Energy metabolism in muscle mitochondria of many parasitic helminths is anaerobic and differs profoundly from that of the host. Unsaturated organic acids are used as terminal electron-acceptors, instead of oxygen, and energy-generation is coupled to the NADH-dependent reductions of fumarate and unique enoyl CoAs. The current proposal is designed to characterize a number of different aspects of organic acid metabolism in the parasitic nematode, Ascaris suum. This topic is important not only for the insight it provides into the functioning of these """"""""anaerobic"""""""" organelles, but also because these pathways impact a number of other novel biochemical processes, many of which are also potential targets for chemotherapy. Specific studies will involve the continued characterization of novel enzymes involved in anaerobic energy-generation, such as the pyruvate dehydrogenase complex and the 2-methyl branched-chain enoyl CoA reductase. These enzymes appear to be specifically modified to function under the reducing conditions present in the host gut and turn out to be also excellent models for study of the corresponding enzymes from aerobic mitochondria. More importantly, insights on the purified enzymes will be expanded to studies of the regulation of anaerobic electron-transport in submitochondrial particles and intact mitochondria, organic acid metabolism in extramuscular tissues, such as hypodermis, and aerobic/anaerobic transitions in developing ascarid larvae. These studies should identify functional differences between aerobic and anaerobic mitochondria with the long term goal of defining the role of organic acid metabolism in the intact helminth and the regulation of mitochondrial biogenesis during larval development.
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