title: Phytanic acid impairs mitochondrial respiration through protonophoric action.
abstract: Refsum disease is a rare, inherited neurodegenerative disorder characterized by accumulation of the dietary branched-chain fatty acid phytanic acid in plasma and tissues caused by a defect in the alphaoxidation pathway. The accumulation of phytanic acid is believed to be the main pathophysiological cause of the disease. However, the exact mechanism(s) by which phytanic acid exerts its toxicity have not been resolved. In this study, the effect of phytanic acid on mitochondrial respiration was investigated. The results show that in digitonin-permeabilized fibroblasts, phytanic acid decreases ATP synthesis, whereas substrate oxidation per se is not affected. Importantly, studies in intact fibroblasts revealed that phytanic acid decreases both the mitochondrial membrane potential and NAD(P)H autofluorescence. Taken together, the results described here show that unesterified phytanic acid exerts its toxic effect mainly through its protonophoric action, at least in human skin fibroblasts.
authors.affiliation: Laboratory Genetic Metabolic Diseases, Department of Clinical Chemistry, Emma Children's Hospital, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands. j.c.komen@amc.uva.nl
authors.forename: J C
authors.initials: JC
authors.lastname: Komen
authors.forename: F
authors.initials: F
authors.lastname: Distelmaier
authors.forename: W J H
authors.initials: WJ
authors.lastname: Koopman
authors.forename: R J A
authors.initials: RJ
authors.lastname: Wanders
authors.forename: J
authors.initials: J
authors.lastname: Smeitink
authors.forename: P H M G
authors.initials: PH
authors.lastname: Willems
mesh_terms: D019297:2,4-Dinitrophenol / Q000494:pharmacology; D000255:Adenosine Triphosphate / Q000096:biosynthesis; D019069:Cell Respiration / Q000187:drug effects; D002478:Cells, Cultured; D042963:Electron Transport Complex II / Q000187:drug effects / Q000378:metabolism; D005453:Fluorescence; D006801:Humans; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism* / Q000648:ultrastructure; D009249:NADP / Q000737:chemistry; D010831:Phytanic Acid / Q000494:pharmacology*; D011522:Protons; D012402:Rotenone / Q000494:pharmacology; D014475:Uncoupling Agents / Q000494:pharmacology
chemical_list: D011522:Protons; D014475:Uncoupling Agents; D012402:Rotenone; D010831:Phytanic Acid; D009249:NADP; D000255:Adenosine Triphosphate; D042963:Electron Transport Complex II; D019297:2,4-Dinitrophenol