- Staff Scientist at the Genetics and Metabolism Section, Liver Diseases Branch, NIDDK, NIH, 2007-present
- Postdoctoral Fellow, Liver Diseases Section, NIDDK, NIH, 2000–2005
- Ph.D., A.V. Palladin Institute of Biochemistry, National Academy of Science of Ukraine, 1997
- M.A., Lviv State University, 1988
Our research intends to understand how the body takes up iron, how it is converted into biologically vital forms, and how it is distributed within cells and among organs. We want to characterize genes and intracellular protein complexes engaged in the trafficking of iron compounds from the site of its synthesis to the cellular organelles where it is used.
Important iron cofactors forming complexes with proteins include iron-sulfur clusters, mono- and dinuclear iron centers. Due to the highly reactive nature of metal ion, its incorporation into a complex with proteins thought to be assisted by metallochaperones. Our lab has made substantial contribution to the discovery and further interpretation of the role of iron chaperones. Initially, PCBP1-4 proteins have been identified as RNA-binding, scaffold proteins affecting stability of RNA and protein complexes. PCBP1 and PCBP2 are abundant cellular proteins that share 83% identity. We have shown that PCBPs work as cytosolic iron chaperones that bind iron and deliver it to an iron storage protein, ferritin, and some iron-dependent enzymes.
We have developed mouse models of PCBP1 and PCBP2 deficiency to explore the function of PCBP proteins in living organism. Initially, we have found that homozygous deletion of PCBP1 was embryonically lethal. For further research we have developed a mouse strain with conditional, floxed allele of PCBP1. This mouse strain has been used for crossing with other mouse strains with specific expression of Cre recombinase to get knock-out of PCBP1 in a specific tissues or in response to a drug.
Applying our Research
Understanding the biology of iron, one of the most essential and abundant microelements in the human body, is vital to develop a treatment for diseases associated with genetic impairment of iron metabolism, such as some forms of anemia and hereditary hemochromatosis. Knowledge of iron homeostasis also gives us an opportunity to help in disorders with secondary impairment of iron metabolism, such as anemia of chronic inflammation, chronic liver inflammation diseases like hepatitis C, and alcoholic liver diseases.
Need for Further Study
In the overview of cellular iron metabolism, the mechanisms and pathways of intracellular transport of iron complexes make up critical parts of the big picture. In fact, this is an important and promising research area. However, at present the questions outnumber answers. Studying mouse models, with targeted “iron genes” is vital for progress in this research area.
- Iron catalysis of lipid peroxidation in ferroptosis: Regulated enzymatic or random free radical reaction?
- Stoyanovsky DA, Tyurina YY, Shrivastava I, Bahar I, Tyurin VA, Protchenko O, Jadhav S, Bolevich SB, Kozlov AV, Vladimirov YA, Shvedova AA, Philpott CC, Bayir H, Kagan VE.
- Free Radic Biol Med (2019 Mar) 133:153-161. Abstract/Full Text
- PCBP1 and NCOA4 regulate erythroid iron storage and heme biosynthesis.
- Ryu MS, Zhang D, Protchenko O, Shakoury-Elizeh M, Philpott CC.
- J Clin Invest (2017 May 1) 127:1786-1797. Abstract/Full Text
Research in Plain Language
Iron is an essential nutrient that is required by all organisms. Iron deficiency leads to anemia, neurological problems, and increased vulnerability to infection. Iron overload is also associated with a number of diseases, such as hereditary hemochromatosis and chronic inflammatory diseases of the liver. Impaired iron metabolism has been reported for diabetes, Alzheimer’s, and Parkinson’s diseases. Despite the importance of iron in human health and illnesses, our knowledge of how cells take up and use iron is limited. Our laboratory studies the genetics and cell biology of iron uptake and utilization. My research is focused on the mouse strains with mutations in “iron genes”. PCBP proteins have unusual property to bind RNA and metals, including iron. Changes in PCBP proteins were found in some diseases or cancers. Understanding how do PCBP proteins work in “iron handling” might help fight these diseases.