ON THE REGULATION OF CELLULAR ENERGETICS IN HEALTH AND DISEASE

Very recent experimental data, obtained by using the permeabilized cel l technique or tissue homogenates for investigation of the mechanisms of regulation of respiration in the cells in vivo, are shortly summari zed. In these studies, surprisingly high values of apparent Km for ADP , exceeding that for isolated mitochondria in vitro by more than order of magnitude, were recorded for heart, slow twitch skeletal muscle, h epatocytes, brain tissue homogenates but not for fast twitch skeletal muscle. Mitochondrial swelling in the hypo-osmotic medium resulted in the sharp decrease of the value of Km for ADP in correlation with the degree of rupture of mitochondrial outer membrane, as determined by th e cytochrome c test. Very similar effect was observed when trypsin was used for treatment of skinned fibers, permeabilized cells or homogena tes. It is concluded that, in many but nor all types of cells, the per meability of the mitochondrial outer membrane for ADP is controlled by some cytoplasmic protein factor(s). Since colchicine and taxol were n ot found to change high values of the apparent Km for ADP, the partici pation of microtubular system seems to be excluded in this kind of con trol of respiration but studies of the roles of other cytoskeletal str uctures seem to be of high interest. In acute ischemia we observed rap id increase of the permeability of the mitochondrial outer membrane fo r ADP due to mitochondrial swelling and concomitant loss of creatine c ontrol of respiration as a result of dissociation of creatine kinase f rom the inner mitochondrial membrane. The extent of these damages was decreased by use of proper procedures of myocardial protection showing that outer mitochondrial membrane permeability and creatine control o f respiration are valuable indices of myocardial preservation. In cont rast to acute ischemia, chronic hypoxia seems to improve the cardiac c ell energetics as seen from better postischemic recovery of phosphocre atine, and phosphocreatine overshoot after inotropic stimulation. In g eneral, adaptational possibilities and pathophysiological changes in t he mitochondrial outer membrane system point to the central role such a system may play in regulation of cellular energetics in vivo.