Uncovering the Basis for the Antioxidant-like Biological Activity of Ionic Manganese
The main focus of our research is to characterize in detail the in vivo mechanism for handling and the antioxidant-like biological action of ionic manganese (i-Mn or Mn) in providing protection against reactive oxygen species (ROS) or conditions that elevate ROS. In several unicellular organisms, i-Mn has been shown to compensate for the lack of the antioxidant enzyme, superoxide dismutase. In the simple multi-cellular model organism, Caenorhabditis elegans, we have previously reported that i-Mn supplementation increases resistance to ROS and extends lifespan.
Cellular Mn handling pathways are not fully characterized, especially in C. elegans, and also it is unclear how Mn exerts its antioxidant-like activity. Our working hypothesis is that i-Mn exerts its antioxidant-like activity primarily through the activation of the Fork head-related transcription factor, DAF-16, that regulates the expression of genes that confer resistance to oxidative stress. Additionally, we postulate that when DAF-16 pathway is disrupted, i-Mn binds to suitable ligands in vivo to form a small molecule with ROS neutralizing ability, which can act as a backup defense system.
Our approach is to use proteomics and genetic approaches to identify the biomolecular targets of i-Mn in vivo; apply other well-established methods to determine the active component(s) responsible for the beneficial effects observed. We expect that the knowledge gained from our studies will provide a more detailed picture of manganese metabolism and will present mechanistic details for the antioxidant-like activity of ionic manganese.
Munroe, W., Kingsley, C., Durazo, A., Gralla, E. B., Imlay, J. A., Srinivasan, C., and Valentine, J. S. Only one of a wide assortment of manganese-containing SOD mimicking compounds rescues the slow aerobic growth phenotypes of both Escherichia coli and Saccharomyces cerevisiae strains lacking superoxide dismutase enzymes. J Inorg Biochem., 2007, 101(11-12):1875-82
Pate, K., Rangel, N., Fraser, B., Clement, M. H. S., and Srinivasan, C. Measuring “free” iron levels in Caenorhabditis elegans using low-temperature Fe(III) electron paramagnetic resonance spectroscopy. Anal. Biochem., 2006, 358(2):199-207
Lin, Y., Hoang, H., Hsieh, S. I., Rangel, N., Foster, A. L., Sampayo, J. N., Lithgow, G. J., and Srinivasan, C. Manganous ion supplementation accelerates wild-type development, enhances stress resistance and rescues the life-span of a short–lived Caenorhabditis elegans mutant. Free Radic. Biol. Med., 2006, 40: 1185-93
Sanchez, R. J., Srinivasan, C., Wallace, M. A., Martins, J., Munroe, W. H., Kao, T. Y., Le, K., and Valentine, J. S. Exogenous manganous ion at millimolar levels rescues all known defects of yeast lacking copper-zinc superoxide dismutase. J. Bioinor. Chem., 2005, 10: 913-23
Jensen, L. T., Sanchez, R. J., Srinivasan, C., Valentine, J. S., and Culotta, V. C. Mutations in Saccharomyces cerevisiae iron sulfur cluster assembly genes and oxidative stress relevant to Cu/Zn superoxide dismutase. J Biol Chem., 2004, 279(29): 29938-43