Mitochondrial Structure and Function in Acute Myocardial Ischemic Injury

Changes in both the structure and function of mitochondria occur in the dog heart as a consequence of severe ischemia produced by acute coronary occlusion. Brief periods of severe ischemia (reversible injury) produced no significant change in mitochondrial infrastructure and no defects in pyruvate or succinate metabolism. However, periods of ischemia of 40-60 minutes' duration (irreversible injury) produced striking structural changes including swelling, an increase in matrix space, disorganization of cristae, and the appearance of amorphous matrix densities. After 60 minutes of severe ischemia, one or more amorphous densities were present in each mitochondrial profile. These osmiophilic structures contained lipid but have not been characterized further. Their presence was typical of the irreversible state. Mitochondria of irreversibly injured cells were fragile, and consequently were more difficult to isolate than mitochondria of control tissue. Furthermore, after isolation from tissue injured by 60 minutes of ischemia, they showed markedly defective function. With pyruvate as substrate, state 3 respiration was absent or greatly reduced and respiratory control was lost. These defects could not be repaired in vitro by fortification of the reaction mixture with cofactors including Mg²⁺, NAD, reduced coenzynte A, and thiamine pyrophosphate. Some pyruvate-malate oxidation did occur in fortified media; however, there was no respiratory control and the state 3 respiration was only 13% of that observed in control mitochondria. Succinic oxidase activity also was reduced. Similar defects were noted in mitochondria isolated from left ventricular myocardium after autolysis in vitro. Mitochondrial swelling induced by brief incubation of control mitochondria without substrate at 37°C in isotonic KCI or mitochondrial fragmentation damage and swelling secondary to sonication produced functional defects similar to those described after ischemia in vivo. The role, if any, that mitochondrial defects play in causing the development of irreversibility remains to be established.