Understanding of mechanisms and sites of heavy metal detoxification in humans: molecular genetic and biochemical studies of a half molecule ATP-binding cassette (ABC) transporter, CeHMT-1, function in heavy metal detoxification:
CALS Impact Statement
Understanding the cellular mechanisms of heavy metal (e.g. cadmium [Cd2+], mercury [Hg2+] and lead [Pb2+]) detoxification is critical for the cure and prevention of heavy metal-caused diseases, such as neurodegenerative conditions, dysfunction of vital organs, and cancer. Among the major contributors to heavy metal detoxification are ATP-binding cassette (ABC) transporters. The specific family members involved, and their functions in evolutionarily diverse organisms, however, are not understood. We have recently discovered that a half-molecule ABC transporter, CeHMT-1, is acutely required for Cd2+ detoxification in the nematode worm, Caenorhabditis elegans. Since CeHMT-1 homologs are present in genomes of higher animals including humans, CeHMT-1 provides a powerful approach to study the mechanisms, structural requirements, and components of this metal detoxification pathway and to relate obtained data to the function of its homologs in humans. In addition, these studies will give insights into which subcellular compartments are involved in metal detoxification in humans, may provide novel models to study mechanisms of metal-promoted diseases, lead to generating new approaches for preventing and/or treating heavy metal poisoning in humans, and will facilitate discovery of novel components that are required for heavy metal detoxification in humans.
Although the adverse health effects of heavy metals have been known for a long time, exposure to heavy metals continues, and even increases in some areas, due to their continued production and emission into the environment. Chronic exposure to heavy metals from the food chain and air leads to their accumulation in tissues, and causes various disease states, such as damaged mental and central nervous function, slowly progressing neurological degenerative processes that mimic Alzheimer`s and Parkinson`s diseases, dysfunction of lungs, kidneys, liver, and other vital organs, and possibly cancer. This project has been initiated because I discovered that an ATP-binding cassette transporter from C. elegans, CeHMT-1 is absolutely required for heavy metal detoxification, and has homologs in humans. Therefore, studies of CeHMT-1 and the HMT-1 pathway for heavy metal detoxification using a well-described and simple model invertebrate animal C. elegans will contribute to our understanding of mechanisms and sites of heavy metal detoxification in humans. The ultimate goal of this project is to contribute to developing novel approaches for preventing and treating heavy metal poisoning in humans.
We have developed molecular-biochemical procedures and generated C. elegans strains necessary for analyses of mechanisms of the CeHMT-1-dependent pathway for heavy metal detoxification.
The results from this project will have an impact on human health for several reasons: 1) All HMT-1 proteins tested to date are required for heavy metal detoxification. Therefore, the data from studies of CeHMT-1 in C. elegans will be related to the function of its homolog in humans in metal detoxification. 2) Our finding that CeHMT-1 is expressed in lysosomal-like structures of head neurons, digestive tract, and in coelomocytes (primitive liver) of C. elegans will give insights into which subcellular compartments are involved in metal detoxification in humans, may provide novel models to study mechanisms of metal-promoted diseases, and lead to generating new approaches for preventing and/or treating heavy metal poisoning in humans. 3) Given the structural and functional conservation of ABC transporters among species, identification of family members that are involved in metal detoxification in C. elegans, will facilitate discovery of novel components that are required for heavy metal detoxification in humans.
Molecular mechanisms of heavy metal detoxification