Phytanic acid and pristanic acid are oxidized by sequential peroxisomal and mitochondrial reactions in cultured fibroblasts

Nanda M Verhoeven,Diane S Roe,Robert M Kok,Ronald J.A Wanders,Cornelis Jakobs,Charles R Roe

doi:10.1016/s0022-2275(20)34204-8

Nanda M Verhoeven, Diane S Roe + Show 4 more

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https://doi.org/10.1016/s0022-2275(20)34204-8

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Abstract

The relationship between peroxisomal and mitochondrial oxidation of the methyl branched fatty acids, phytanic acid and pristanic acid, was studied in normal and mutant human skin fibroblasts with established enzyme deficiencies. Tandem mass spectrometry was used for analysis of the acylcarnitine intermediates. In normal cells, 4,8-dimethylnonanoylcarnitine (C11:0) and 2,6-dimethylheptanoylcarnitine (C9:0) accumulated after incubation with either phytanic acid or pristanic acid. These intermediates were not observed when peroxisome-deficient cells from Zellweger patients were incubated with the same compounds, pointing to the involvement of peroxisomes in the formation of these acylcarnitine intermediates. Similar experiments with fibroblasts deficient in carnitine palmitoyltransferase I, carnitine-acylcarnitine translocase or carnitine palmitoyltransferase II revealed that mitochondrial carnitine palmitoyltransferase I is not required for the oxidation of phytanic acid or pristanic acid, whereas both carnitine-acylcarnitine translocase and carnitine palmitoyltransferase II are necessary. These studies demonstrate that both phytanic acid and pristanic acid are initially oxidized in peroxisomes to 4,8-dimethylnonanoyl-CoA, which is converted to the corresponding acylcarnitine (presumably by peroxisomal carnitine octanoyltransferase), and exported to the mitochondrion. After transport across the mitochondrial membrane and transfer of the acylgroup to coenzyme A, further oxidation to 2,6-dimethylheptanoyl-CoA occurs.—Verhoeven, N. M., D. S. Roe, R. M. Kok, R. J. A. Wanders, C. Jakobs, and C. R. Roe. Phytanic acid and pristanic acid are oxidized by sequential peroxisomal and mitochondrial reactions in cultured fibroblasts. J. Lipid Res. 1998. 39: 66–74.

Highlights

The relationship between peroxisomal and mitochondrial oxidation of the methyl branched fatty acids, phytanic acid and pristanic acid, was studied in normal and mutant human skin fibroblasts with established enzyme deficiencies
Medium, and long chain fatty acids are mainly degraded in mitochondria while oxidation of fatty acids of greater chain length (Ͼ20 carbons) or methyl branched fatty acids, such as phytanic acid and pristanic acid, occurs in peroxisomes [5, 7, 8]
Phytanic acid is activated to phytanoyl-CoA by phytanoyl-CoA synthetase in the peroxisomal outer membrane [20, 21]

Summary

Introduction

The relationship between peroxisomal and mitochondrial oxidation of the methyl branched fatty acids, phytanic acid and pristanic acid, was studied in normal and mutant human skin fibroblasts with established enzyme deficiencies. Cell lines obtained from patients with established deficiencies of either CPT I, CPT II, or carnitine-acylcarnitine translocase were studied to explore the involvement of these mitochondrial enzymes in the ␣-oxidation of phytanic acid and subsequent ␤-oxidation of pristanic acid.

Results

Conclusion