Heme and Iron Metabolism
Heme is an essential iron-containing cofactor for cellular functions but when released as a result of hemolysis drives tissue injury through oxidative damage. Heme drives inflammation oxidation-induced tissue injury and fibrosis in multiple pathologies. Macrophages are central to heme detoxification via the heme oxygenase (HMOX) enzyme system, which is crucial for maintaining redox homeostasis. We previously identified how macrophages rewire their intracellular metabolism toward the pentose phosphate pathway (PPP) to support HMOX-dependent heme degradation. Ongoing projects in the lab are exploring roles for heme and iron metabolism in pathogenesis of a variety of acute and chronic disease states. This project is funded by R56HL158886.
Macrophage PFKFB3 as a regulator of heme-induced inflammation in Sickle Cell Disease
Using a combination of patient-derived samples, in vitro bioenergetic, pharmacologic, and functional approaches, and in vivo models of acute and chronic hemolysis, we are now investigating how differential macrophage metabolic rewiring, dependent on the glycolytic regulator PFKFB3, drives heme-mediated inflammation in exacerbation of SCD.
Heme and iron metabolism in heart failure
There is also increasing evidence that heme and iron metabolism and related oxidative stress are drivers of inflammation and organ dysfunction in multiple chronic disease states including heart failure. New efforts in our group are aiming to understand the mechanisms behind iron-driven oxidative stress in cardiometabolic disease, particularly the interplay between heme- and iron-clearance, lipid oxidation, and intracellular metabolism in models of heart failure.