Inhibition of mitochondrial respiration by furancarboxylic acid accumulated in uremic serum in its albumin-bound and non-dialyzable form.

3-carboxy-4-methyl-5-propyl-2-furanpropionic acid (CMPF) accumulates markedly in uremic serum in its albumin-bound form. To determine if CMPF can be removed by newly developed dialyzers with high-flux membranes which are permeable to low-molecular-weight proteins, such as beta 2-microglobulin (beta 2-MG), serum levels of CMPF were determined before and after hemodialysis using these high-flux membrane dialyzers. In addition, to determine the pathogenic role of CMPF in uremic patients, its cellular toxicity due to its effect on mitochondrial respiration was studied. The reduction rates of CMPF by hemodialysis using the dialyzers ranged from -17% to -24%, demonstrating the nondialyzability of CMPF due to its strong albumin-binding, while those of beta 2-MG ranged from 11% to 43%. CMPF inhibited ADP-stimulated oxidation of NADH-linked substrates in isolated mitochondria dose-dependently regardless of the presence of serum albumin. This inhibition was observed even at a concentration of 0.2 mM, which is comparable to the serum levels of CMPF in the hemodialysis patients. In conclusion CMPF which cannot be removed even by high-flux membrane dialyzers, is a strong inhibitor of mitochondrial respiration, and novel purification methods to remove CMPF from the blood of uremic patients should be developed.