There is growing interest in the use of the
ketogenic diet (KD) to treat inherited
metabolic diseases including
mitochondrial disorders. However, neither the mechanism whereby the diet may be working, nor if it could benefit all patients with
mitochondrial disease, is known. This study focusses on
decanoic acid (C10), a component of the medium chain
triglyceride KD, and a
ligand for the
nuclear receptor PPAR-γ known to be involved in mitochondrial biogenesis. The effects of C10 were investigated in primary fibroblasts from a cohort of patients with
Leigh syndrome (LS) caused by nuclear-encoded defects of respiratory chain complex I, using mitochondrial respiratory chain
enzyme assays, gene expression microarray, qPCR and flow cytometry. Treatment with C10 increased
citrate synthase activity, a marker of cellular mitochondrial content, in 50 % of fibroblasts obtained from individuals diagnosed with LS in a
PPAR-γ-mediated manner. Gene expression analysis and qPCR studies suggested that treating cells with C10 supports
fatty acid metabolism, through increasing
ACADVL and CPT1 expression, whilst downregulating genes involved in
glucose metabolism (PDK3, PDK4). PCK2, involved in blocking
glucose metabolism, was upregulated, as was CAT, encoding
catalase. Moreover, treatment with C10 also decreased oxidative stress in complex I deficient (
rotenone treated) cells. However, since not all cells from subjects with LS appeared to respond to C10, prior cellular testing in vitro could be employed as a means for selecting individuals for subsequent clinical studies involving C10 preparations.