Phytanic acid (3,7,11,15-tetramethylhexadecanoic acid) accumulates at high levels throughout the body in the adult form of
Refsum disease, a peroxisomal
genetic disorder. However, it is still unclear why increased levels of
phytanic acid have cytotoxic effects. In the present study, we examined the influence of non-esterified
phytanic acid on energy-related functions of mitochondria from adult rat brain.
Phytanic acid at low concentrations (5-20 microM, i.e. 5-20 nmol/mg of
mitochondrial protein) de-energized mitochondria, as indicated by depolarization, stimulation of non-phosphorylating
oxygen uptake and inhibition of the reduction of the tetrazolium
dye 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium
bromide. The unbranched homologue
palmitic acid exerted much smaller effects. In addition,
phytanic acid reduced state 3 respiration, which was partly due to inhibition of the
ADP/ATP carrier.
Phytanic acid decreased the rate of
adenine nucleotide exchange and increased the degree of control, which the
ADP/ATP carrier has on state 3 respiration. Important for functional consequences is the finding that mitochondria, which are preloaded with small amounts of Ca2+ (100 nmol/mg of
protein), became highly sensitized to rapid permeability transition even when only low concentrations of
phytanic acid (below 5 microM) were applied. In conclusion, the incorporation of
phytanic acid into the inner mitochondrial membrane increases the membrane H+ conductance and disturbs the
protein-linked functions in energy coupling. This is most probably essential for the short-term toxicity of
phytanic acid. Thus in neural tissue, which becomes enriched with
phytanic acid, the reduction in mitochondrial
ATP supply and the facilitation of the opening of the permeability transition pore are two major mechanisms by which the branched-chain
fatty acid phytanic acid induces the onset of degenerative processes.