Mitochondrial dysfunction upon impaired oxygen delivery: cardiac arrest versus hemorrhagic shock

Cardiac arrest (CA) and hemorrhagic shock (HS) have similar mortality but differ in oxygen delivery patterns: HS is a progressive low-flow state, while CA causes abrupt no-flow ischemia followed by reperfusion. Whether these distinct conditions lead to similar mitochondrial dysfunction remains unclear. Rats were subjected to either CA (8 min, followed by extracorporeal resuscitation and 24 h recovery, n = 5) or HS (MAP 40 mmHg for 1 h, followed by 24 h recovery, n = 7), with SHAM controls (n = 6). Shock severity was assessed via lactate and base excess. After 24 h, brain and liver tissues were analyzed for mitochondrial respiration and oxoglutarate dehydrogenase complex (OGDHC) activity. Both CA and HS impaired mitochondrial function, but via different mechanisms. CA primarily disrupted the inner mitochondrial membrane, increasing leak respiration. In contrast, HS impaired electron transfer between complexes III and IV, likely due to leak of cytochrome c through outer membrane permeability. This defect was more pronounced with with complex I substrates compared to complex II substrate. In the brain, CA was associated with increased succinate-driven respiration, suggesting activation of compensatory reaction. These findings indicate that CA and HS induce distinct mitochondrial injuries, affecting inner versus outer membranes, respectively, with implications for targeted therapeutic strategies.