Project Details
Projekt
Exploring TFR2 as a central hub of mitochondrial metabolism within the liver-bone-inflammation axis
Applicant
Maria G. Ledesma Colunga, Ph.D.
Subject Area
Endocrinology, Diabetology, Metabolism
Term
since 2025
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 436298031
Transferrin receptor 2 (TFR2) is a key regulator of iron homeostasis, particularly in hepatocytes. Recent studies have expanded the known functions of TFR2 beyond the liver, highlighting its essential roles in erythropoiesis, bone mass maintenance, and inflammation regulation. New evidence shows that TFR2 is also present at the mitochondrial membrane, where it regulates mitochondrial function in erythroid and neuronal cells. Moreover, we have demonstrated that TFR2 modulates the activation and polarization of M1-like macrophages, influencing the progression of arthritis. Start-up funding from FerrOs enabled further research revealing that TFR2 deficiency worsens inflammatory bowel disease by altering macrophage polarization, suggesting a universal mechanism of TFR2-mediated inflammation. Consistent with published findings, our study shows that TFR2-deficient macrophages exhibit disrupted mitochondrial morphology and function, showing reduced oxidative phosphorylation, decreased expression of complex I and II, and increased glycolysis. To date, it remains unclear how TFR2 regulates these activities, including whether it interacts with other receptors or iron regulators, if its functions are iron-dependent, whether its extracellular domain acts as a scavenger for (inflammatory) proteins, and how its cellular localization (e.g., cell membrane, mitochondria) influences its role. Thus, in this project, we aim to characterize the role of TFR2 in mitochondrial respiration in macrophages in detail using mitochondrial morphology assays, cellular fractioning, and detailed metabolic assays, including Seahorse and flux analyses of the TCA cycle. Additionally, we will assess whether the regulation of mitochondrial respiration by TFR2 is dependent on iron/transferrin through in vitro cultures. To further understand the impact of TFR2 on macrophage polarization, we will investigate potential binding partners and downstream signaling pathways of TFR2 that determine the polarization of macrophages using double-deficient mice, knockdown/pathway inhibitor studies and pull-down assays in vitro. Once these mechanisms are characterized in macrophages, we will explore whether similar TFR2-mediated mitochondrial functions are also present in hepatocytes, bone cells, potentially influencing inflammatory bone loss or liver damage.
DFG Programme
Research Units
