PHYTANIC ACID AND PRISTANIC ACID ARE OXIDIZED BY SEQUENTIAL PEROXISOMAL AND MITOCHONDRIAL REACTIONS IN CULTURED FIBROBLASTS

The relationship between peroxisomal and mitochondrial oxidation of th e methyl branched fatty acids, phytanic acid and pristanic acid, was s tudied in normal and mutant human skin fibroblasts with established en zyme;me deficiencies. Tandem mass spectrometry: was used for analysis of the acylcarnitine intermediates. In normal cells, 4,8-dimethylnonan oylcarnitine (Cll:0) and 2,6-dimethylheptanoylcarnitine (C9:0) accumul ated after incubation with either phytanic acid or pristanic acid. The se intermediates were not observed when peroxisome-deficient cells fro m Zellweger patients were incubated with the same compounds, pointing to the involvement of peroxisomes in the formation of these acylcarnit ine intermediates. Similar experiments with fibroblasts deficient in c arnitine palmitoyltransferase I, carnitine-acylcarnitine translocase o r carnitine palmitoyltransferase II revealed that mitochondrial carnit ine palmitoyltransferase I is not required for the oxidation of phytan ic acid or pristanic acid, whereas both carnitine-acylcarnitine transl ocase and carnitine palmitoyltransferase II are necessary. These studi es demonstrate that both phytanic acid and pristanic acid are initiall y oxidized in peroxisomes to 4,8-dimethylnonanoyl-CoA, which is conver ted to the corresponding acylcarnitine (presumably by peroxisomal carn itine octanoyltransferase!, and exported to the mitochondrion. After t ransport across the mitochondrial membrane and transfer of the acylgro up to coenzyme A, further oxidation to 2,6-dimethylheptanoyl-CoA) occu rs.