Phytanic Acid Toxicity: Implications for the Permeability of the Inner Mitochondrial Membrane to Ions

Abstract

Phytanic acid (3,7,11,15-tetramethylhexadecanoic acid), a degradation product of chlorophyll formed in the intestinal tracts of ruminants, is a constituent of milk products and meat. Because it is a branched-chain fatty acid, degradation of phytanic acid is initiated in mammalian peroxisomes. In certain peroxisomal disorders such as in Refsum disease, phytanic acid accumulates dramatically throughout the body to levels that are believed to be associated with neurological and cardiac abnormalities. Here it is shown that nonesterified phytanic acid alters the permeability of the inner mitochondrial membrane by (1) increasing the conductance to hydrogen H+; (2) promoting opening of the permeability transition pore; and (3) initiating the release of endogenous Mg++. But contrary to nonesterified long-chain fatty acids, phytanic acid only slightly stimulates the conductance of the inner membrane to K+ and Cl−. These results suggest that pathologically high tissue levels of nonesterified phytanic acid increase the permeability of the inner membrane by ions through activities that are harmful for the synthesis of mitochondrial adenosine 5′-triphosphate as well as for mitochondrial integrity.