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-lM 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 c agonist, and the use of a peroxisome proliferator activator receptor c 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.

Neuronal decanoic acid oxidation is markedly lower than that of octanoic acid: A mechanistic insight into the medium‐chain triglyceride ketogenic diet

“…Thus C10, and not C8, has previously been reported by us to elicit PPARγ-dependent increases in neuronal mitochondrial content, complex I and catalase activity 5 . These findings, coupled with the direct inhibitory effect of C10 on AMPA receptors 6 , provide mechanistic evidence whereby C10 could elicit seizure control.…”

“…In studies conducted by Wlaź et al, C10 levels were also determined in the brains of mice following C10-enriched feeding. Interestingly, the concentration of C10 in mouse brain was found to average at 240-250μM, corresponding with therapeutic levels 4 reported in patient plasma on the MCT KD, as well as the optimum concentration (250µM) for mitochondrial proliferation in our previous studies 5,12 .…”

“…Cells were treated with 3mM 13 C-labelled glucose, in order to replicate physiological levels observed in patients under the MCT KD. 13 C-labelled C10 and C8 were added separately to a final concentration of 250µM, this being the concentration of C10, previously determined by us 5 , for optimum effects upon mitochondria and antioxidant status.…”

“…To address this question, we here assessed the rates of β-oxidation of C8 and C10 in the human SH-SY5Y neuroblastoma cell line, i.e. following on from our previous work 5 . A well-characterised cell line, SH-SY5Y cells exhibit a range of neuron-like properties, providing a suitable model for this study.…”

Food science: Fat chance

“…One example is decanoic acid 8 . Simon Heales, a clinical chemist at University College London, showed that decanoic acid increases mitochondrial numbers in brain cells 9 . The mitochondria produce ATP, which helps transmit signals along the neurons, and its increased production could provide better control of potassium channels related to the seizure gates that Yellen mentions.…”