrial disease manifestations. In addition, increasing evidence suggests significant overlap between interventions that increase survival in NDUFS4 knockout mice and that extend life span during normative aging. This chapter discusses the practical aspects of handling and studying these mice, which can be challenging due to their severe disease phenotype. Common procedures such as breeding, genotyping, weaning, or treating these transgenic mice are also discussed.

Topics: Aging; Animal Feed; Animals; Electron Transport Complex I; Female; Genotyping Techniques; Humans; Leigh Disease; Male; Mice, Knockout; Mitochondrial Diseases; Sirolimus

Leigh syndrome is a fatal neurometabolic disorder caused by defects in mitochondrial function. Mechanistic target of rapamycin (mTOR) inhibition with rapamycin attenuates disease progression in a mouse model of Leigh syndrome (Ndufs4 knock-out (KO) mouse); however, the mechanism of rescue is unknown. Here we identify protein kinase C (PKC) downregulation as a key event mediating the beneficial effects of rapamycin treatment of Ndufs4 KO mice. Assessing the impact of rapamycin on the brain proteome and phosphoproteome of Ndufs4 KO mice, we find that rapamycin restores mitochondrial protein levels, inhibits signalling through both mTOR complexes and reduces the abundance and activity of multiple PKC isoforms. Administration of PKC inhibitors increases survival, delays neurological deficits, prevents hair loss and decreases inflammation in Ndufs4 KO mice. Thus, PKC may be a viable therapeutic target for treating severe mitochondrial disease.

Topics: Animals; Brain Chemistry; Down-Regulation; Electron Transport Complex I; Leigh Disease; Mice; Mice, Inbred C57BL; Mice, Knockout; Mitochondrial Diseases; Protein Kinase C; Protein Kinase Inhibitors; Proteome; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases

Topics: Animals; Leigh Disease; Mitochondrial Diseases; Molecular Targeted Therapy; Multiprotein Complexes; Neuroprotective Agents; Sirolimus; TOR Serine-Threonine Kinases

Topics: Animals; Caloric Restriction; Disease Models, Animal; Dose-Response Relationship, Drug; Electron Transport Complex I; Humans; Leigh Disease; Mice; Molecular Targeted Therapy; Saccharomyces cerevisiae; Sirolimus; TOR Serine-Threonine Kinases

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.

Topics: Animals; Brain; Disease Models, Animal; Electron Transport Complex I; Glycolysis; Leigh Disease; Mechanistic Target of Rapamycin Complex 1; Mice; Mice, Knockout; Mice, Mutant Strains; Mitochondria; Mitochondrial Diseases; Molecular Targeted Therapy; Multiprotein Complexes; Neuroprotective Agents; Sirolimus; TOR Serine-Threonine Kinases

Topics: Animals; Leigh Disease; Mechanistic Target of Rapamycin Complex 1; Mitochondrial Diseases; Molecular Targeted Therapy; Multiprotein Complexes; Neuroprotective Agents; Sirolimus; TOR Serine-Threonine Kinases