biostudies-literatureLlorente-Folch IScience Foundation Ireland19664https://www.ebi.ac.uk/biostudies/studies/S-EPMC10640643biostudies-literatureUnknown13(1)The ketogenic diet is an emerging therapeutic approach for refractory epilepsy, as well as certain rare and neurodegenerative disorders. The main ketone body, β-hydroxybutyrate (BHB), is the primary energy substrate endogenously produced in a ketogenic diet, however, mechanisms of its therapeutic actions remain unknown. Here, we studied the effects of BHB on mitochondrial energetics, both in non-stimulated conditions and during glutamate-mediated hyperexcitation. We found that glutamate-induced hyperexcitation stimulated mitochondrial respiration in cultured cortical neurons, and that this response was greater in cultures supplemented with BHB than with glucose. BHB enabled a stronger and more sustained maximal uncoupled respiration, indicating that BHB enables neurons to respond more effiScientific reportsKetone body β-hydroxybutyrate (BHB) preserves mitochondrial bioenergetics.PMC1064064308/IN.1/B194914/JPND/B3077Llorente-Folch IWatters ODussmann HPrehn JHMConnolly NMCfalseKetone body β-hydroxybutyrate (BHB) preserves mitochondrial bioenergetics.The ketogenic diet is an emerging therapeutic approach for refractory epilepsy, as well as certain rare and neurodegenerative disorders. The main ketone body, β-hydroxybutyrate (BHB), is the primary energy substrate endogenously produced in a ketogenic diet, however, mechanisms of its therapeutic actions remain unknown. Here, we studied the effects of BHB on mitochondrial energetics, both in non-stimulated conditions and during glutamate-mediated hyperexcitation. We found that glutamate-induced hyperexcitation stimulated mitochondrial respiration in cultured cortical neurons, and that this response was greater in cultures supplemented with BHB than with glucose. BHB enabled a stronger and more sustained maximal uncoupled respiration, indicating that BHB enables neurons to respond more effi2023-01-01T00:00:00Z2023 Nov2025-04-21T15:57:27.814Z2025-04-21T15:57:27.814ZS-EPMC106406433795204810.1038/s41598-023-46776-8