Mitochondrial Function In Brain Tissues Research Articles

Accumulation of lactate in the rat brain during hyperammonaemia is not associated with impaired mitochondrial respiratory capacity

In acute liver failure (ALF) cerebral oedema and high intracranial pressure (ICP) are potentially deadly complications. Astrocytes cultured in ammonia have shown mitochondrial dysfunction and in rat models of liver failure, de novo lactate production in the brain has been observed and has led to a hypothesis of compromised brain metabolism during ALF. In contrast, normal lactate levels are found in cerebral microdialysate of ALF patients and the oxygen: glucose ratio of cerebral metabolic rates remains normal. To investigate this inconsistency we studied the mitochondrial function in brain tissue with respirometry in animal models of hyperammonaemia. Wistar rats with systemic inflammation induced by lipopolysaccharide or liver insufficiency induced by 90% hepatectomy were given ammonium or sodium acetate for 120min. A cerebral cortex homogenate was studied with respirometry and substrates of the citric acid cycle, uncouplers and inhibitors of the mitochondrial complexes were successively added to investigate the mitochondrial function in detail. In a separate dose-response experiment cortex from healthy rats was incubated for 120min in ammonium acetate in concentrations up to 80mM prior to respirometry. Hyperammonaemia was associated with elevated ICP and increased tissue lactate concentration. No difference between groups was found in total respiratory capacity or the function of individual mitochondrial complexes. Ammonium in concentrations of 40 and 80mM reduced the respiratory capacity in vitro. In conclusion, acute hyperammonaemia leads to elevated ICP and cerebral lactate accumulation. We found no indications of impaired oxidative metabolism in vivo but only in vitro at extreme concentrations of ammonium.

Sepsis induces brain mitochondrial dysfunction

Mitochondrial dysfunctions have been associated with the pathogenesis of sepsis. A systematic survey of mitochondrial function in brain tissues during sepsis is lacking. In the present work, we investigate brain mitochondrial function in a septic mouse model. Prospective animal study. University research laboratory. Male Swiss mice, aged 6-8 wks. Mice were subjected to cecal ligation and perforation (sepsis group) with saline resuscitation or to sham operation (control group). Oxygen consumption was measured polarographically in an oximeter. Brain homogenates from septic animals presented higher oxygen consumption in the absence of adenosine 5'-diphosphate (state 4) compared with control animals. The increase in state 4 respiration in animals in the cecal ligation and perforation group resulted in a drastic decrease in both respiratory control and adenosine 5'-diphosphate/oxygen ratios, indicating a reduction in the oxidative phosphorylation efficiency. Septic animals presented a significant increase in the recovery time of mitochondrial membrane potential on adenosine 5'-diphosphate addition compared with control animals, suggesting a proton leak through the inner mitochondrial membrane. The septic group presented a general reduction in the content of cytochromes. Moreover, the activity of cytochrome c oxidase was specifically and significantly decreased in the brain during sepsis. Hydrogen peroxide generation by brain mitochondria from septic mice did not respond to substrates of electron transport chain or to adenosine 5'-diphosphate, showing that mitochondrial function may be compromised in a critical level in the brain during sepsis. The mitochondrial dysfunctions demonstrated here indicate that uncoupling of oxidative phosphorylation takes place in the brain of septic mice, compromising tissue bioenergetic efficiency.

Mitochondrial function in brain tissue in primary degenerative dementia

Previous in vitro and in vivo studies of the brain in Alzheimer's disease indicated alterations in metabolism related to energy production although the relationships between these changes remains obscure. To help resolve this issue, in vitro oxygen uptake by homogenates of fresh samples of frontal neocortex from patients with dementia and neurosurgical controls has been examined as a measure of energy-related metabolism and mitochondrial function. Maximal respiratory rates (measured in the presence of an uncoupling agent) were similar for samples from 7 controls, 5 patients with Alzheimer's disease and two patients diagnosed clinically as Pick's disease, suggesting that there was little or no effect of these dementias on the maximal metabolic capacity of the tissue. However, under some conditions producing sub-maximal metabolic activity (which are of potentially greater physiological relevance) oxygen uptake rates were significantly elevated in the dementia group. The ratio of oxygen uptake rates in the presence and absence of ADP was significantly reduced (to 58% of control; P < 0.02) for the dementia patients compared with controls, possibly indicative of partial mitochondrial uncoupling. These results indicate metabolic changes expressed in vitro which may be relevant to the pathogenesis of Alzheimer's disease and some related dementias.