title: The pleiotropic effects of decanoic acid treatment on mitochondrial function in fibroblasts from patients with complex I deficient Leigh syndrome.
abstract: 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.
authors.affiliation: Genetics and Genomic Medicine, UCL Institute of Child Health, 30 Guilford Street, London, WC1N 1EH, UK.
authors.forename: Marta
authors.initials: M
authors.lastname: Kanabus
authors.affiliation: Genetics and Genomic Medicine, UCL Institute of Child Health, 30 Guilford Street, London, WC1N 1EH, UK.
authors.forename: Elisa
authors.initials: E
authors.lastname: Fassone
authors.affiliation: Genetics and Genomic Medicine, UCL Institute of Child Health, 30 Guilford Street, London, WC1N 1EH, UK.|Chemical Pathology, Great Ormond Street Hospital for Children NHS Foundation Trust, London, WC1N 3JH, UK.
authors.forename: Sean David
authors.initials: SD
authors.lastname: Hughes
authors.affiliation: Genetics and Genomic Medicine, UCL Institute of Child Health, 30 Guilford Street, London, WC1N 1EH, UK.
authors.forename: Sara Farahi
authors.initials: SF
authors.lastname: Bilooei
authors.affiliation: Vitaflo International, Liverpool, UK.
authors.forename: Tricia
authors.initials: T
authors.lastname: Rutherford
authors.affiliation: Vitaflo International, Liverpool, UK.
authors.forename: Maura O'
authors.initials: MO
authors.lastname: Donnell
authors.affiliation: Genetics and Genomic Medicine, UCL Institute of Child Health, 30 Guilford Street, London, WC1N 1EH, UK.|Chemical Pathology, Great Ormond Street Hospital for Children NHS Foundation Trust, London, WC1N 3JH, UK.|Neurometabolic Unit, National Hospital for Neurology and Neurosurgery, London, WC1N 3BG, UK.
authors.forename: Simon J R
authors.initials: SJR
authors.lastname: Heales
authors.affiliation: Genetics and Genomic Medicine, UCL Institute of Child Health, 30 Guilford Street, London, WC1N 1EH, UK. shamima.rahman@ucl.ac.uk.|Metabolic Department, Great Ormond Street Hospital Foundation Trust, London, WC1N 3JH, UK. shamima.rahman@ucl.ac.uk.
authors.forename: Shamima
authors.initials: S
authors.lastname: Rahman
mesh_terms: D002478:Cells, Cultured; D003652:Decanoic Acids / Q000494:pharmacology*; D055423:Diet, Ketogenic / Q000379:methods; D042967:Electron Transport Complex I / Q000378:metabolism*; D005227:Fatty Acids / Q000378:metabolism; D005347:Fibroblasts / Q000187:drug effects* / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D005947:Glucose / Q000378:metabolism; D006801:Humans; D007888:Leigh Disease / Q000188:drug therapy* / Q000378:metabolism; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D028361:Mitochondrial Diseases / Q000188:drug therapy* / Q000378:metabolism
chemical_list: D003652:Decanoic Acids; D005227:Fatty Acids; D042967:Electron Transport Complex I; D005947:Glucose