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

Bornstein, Rebecca, James, Katerina, Stokes, Julia, Park, Kyung Yeon, Kayser, Ernst-Bernhard, Snell, John, Bard, Angela, Chen, Yihan, Kalume, Franck and Johnson, Simon (2022) Differential effects of mTOR inhibition and dietary ketosis in a mouse model of subacute necrotizing encephalomyelopathy. Neurobiology of Disease, 163. p. 105594. ISSN 0969-9961

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Official URL: https://doi.org/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.

Item Type: Article
Additional Information: Funding Information: This work was funded by an NIH/GM R00 126147 , an NIH/NS R01 102796 , and seed funds provided by the Northwest Mitochondrial Research Guild.
Uncontrolled Keywords: Epilepsy, Ketogenic diet, Ketosis, Mitochondrial disease, Seizure, mTOR
Subjects: A300 Clinical Medicine
C400 Genetics
C700 Molecular Biology, Biophysics and Biochemistry
Depositing User: Rachel Branson
Date Deposited: 07 Dec 2022 09:30
Last Modified: 07 Dec 2022 09:45
URI: https://nrl.northumbria.ac.uk/id/eprint/50821

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