Differential effects of mTOR inhibition and dietary ketosis in a mouse model of subacute necrotizing encephalomyelopathy

• Published in: Neurobiology of disease 2022-02, Vol.163, p.105594-105594, Article 105594
• Main Authors: Bornstein, Rebecca, James, Katerina, Stokes, Julia, Park, Kyung Yeon, Kayser, Ernst-Bernhard, Snell, John, Bard, Angela, Chen, Yihan, Kalume, Franck, Johnson, Simon C.
• Format: Article
• Language: English
• Subjects: Animals; Diet, Ketogenic; Disease Models, Animal; Electron Transport Complex I - genetics; Epilepsy; Ketogenic diet; Ketosis; Leigh Disease - diet therapy; Leigh Disease - drug therapy; Leigh Disease - genetics; Leigh Disease - therapy; Mice; Mice, Knockout; Mitochondrial disease; mTOR; Seizure; Sirolimus - pharmacology; Sirolimus - therapeutic use; TOR Serine-Threonine Kinases - antagonists & inhibitors; Treatment Outcome
• ISSN: 0969-9961; 1095-953X
• DOI: 10.1016/j.nbd.2021.105594

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. •Spontaneous interictal spikes and exercise-induced seizures occur in the Ndufs4(KO) model of mitochondrial disease•Dietary ketosis and mTOR inhibition both attenuate exercise induced seizures in the Ndufs4(KO) model•Dietary ketosis fails to impact CNS degeneration or disease progression in the Ndufs4(KO)•mTOR inhibition and ketosis both lower blood glucose, but mTOR inhibition does not induce ketosis•Dietary ketosis does not reduce mTOR signaling in mouse cortex