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The methyl group in \u03b2\u2010position prevents degradation of phytanic acid by the \u03b2\u2010oxidation pathway. Therefore, degradation of phytanic acid is initiated by \u03b1\u2010oxidation in peroxisomes. The inherited peroxisomal disorder Refsum disease is characterised by accumulation of phytanic acid. Unusually high concentrations of phytanic acid can be found in the plasma of Refsum disease patients, who suffer from neurodegeneration and muscle dystrophy. Phytanic acid has been suggested to be causally involved in the clinical symptoms. To elucidate the pathogenic mechanism, we investigated the influence of phytanic acid in rat hippocampal astrocytes by monitoring the cytosolic Ca<jats:sup>2+<\/jats:sup> concentration, the mitochondrial membrane potential (\u0394<jats:italic>\u03c8<\/jats:italic><jats:sub>m<\/jats:sub>), the generation of reactive oxygen species as well as the cellular ATP level. In response to phytanic acid (100 \u03bcM) cytosolic Ca<jats:sup>2+<\/jats:sup> was quickly increased. The phytanic acid\u2010evoked Ca<jats:sup>2+<\/jats:sup> response was transient and involved activation of intracellular Ca<jats:sup>2+<\/jats:sup> stores. In isolated rat brain mitochondria, phytanic acid dissipated \u0394<jats:italic>\u03c8<\/jats:italic><jats:sub>m<\/jats:sub> in a reversible and dose\u2010dependent manner. Moreover, phytanic acid released cytochrome <jats:italic>c<\/jats:italic> from mitochondria. Depending on the mitochondrial activity state, phytanic acid either stimulated or inhibited the electron flux within the respiratory chain. In addition, phytanic acid induced substantial generation of reactive oxygen species in isolated mitochondria as well as in intact cells. Phytanic acid caused cell death of astrocytes within a few hours of exposure. In conclusion, we suggest that phytanic acid initiates astrocyte cell death by activating the mitochondrial route of apoptosis.<\/jats:p><\/jats:sec>","DOI":"10.1016\/j.ijdevneu.2005.11.002","type":"journal-article","created":{"date-parts":[[2006,1,19]],"date-time":"2006-01-19T19:06:46Z","timestamp":1137697606000},"page":"113-122","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":52,"title":["Mechanism of toxicity of the branched\u2010chain fatty acid phytanic acid, a marker of Refsum disease, in astrocytes involves mitochondrial impairment"],"prefix":"10.1002","volume":"24","author":[{"given":"Georg","family":"Reiser","sequence":"first","affiliation":[{"name":"Institut f\u00fcr Neurobiochemie Otto\u2010von\u2010Guericke\u2010Universit\u00e4t Magdeburg Leipziger Str. 44 D\u201039120 Magdeburg 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