The ATP-sensitive K channel is seizure protective and required for effective dietary therapy in a model of mitochondrial encephalomyopathy

Abstract

Effective therapies are lacking for mitochondrial encephalomyopathies (MEs). MEs are devastating diseases that predominantly affect the energy-demanding tissues of the nervous system and muscle, causing symptoms such as seizures, cardiomyopathy, and neuro- and muscular degeneration. Even common anti-epileptic drugs which are frequently successful in ameliorating seizures in other diseases tend to have a lower success rate in ME, highlighting the need for novel drug targets, especially those that may couple metabolic sensitivity to neuronal excitability. Furthermore, alternative epilepsy therapies such as dietary modification are gaining in clinical popularity but have not been thoroughly studied in ME. Using the Drosophila ATP6¹ model of ME, we have studied dietary therapy throughout disease progression and found that it is highly effective against the seizures of ME, especially a high fat/ketogenic diet, and that the benefits are dependent upon a functional K_ATP channel complex. Further experiments with K_ATP show that it is seizure-protective in this model, and that pharmacological promotion of its open state also ameliorates seizures. These studies represent important steps forward in the development of novel therapies for a class of diseases that is notoriously difficult to treat, and lay the foundation for mechanistic studies of currently existing therapies in the context of metabolic disease.

Keywords:

• ATP6
• Drosophila
• mitochondria
• seizure

Acknowledgements

The authors thank Dr. Edwin Levitan and Dr. Kristal Tucker for shared equipment, helpful discussion, and technical advice; Kristin Morder, Maria Lebedev, Aaron Crain, and Kim Stuchul for technical support; Dr. Patrick O’Farrell and Dr. Hansong Ma for the ATP6^1R mitochondrial recombinant line: and Dr. Todd Holmes for the CRYGAL4-UAS-NC1 recombinant line.

Disclosure statement

The authors declare no conflicts of interest.