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Betty Leibold

Professor of Medicine and of Oncological Sciences

B.A. State University of New York

Ph.D. Massachusetts Institute of Technology

Research

References

betty.leibold@hmbg.utah.edu

 

Research

Our research is focused on understanding how eukaryotic cells sense and respond to changes in cellular iron concentration.   Iron has an essential role in many biological processes, including DNA synthesis, respiration, oxygen transport and heme synthesis.   But iron can also be toxic due to its ability to generate free radicals that damage macromolecules.   In humans, the accumulation of excess iron can result in neurodegeneration, cardiomyopathy, cirrhosis and increased risk of cancer while iron deficiency perinatally or postnatally can result in neurocognitive and motor impairments in children.   Because of the deleterious yet beneficial effects of iron, all organisms have developed highly regulated mechanisms to sense, acquire and store this metal.

Mammalian iron homeostasis is regulated post-transcriptionally by iron regulatory proteins 1 and 2 (IRP1 and IRP2).  IRPs are cytosolic proteins that bind to specific RNA stem-loop structures, known as iron-responsive elements (IREs) that are located in the untranslated regions of specific mRNAs encoding transferrin receptor and ferritin, which are proteins involved in iron uptake and sequestration, respectively.   When cells are iron-deplete, IRPs bind IREs with high affinity, repressing ferritin translation and promoting the stabilization of transferrin receptor mRNA.   When cells are iron sufficient, IRPs bind with low affinity to IREs, increasing ferritin synthesis while promoting the degradation of the transferrin receptor.   Regulating the amount of iron sequestered by ferritin and taken up by transferrin receptor ensures that cells acquire sufficient iron for their needs, while preventing iron toxicity.   Deletion of IRP2 in mice or mutations in ferritin in humans results in neurodegenerative disease, highlighting the importance of regulating iron homeostasis in brain.

Although IRP1 and IRP2 share similar sequences, they differ with respect to the mechanism by which they sense iron.  Iron causes IRP1 to form a [4Fe-4S] cluster and lose RNA-binding activity while iron causes IRP2 to be rapidly degraded by the proteasome.  Our goal is to identify the mechanisms by which IRPs sense iron and alter the post-transcriptional regulation of downstream target IRE-mRNAs.   We are determining how phosphorylation and other post-translational modifications of IRPs affect RNA-binding activity and/or protein stabilization.   Our approaches are to use cell culture-based systems, biochemistry and mouse genetic models as tools to study IRP regulation. IRP activity is also regulated during oxidative stress and hypoxia, which are conditions where reactive oxygen species are altered. Hypoxia is important for normal tissue physiology as well as being a component of pathophysiological conditions, including heart and cerebrovascular diseases and tumor growth. Our emphasis is to determine how hypoxia regulates IRPs and the physiological consequences of this regulation.

We are using Caenorhabditis elegans as a genetic model system for studying iron homeostasis.  C. elegans express homologs of genes encoding proteins involved in mammalian iron metabolism, indicating that iron homeostasis is similar in worms and mammals.   One aim is to determine how genes are transcriptionally regulated by iron, and specifically to identify DNA elements and proteins that are sensitive to iron. C. elegans provides us with genetic and biochemical approaches to identify novel iron-regulated genes that have counterparts in mammals.

References