A study of the cytotoxicity of branched-chain phytanic acid with mitochondria and rat brain astrocytes.

Phytanic acid, a saturated fatty acid of 20-carbon-atoms with isoprenoic structure, is formed from the phytol-side chain of chlorophyll in ruminants. Degradation of phytanic acid is blocked in Refsum disease by several enzymatic defects of peroxisomal degradation of branched-chain fatty acids. Refsum disease is an inherited neurological disorder progressively developing from early childhood to adultness. Clinical signs are attributed to toxicity of phytanic acid, which accumulates to unusually high levels in the tissue and serum of patients suffering from untreated Refsum disease. We report here that hippocampal astrocytes isolated from rat brain, which were exposed to phytanic acid (50 microM) die within a few hours. In situ depolarization of mitochondria and an increase of cytosolic Ca2+ precede cell death. Therefore, we also investigated the influence of phytanic acid on physiology of mitochondria isolated from rat brain. Mitochondria become functionally impaired by phytanic acid, as indicated by uncoupling (resting state), inhibition of the electron transport (state 3), stimulation of ROS-generation, decline of Ca2+ loading and severe release of cytochrome c. Thus, phytanic acid seems to initiate astrocyte cell death by activating the mitochondrial route of apoptosis.