Oxidation, Physiological

Mitochondrial disorders resulting from defects in oxidative phosphorylation are the most common form of inherited metabolic disease. Mutations in the human mitochondrial translation elongation factor GFM1 have recently been shown to cause the lethal pediatric disorder Combined Oxidative Phosphorylation Deficiency Syndrome (COXPD1). Children harboring mutations in GFM1 exhibit severe developmental, metabolic and neurological abnormalities. This work describes the identification and extensive characterization of the first known mutations in iconoclast (ico), the Drosophila orthologue of GFM1. Expression of human GFM1 can rescue ico null mutants, demonstrating functional conservation between the human and fly proteins. While point mutations in ico result in developmental defects and death during embryogenesis, animals null for ico survive until the second or third instar larval stage. These results indicate that in addition to loss-of-function consequences, point mutations in ico appear to produce toxic proteins with antimorphic or neomorphic effects. Consistent with this hypothesis, transgenic expression of a mutant ICO protein is lethal when expressed during development and inhibits growth when expressed in wing discs. In addition, animals with a single copy of an ico point mutation are more sensitive to acute hyperthermic or hypoxic stress. Removal of the positively-charged tail of the protein abolishes the toxic effects of mutant ICO, demonstrating that this domain is necessary for the harmful gain-of-function phenotypes observed in ico point mutants.

Aging is a process characterized by accumulated oxidative damage to DNA, proteins, and lipids,which leads to the gradual degeneration of cellular activity. Mitochondria play a central role in aging because they produce both cellular energy and oxidative stress. As resultof accumulated oxidative damage, mitochondria function decays, which leads to a cellular energy deficit and compromises cellular function. Iron is an essential nutrient reequired by mitodhondria to function optimally. It has been proved that iron supplementation increases the lifespan of several yeast strains, including superoxide dismutase mutants. We are interested in finding where the iron is going and what it might be doing that is beneficial to the cell. We have used Saccharomyces cerevisiae as our molecular model of aging. Our results indicate that the extra iron is being transported into the mitochoindria.