FATTY-ACIDS AS NATURAL UNCOUPLERS PREVENTING GENERATION OF O-2(CENTER-DOT-) AND H2O2 BY MITOCHONDRIA IN THE RESTING STATE

Both natural (laurate) and artificial (m-chlorocarbonylcyanide phenylh ydrazone; CCCP) uncouplers strongly inhibit O-2(.-) and H2O2 formation by rat heart mitochondria oxidizing succinate, Carboxyatractylate, an ATP/ADP antiporter inhibitor, abolishes the laurate inhibition, the C CCP inhibition being unaffected. Atractylate partially releases the in hibition by laurate and decelerates the releasing effect of carboxyatr actylate. GDP is much less effective than carboxyatractylate in releas ing the laurate inhibition of reactive oxygen species (ROS) formation. Micromolar laurate concentrations arresting the ROS formation cause s trong inhibition of reverse electron transfer from succinate to NAD(+) , whereas State 4 respiration and the transmembrane electric potential difference (Delta Psi) level are affected only slightly, It is sugges ted that (i) free fatty acids operate as natural 'mild uncouplers' pre venting the transmembrane electrochemical H+ potential difference (Del ta<(mu)over bar>(H+)) from being above a threshold critical for ROS fo rmation by complex 1 and, to a lesser degree, by complex m of the resp iratory chain, and (ii) it is the ATP/ADP-antiporter, rather than unco upling protein 2, that is mainly involved in this antioxidant mechanis m of heart muscle mitochondria, (C) 1998 Federation of European Bioche mical Societies.