Brain pyruvate and 2-oxoglutarate dehydrogenase complexes are mitochondrial targets of the CoA ester of the Refsum disease marker phytanic acid

• Published in: FEBS letters 2006-06, Vol.580 (14), p.3551-3557
• Main Authors: Bunik, Victoria I., Raddatz, Günter, Wanders, Ronald J.A., Reiser, Georg
• Format: Article
• Language: English
• Subjects: 2-Oxo acid dehydrogenase complex; 2-oxoglutarate dehydrogenase; 2-oxoglutarate dehydrogenase complex; Animals; Biomarkers - metabolism; Brain - enzymology; Brain - metabolism; Coenzyme A - chemistry; Coenzyme A - metabolism; dihydrolipoamide acetyltransferase; dihydrolipoamide dehydrogenase; dihydrolipoamide succinyltransferase; E1o; E1p; E2o; E2p; Female; Ketoglutarate Dehydrogenase Complex - metabolism; Long chain acyl-CoA; Models, Molecular; Neurodegeneration; OGDHC; PDHC; Peroxisomal inherited disorder; Phytanic acid; Phytanic Acid - analogs & derivatives; Phytanic Acid - chemistry; Phytanic Acid - metabolism; pyruvate dehydrogenase; pyruvate dehydrogenase complex; Pyruvic Acid - metabolism; Rats; reactive oxygen species; Refsum Disease - enzymology; Refsum Disease - metabolism; ROS; ThDP; Thiamine; thiamine diphosphate
• ISSN: 0014-5793; 1873-3468
• DOI: 10.1016/j.febslet.2006.05.040

Pyruvate and 2-oxoglutarate dehydrogenase complexes are strongly inhibited by phytanoyl-CoA (IC 50 ≈ 10 −6–10 −7 M). Palmitoyl-CoA is 10-fold less potent. Phytanic or palmitic acids have no inhibitory effect up to 0.3 mM. At the substrate saturation, the acyl-CoA’s affect the first and second enzymatic components of the 2-oxoglutarate dehydrogenase complex, while the third component is inhibited only at a low saturation with its substrate dihydrolipoamide. Thus, key regulatory branch points of mitochondrial metabolism are targets of a cellular derivative of phytanic acid. Decreased activity of the complexes might therefore contribute to neurological symptoms upon accumulation of phytanic acid in Refsum disease.