Professor of Internal Medicine and Adjunct Professor of Oncological Sciences
Iron Metabolism, Diabetes, Mitosis
Research in our laboratory focuses on how eukaryotic cells sense and respond to iron and how dysregulation of iron homeostasis leads to disease. Most cells require iron for growth and proliferation due to its presence in proteins involved in hemoglobin synthesis, DNA synthesis and mitochondrial respiration. Regulation of cellular iron content is crucial: excess iron catalyzes the generation of toxic reactive oxygen species that damage cellular macromolecules while cellular iron deficiency causes cell cycle arrest and reduces cell proliferation. Dysregulation of iron homeostasis caused by iron deficiency or iron excess leads to common hematological, neurodegenerative and metabolic diseases. All organisms have therefore developed mechanisms to sense, acquire and store iron.
In vertebrates, cellular iron homeostasis is controlled post-transcriptionally by iron regulatory proteins 1 and 2 (IRP1 and IRP2). IRPs bind to RNA stem-loop structures known as iron-responsive elements (IREs) in the mRNAs of proteins involved in iron uptake, sequestration and export. The binding of IRPs to IREs regulates either the translation or stability of the mRNA. IRPs also regulate other IRE-mRNAs that encode proteins involved in tricarboxylic acid cycle, heme biosynthesis and the cell cycle. Our goals are to understand the mechanisms by which IRPs sense iron and how dysregulation of iron homeostasis due to IRP deficiency causes disease. To this end, we use transgenic mice and the nematode Caenorhabditis elegans, as well as cultured cells, to study iron homeostasis. Our research is focused several areas.
Mechanisms for IRP2 Regulation
We have discovered two novel pathways for regulating IRP2 function. One pathway regulates the iron-dependent proteolysis of IRP2 by an iron-regulated E3 ubiquitin FBXL5 ligase during cellular iron overload, which protects cells from toxic effects of excess iron. The other pathway involves the iron-independent regulation of IRP2 by phosphorylation during the cell cycle, which may provide a mechanism to regulate proliferation by altering iron metabolism during the cell cycle. Our goal is to understand how IRP2 is regulated by these pathways and how IRP2 affects cell cycle progression and the proliferation of cancer cells.
Iron and Disease
Dysregulation of iron homeostasis is associated with common hematological, neurological and metabolic diseases. Mice with a targeted deletion of the Irp2 gene develop anemia, balance and motor abnormalities, and diabetes. We have also found that IRP2 deficiency leads to diabetes. Our current goal is to understand how alterations in iron homeostasis in IRP2 deficient mice cause diabetes.
C. elegans as a Genetic Model for Iron and Oxygen Homeostasis
We are using C. elegans as a model to identify novel iron-regulated genes and pathways in worms that have similar roles in mammals. Our previous studies identified an iron enhancer in genes that are regulated by iron and oxygen. We are identifying the proteins involved in iron-dependent transcription and studying the molecular mechanisms by which iron coordinately regulates the transcriptional activation and repression of these genes. Biochemical approaches and genetic screens are being employed to identify components involved in this process.
- Ferreira dos Santos MC, Anderson CP, Neschen S, Zumbrennen-Bullough KB, Romney SJ, Kahle-Stephan, Rahkolb B, Gailus-Durner V, Fuchs H, Wolf E, Rozman J, Hrabe de Angelis M, Cai WC, Rajan M, Hu J, Dedon PC, Leibold EA (2020). Irp2 regulates insulin production through iron-mediated Cdkal1-catalyzed tRNA modification. Nature Commun 11, 296
- Wang H, Shi H, Rajan M, Canarie ER, Hong S, Simoneschi D, Pagano M, Bush MF, Stoll S, Leibold EA, Zheng N (2020). FBXL5 regulates IRP2 stability in iron homeostasis via an oxygen-responsive [2Fe2S] cluster. Molecular Cell 78, 1-11
Rajan M, Anderson CP, Rindler PM, Romney SJ, dos Santos MCF, Gertz J and Leibold EA (2019) NHR-14 loss of function couples intestinal iron uptake with innate immunity in C. elegans through PQM-1 signaling. eLife 2019;8:e44674 DOI: 10.7554/eLife.44674
- Zumbrennen-Bullough KB, Becker L, Garrett L, Hölter SM, Calzada-Wack J, Mossbrugger I, Quintanilla-Fend L, Racz I, Rathkolb B, Klopstock T, Wurst W, Zimmer A, Wolf E, Fuchs H, Gailus-Durner V, Hrabě de Angelis M, Romney SJ and Leibold EA (2014). Abnormal brain iron metabolism in Irp2 deficient mice is associated with mild neurological and behavioral impairments. PLOS One, 9(6):e98072
- Anderson CP and Leibold EA (2014). Mechanisms of iron metabolism in Caenorhabditis elegans. Frontiers in Pharmacology, 5:113
- Anderson CP, Shen M, Eisenstein RS, Leibold EA (2012). Mammalian iron metabolism and its control by iron regulatory proteins. Biochim Biophys Acta, 1823(9):1468-83
- Romney SJ, Newman BS, Thacker C, Leibold EA (2011) HIF-1 regulates iron homeostasis in Caenorhabditis elegans by activation and inhibition of genes involved in iron uptake and storage. PLoS Genetics, 7(12):e1002394
- Vashisht AA, Zumbrennen KB, Huang X, Powers DN, Durazo A, Sun D, Bhaskaran N, Persson A, Uhlen M, Sangfels O, Spruck C, Leibold EA, Wohlschlegel JA (2009) Proteolytic degradation of IRP2 by an iron-regulated FBXL5 ubiquitin ligase. Science, 326:718-721
- Zumbrennen KB, Wallander MW, Romney SJ, Leibold EA (2009) Cysteine oxidation regulates the RNA-binding activity of IRP2 during oxidative stress. Mol Cell Bio, 29:2219-2229
- Wallander ML, Zumbrennen KB, Rodansky ES, Romney SJ, Leibold EA (2008) Iron-independent phosphorylation of IRP2 regulates ferritin during the cell cycle. J Biol Chem, 283:23589-23598
- Romney SJ, Thacker C, Leibold EA (2008). An iron enhancer element in the ftn-1 gene directs iron dependent expression in C. elegans intestine. J Biol Chem, 283(2):716-725
- Zumbrennen KB, Hanson ES, Leibold EA (2008) HOIL-1 is not required for iron-mediated degradation of IRP2 in HEK293 cells. Biochim Biophys Acta, 1783(2):246-252