CONICET | Buscador de Institutos y Recursos Humanos

Although the precise mechanism by which sepsis leads to organ dysfunction has not been yet clarified, several authors addressed the relevance of mitochondrial function during endotoxemia and sepsis, as it may play a role in the genesis of tissue injury described in these syndromes. This work is focused on the mechanism of mitochondrial bioenergetic dysfunction in heart in an acute model of endotoxemia induced in female Sprague Dowley rats (45 days) by LPS (10 mg/kg ip). Assays were performed after 6h of treatment. We analyzed pathways of tissue O2 uptake as mitochondrial O2 consumption and NADPH oxidase activity. In mitochondria, NO, H2O2, and O2- production were measured. We determined ATP bioavailability and production rate, and membrane potential. The ratio between O2 consumed by mitochondria and by non-mitochondrial pathways decreased by 25% in LPS group compared to control group. This observation may be due to a 2-fold increase in NADPH oxidase activity found in LPS group (control: 13250 ± 3020 cpm/mg tissue, p <0.05). Mitochondrial complex I activity and mitochondrial O2 consumption were found impaired and ATP levels and production by FoF1 ATP synthase were found decreased, while no changes were observed in mitochondrial membrane potential. This scenario was accompanied by a 65% increased production of O2- (control: 2.34 ± 0.25 nmol/min mg protein, p < 0.0001) and a 20% increased production of H2O2 (control: 1.17 ± 0.13 nmol/min mg protein, p < 0.0001) probably due to electron-leackage. Increased NO production was positively correlated to mtNOS functional activity. We suggest that bioenergetic impairment observed in heart endotoxemia is mainly due to impairment of ATP bioavailability and oxygen consumption through complex I inhibition without affecting mitochondrial membrane integrity. Supported by: UBA, ANPCYT and CONICET.