Ischemia mitochondrial dysfunction

Alteration in mental status occurring in patients with systanic sepsis always carries a serious prognosis. The mechanisms of impaired brain function are poorly understood and are probably multifactorial. Considerations include hypoxia, ischemia, mitochondrial dysfunction and anaerobic cerebral energy metabolism, blood-brain barrier dysfunction or impaired transporter function, cerebral edema, toxins like ammonia or endotoxins, and last but not least, clinical use of cerebral depressants and sedatives in severely ill patients. In patients with multi-organ failure, clearance of common short-acting sedatives can become prolonged, resulting in severe and protracted alteration of mentation. 

PetrosiUo, G., Di Venosa, N., Ruggiero, F.M., Pistolese, M., D Agostino, D., Tiravanti, E., Fiore, T., and Paradies, G. 2005. Mitochondrial dysfunction associated with cardiac ischemia/reperfusion can be attenuated by oxygen tension control. Role of oxygen-free radicals and cardiolipin. Biochim. Biophys. Acta 1710 78-86. 

E.J. Lesnefsky, S. Moghaddas, B. Tandler, J. Kemer and C.L. Hoppel, Mitochondrial dysfunction in cardiac disease ischemia-reperfusion, aging, and heart failure, J. Mol. Cell. Cardiol. 33, 1065-1089 (2001). 

V. Borutaite, A. Jekabsone, R. Morkuniene, G. C. Brown, Inhibition of mitochondrial permeability transition prevents mitochondrial dysfunction, cytochrome C release and apoptosis induced by heart ischemia, J Moll Cell Cardiol 35, 357-366 (2003). 

Peroxynitrite is a powerful oxidant that, as a charged species, is poorly diffusible from the intramitochondrial space. When ONOO is produced in excess, as in inflammation and in ischemia-reperfusion, there is tyrosine nitration of the mitochondrial proteins. Mitochondrial levels of 2-5 nM ONOO" have been estimated for the mitochondrial matrix under physiological conditions [12,22], and levels above 20-30 nM are considered cytotoxic. The existence of a stable low ONOO concentration is indicated by the detection of nitrotyrosine in normal mitochondria [36]. At high levels, ONOO overwhelms the reducing reactions, and oxidation and nitration of lipids and proteins may impair mitochondrial function. The whole syndrome of mitochondrial dysfunction appears driven by excess NO and ONOO. This mitochondrial syndrome, observed in ischemia-reperfusion, inflammation, and aging [37-39] is characterized by decreased rates of state 3 respiration and ATP synthesis, decreased respiratory controls and membrane potential, increased rates of state 4 respiration, and increased mitochondrial size and fragility. 

Mitochondrial dysfunction has long been considered to play a central role in the development of cell injury during ischemia-reperfusion and hypoxia-reoxygenation [19]. Besides the inhibition of fatty acid oxidation, mitochondrial energy generation is diminished because of defects in respiratory chain function. Inhi-hition of the FO-Fl-ATPase leading to impaired function of respiratory complex I has been observed in I/R injury. Similar to ischemia, dsplatin has been shown to affed mitochondrial respiratory complexes and func-... 

The mechanisms of secondary injury include neurotransmitter-mediated excitotoxicity free-radical injury to cell membranes, electrolyte imbalances, mitochondrial dysfunction, inflammatory responses, apoptosis, secondary ischemia from vasospasm, focal microvascular occlusion, and vascular injury (Werner and Engelhard, 2007). These events can lead to cerebral edema and further increases in ICR The detailed molecular mechanisms of these events are described later in this chapter. 

Jessup, JXl., Battle, P., Waller, H., Edmiston, K.H., Stolz, D.B., Watkins, S.C., Ixx ker, J., and Skena, K. (1999). Reactive nitrogen and oxygen radicals formed during hepatic ischemia-reperfiision loll weakly metastatic colorectal cancer cells. Cancer Res. 59(8), 1825-1829. Joseph, B., Marchetti, P., Formstecher, P., Kroemer, G., Lewensohn, R., and Zhivotovsky, B. (2002). Mitochondrial dysfunction is an essential step for killing of non-smaU cell lung carcinomas resistant to conventional treatment. Oncogene 27(1), 65-77. 

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