Transferrin receptor 1 (Tfr1) is a widely expressed protein that mediates cellular iron uptake through receptor-mediated endocytosis of Fe-transferrin. Tfr1-/- embryos die in mid-gestation from ineffective erythropoiesis, precluding assessment of roles of Tfr1 later in development and after birth. To determine whether Tfr1 is important in other tissues, we developed a conditional (floxed) Tfr1 mouse model that allows for inactivation of the Tfr1 gene in cells expressing transgenic Cre recombinase from tissue- specific promoters. We focused on skeletal and cardiac muscle because both tissues are highly metabolic and require iron for myoglobin production, mitochondrial biogenesis and mitochondrial function. Our preliminary results indicate that Tfr1 is critically important in both skeletal muscle and heart, and suggest an unanticipated link between iron homeostasis and energy metabolism. In our first Aim, we will characterize a severe phenotype observed in mice lacking Tfr1 in skeletal muscle, to understand how Tfr1 and iron transport contribute to muscle development, muscle iron homeostasis, mitochondrial biogenesis and regulation of energy metabolism. In our second Aim, we will perform similar studies to elucidate the role of Tfr1 in the heart, an organ in which iron balance must be tightly regulated to maintain constant, high-level function while avoiding deleterious effects of iron deficiency and iron overload.

Public Health Relevance

Skeletal and heart muscle require more iron than most tissues because they need to produce energy for the work they do. They differ in several ways - heart muscle is working continuously and sensitive to too much or too little iron;skeletal muscle is used intermittently and is sensitive to iron deficiency but not iron overload. Little is known about how iron enters either type of muscle cell. This project takes advantage of unique mouse mutants, engineered in the Andrews laboratory, to learn about muscle iron transport and its relationship to heart failure, diabetes, and muscle diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
1R01DK089705-01A1
Application #
8128130
Study Section
Cardiovascular Differentiation and Development Study Section (CDD)
Program Officer
Wright, Daniel G
Project Start
2011-07-01
Project End
2015-06-30
Budget Start
2011-07-01
Budget End
2012-06-30
Support Year
1
Fiscal Year
2011
Total Cost
$392,500
Indirect Cost
Name
Duke University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
044387793
City
Durham
State
NC
Country
United States
Zip Code
27705
Matak, Pavle; Matak, Andrija; Moustafa, Sarah et al. (2016) Disrupted iron homeostasis causes dopaminergic neurodegeneration in mice. Proc Natl Acad Sci U S A 113:3428-35
Jabara, Haifa H; Boyden, Steven E; Chou, Janet et al. (2016) A missense mutation in TFRC, encoding transferrin receptor 1, causes combined immunodeficiency. Nat Genet 48:74-8
Xu, Wenjing; Barrientos, Tomasa; Mao, Lan et al. (2015) Lethal Cardiomyopathy in Mice Lacking Transferrin Receptor in the Heart. Cell Rep 13:533-545
Barrientos, Tomasa; Laothamatas, Indira; Koves, Timothy R et al. (2015) Metabolic Catastrophe in Mice Lacking Transferrin Receptor in Muscle. EBioMedicine 2:1705-17
Chen, Alan C; Donovan, Adriana; Ned-Sykes, Renee et al. (2015) Noncanonical role of transferrin receptor 1 is essential for intestinal homeostasis. Proc Natl Acad Sci U S A 112:11714-9
Andrews, Nancy C (2015) Hungry irony. J Clin Invest 125:3422-3
Zheng, Lingling; Yan, Xiao; Suchindran, Sunil et al. (2014) Biological pathway selection through Bayesian integrative modeling. Stat Appl Genet Mol Biol 13:435-57
Xu, Wenjing; Barrientos, Tomasa; Andrews, Nancy C (2013) Iron and copper in mitochondrial diseases. Cell Metab 17:319-28
Andrews, Nancy C (2012) Closing the iron gate. N Engl J Med 366:376-7