Reversal of ischemic mitochondrial dysfunction.

Liver ischemia in intact rats is associated with a series of alterations in mitochondrial structure and function that include: a complete loss of respiratory control; a loss of adenine nucleotide translocase activity; decreases in, at least, the heme portions of cytochromes aa and c + cl; a decrease in dinitrophenolactivated ATPase; a loss of the ability of dinitrophenol to stimulate 02 uptake; a decrease in the content of one nfr = 83,000 protein band; and lastly, changes in mitochondrial ultrastructure characterized by swelling, loss of a tightly folded and contorted inner membrane, and the appearance of amorphous matrix densities. After 3 h of ischemia, none of these alterations are restored upon reestablishment of liver blood flow. An identical sequence of mitochondrial alterations occurs in ischemic liver tissue that has been pretreated with chlorpromazine. However, in the chlorpromazine-treated animals all of these mitochondrial alterations are completely reversible even after 3 h of ischemia. The inability to restore mitochondrial function during reperfusion in the absence of chlorpromazine, therefore, cannot be the direct consequence of any of these alterations. Rather, it would seem to be the metabolic consequence of reperfusion itself. In the same way, these mitochondrial alterations cannot be the cause of the irreversibility of the cellular deterioration and death during the reperfusion period. The mechanisms for the effects of ischemia on mitochondrial structure and function and the ability to reverse these changes in the presence of chlorpromazine are discussed.