Our lab utilizes a genomic and molecular approach to identify the genes and molecules involved in heme homeostasis and trafficking in humans by using Caenorhabditis elegans as a genetic animal model of heme auxotrophy.
The major focus of our research is to elucidate the mechanisms that govern cellular metal homeostasis in biological systems. Transition metals such as copper, iron, zinc, and manganese are essential micronutrients for sustenance of life. Organisms use these metals as cofactors in diverse biochemical pathways. Excess of these redox-active metals are toxic to cells because of their ability to generate reactive oxygen and hydroxyl radicals. Thus, in organisms specific intracellular pathways must exist for efficient acquisition, sequestration and delivery of metals and metallo-cofactors.
Iron deficiency is the most common nutritional disorder. According to the World Health Organization, four out of five people in the world may be iron deficient, making nutritional iron deficiency one of the top ten risk factors in both developed and developing countries (WHO/UNICEF). In developing countries, iron deficiency is multi-factorial due to dietary insufficiencies that are compounded by the destruction of red cells from endemic malaria and intestinal bleeding because of parasitic hookworms.
Although the most bioavailable form of iron for human consumption is postulated to be heme (iron-protoporphyrin IX), the pathways and molecules that mediate heme absorption and subsequent utilization in humans are poorly understood. Our long-term research objectives are to define the cellular and molecular determinants of heme homeostasis in humans. Understanding how heme-iron is utilized in humans will permit the design of novel nutritional strategies to ameliorate iron deficiency anemia.
From a cell biological perspective, hemes are prosthetic groups for many important biological processes, and in eukaryotes it is synthesized in the mitochondrial matrix via a highly conserved multi-step pathway. Disruption in mitochondrial heme homeostasis leads to respiratory chain defects in humans resulting in a spectrum of clinical phenotypes ranging from isolated myopathies to multi-system disease, with onset from childhood to adulthood. Because heme is a hydrophobic molecule and is cytotoxic due to its intrinsic peroxidase activity, we hypothesize that heme does not merely diffuse through lipid bilayers but is actively assimilated via specific intracellular pathways that comprise heme uptake, trafficking and sequestration.
We found that C. elegans is the only known genetic animal model that is unable to synthesize heme de novo, albeit requiring heme to sustain metabolic processes (PNAS 2005). Since this organism lacks the ability to make heme, it provides us with a clean genetic background devoid of endogenous heme, and the ability to externally control the metabolic flux of heme. More than 70% of all human genes are conserved in C. elegans, and methods are in place for identifying genes by forward and reverse genetic screens. Importantly, genetic analyses in this roundworm will provide us with a molecular blueprint to pinpoint orthologous genes and pathways in mammals. Our eventual goal is to obtain a comprehensive view of the pathways which mediate heme homeostasis in humans that have heretofore remained elusive.
Our research is funded by grants from the NIH and March of Dimes to I.H.