Grant: Operating Grant

Life on earth without iron is virtually impossible. Iron is critical for many functions in our body, and probably best known for its role in transporting oxygen as part of hemoglobin. This molecule consists of a heme group (which contains iron) and the globin protein. Heme groups are also very important for other proteins, such as the cytochrome P450 enzymes, which are proteins that have many important roles, including the removal of harmful toxins, and the production of steroid hormones. Using the fruitfly as a model, we have discovered that steroid hormone-producing cells have incredibly high levels of these cytochrome P450 enzymes. It follows that these cells need a correspondingly high amount of iron to equip all P450 enzymes with the heme cofactor. Our lab has discovered a novel signaling mechanism that prepares these steroid hormone-producing cells for an upcoming demand in iron. Surprisingly, we found that a neurotrophin (a type of nerve growth factor) is the first step in a series of signals that increase iron availability to make more heme. When we disrupt this signaling mechanism, the steroid hormone producing cells develop a strange defect: They shine in a bright red color. It turns out that these defect cells can neither make sufficient heme nor steroid hormones, and instead accumulate extremely high levels of heme precursors, which causes the red coloring. This defect is remarkably similar to a disease in humans called porphyria. Interestingly, the only known cause for this disease are defects in the enzymes that make heme. Our research, however, has unearthed that we can trigger this defect not only by mutations in the corresponding fly enzymes that make heme, but also by manipulating our newly identified neurotrophin pathway that controls heme production. Very little is known about the regulation of heme biosynthesis in humans, and our findings reveal an unsuspected complexity that governs heme production, with important implications for human health.