Abstract
Oxidative and nitrative stress is associated with a broad range of pathologies which involve mitochondrial dysfunction including diabetes, ethanol toxicity and cardiac failure. However, the significance of mitochondrial damage to the underlying progression of disease has been difficult to assess because in the cell the bioenergetic demand on the cell is generally below the maximal capacity. The presence of this “reserve capacity” suggests that pathological effects will not emerge until this reserve is exceeded. The availability of a new technology, the extracellular flux analyzer, has allowed us to test this hypothesis in the context of the bioenergetic function induced by chronic alcohol consumption. This instrumentation allows the measurement of mitochondrial function in adherent cells, with sensitivity and high throughput. Using this approach we have determined how cellular mitochondrial function changes in hepatocytes isolated from an in vivo model with and without chronic alcohol consumption. We found that mitochondria in hepatocytes were highly coupled and possess a considerable bioenergetic reserve capacity which was depleted by chronic alcohol consumption. In alcohol-dependent hepatotoxicity cells are exposed to both reactive oxygen and nitrogen species (ROS/RNS) and hypoxia. We found that the decreased bioenergetic reserve capacity resulted in the hepatocytes being more sensitive to nitrative and hypoxic stress. Taken together our data demonstrate that mitochondrial reserve capacity in cells is essential in the cellular response to oxidative stress and is uniquely sensitive to nitric oxide.
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