Endotoxin-induced mitochondrial damage correlates with impaired respiratory activity

OBJECTIVE: This study was designed to determine whether mitochondrial function in a systemic organ is acutely impaired in a resuscitated model of sepsis (endotoxemia, lipopolysaccharide) and the relationship, if any, between this impairment and the extent of mitochondrial ultrastructural damage that occurs. DESIGN: Perspective, controlled laboratory investigation. SETTING: Animal laboratory in a university research institute. SUBJECTS: Adult male cats. INTERVENTIONS: A well-established feline model of acute endotoxemia was used wherein measures were taken to minimize tissue hypoxia. After lipopolysaccharide (3 mg/kg intravenously, n = 9) or isotonic saline vehicle (control, n = 5) administration, liver samples were obtained at 4 hrs posttreatment, and mitochondrial ultrastructure and respiratory function were assessed. Mitochondrial ultrastructural injury was graded on a scale of 0 (no injury) to 5 (severe injury), and mitochondrial respiration was evaluated by using standard techniques. MEASUREMENTS AND MAIN RESULTS: Significant mitochondrial injury was apparent by 4 hrs, but only in the lipopolysaccharide-treated group (2.5 +/- 0.2 vs. 1.3 +/- 0.2, p <.001) and despite maintenance of tissue oxygen availability. In addition, lipopolysaccharide treatment reduced the rate of state 3 (adenosine 5'-diphosphate-dependent) respiration, especially at complex IV (40% inhibition), and increased the rate of state 4 (adenosine 5'-diphosphate-independent) respiration, reflecting partial uncoupling of mitochondrial oxidative phosphorylation. Finally, a significant correlation was demonstrated between the severity of ultrastructural injury and the magnitude of mitochondrial respiratory dysfunction after lipopolysaccharide treatment and despite resuscitation efforts. CONCLUSION: Mitochondrial function is significantly impaired during acute sepsis, and this impairment is strongly associated with the extent of mitochondrial ultrastructural abnormalities present in the tissues. These findings in conjunction with those previously shown suggest that mitochondrial functional impairment may contribute to the pathogenesis of altered oxygen metabolism in systemic organs during sepsis.