title: The ketogenic diet component decanoic acid increases mitochondrial citrate synthase and complex I activity in neuronal cells.
abstract: The Ketogenic diet (KD) is an effective treatment with regards to treating pharmaco-resistant epilepsy. However, there are difficulties around compliance and tolerability. Consequently, there is a need for refined/simpler formulations that could replicate the efficacy of the KD. One of the proposed hypotheses is that the KD increases cellular mitochondrial content which results in elevation of the seizure threshold. Here, we have focussed on the medium-chain triglyceride form of the diet and the observation that plasma octanoic acid (C8) and decanoic acid (C10) levels are elevated in patients on the medium-chain triglyceride KD. Using a neuronal cell line (SH-SY5Y), we demonstrated that 250-μM C10, but not C8, caused, over a 6-day period, a marked increase in the mitochondrial enzyme, citrate synthase along with complex I activity and catalase activity. Increased mitochondrial number was also indicated by electron microscopy. C10 is a reported peroxisome proliferator activator receptor γ agonist, and the use of a peroxisome proliferator activator receptor γ antagonist was shown to prevent the C10-mediated increase in mitochondrial content and catalase. C10 may mimic the mitochondrial proliferation associated with the KD and raises the possibility that formulations based on this fatty acid could replace a more complex diet. We propose that decanoic acid (C10) results in increased mitochondrial number. Our data suggest that this may occur via the activation of the PPARγ receptor and its target genes involved in mitochondrial biogenesis. This finding could be of significant benefit to epilepsy patients who are currently on a strict ketogenic diet. Evidence that C10 on its own can modulate mitochondrial number raises the possibility that a simplified and less stringent C10-based diet could be developed.
authors.affiliation: Clinical and Molecular Genetics Unit, UCL Institute of Child Health, London, UK; Chemical Pathology, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK.
authors.forename: Sean David
authors.initials: SD
authors.lastname: Hughes
authors.forename: Marta
authors.initials: M
authors.lastname: Kanabus
authors.forename: Glenn
authors.initials: G
authors.lastname: Anderson
authors.forename: Iain P
authors.initials: IP
authors.lastname: Hargreaves
authors.forename: Tricia
authors.initials: T
authors.lastname: Rutherford
authors.forename: Maura
authors.initials: M
authors.lastname: O'Donnell
authors.forename: J Helen
authors.initials: JH
authors.lastname: Cross
authors.forename: Shamima
authors.initials: S
authors.lastname: Rahman
authors.forename: Simon
authors.initials: S
authors.lastname: Eaton
authors.forename: Simon J R
authors.initials: SJ
authors.lastname: Heales
mesh_terms: D002460:Cell Line; D002950:Citrate (si)-Synthase / Q000378:metabolism*; D003652:Decanoic Acids / Q000494:pharmacology*; D055423:Diet, Ketogenic; D042967:Electron Transport Complex I / Q000378:metabolism; D004789:Enzyme Activation; D006801:Humans; D008928:Mitochondria / Q000187:drug effects* / Q000201:enzymology*; D009474:Neurons / Q000187:drug effects* / Q000201:enzymology
chemical_list: D003652:Decanoic Acids; C031071:decanoic acid; D002950:Citrate (si)-Synthase; D042967:Electron Transport Complex I
keywords: PPAR; decanoic acid; ketogenic diet; mitochondria