CONICET | Buscador de Institutos y Recursos Humanos

Mitochondrial dysfunction and organ failure are key features in endotoxemia and the associated MOF syndrome including heart failure. Mitochondrial dysfunction in endotoxic shock has been observed including inhibition of electron transfer and ATP synthesis using a series of experimental designs. However, no systematic analysis with a bioenergetic approach has been carried out using a unique experimental model, thus lacking precise information about impaired cellular energy metabolism. Acute endotoxemia (LPS, 10 mg/kg ip, Sprague Dawley rats, 45 days old, 180 g) decreased the O2 consumption of rat heart (1 mm3 tissue cubes) by 33% (from 4.69 to 3.11 mol O2/min. g tissue). Mitochondrial O2 consumption and complex I activity were also decreased by 27% and 29%, respectively. Impaired respiration was associated to decreased ATP synthesis (from 417 to 168 nmol/min. mg protein) and ATP content (from 5.40 to 4.18 nmol ATP/mg protein), without affecting mitochondrial membrane potential. This scenario is accompanied by an increased production of O2●- and H2O2 due to complex I inhibition. The increased NO production, is expected to fuel an increased ONOO- generation that is considered relevant in terms of the biochemical mechanism. Heart mitochondrial bioenergetic dysfunction with decreased O2 uptake, ATP production and contents may indicate that preservation of mitochondrial function will prevent heart failure in endotoxemia. Overall, the data support the hypothesis that heart complex I activity and mitochondrial O2 consumption impairment in endotoxemia, contribute to a decreased ATP production by FoF1-ATP synthase and to decreased mitochondrial ATP content without affecting inner membrane potential. To our knowledge this is the first study in which ?Complex I syndrome? is described in endotoxemia.

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