Caryn E. Outten
|Title:||Associate Professor and Guy F. Lipscomb Professor of Chemistry / Biochemistry and
Bioinorganic / Biophysical
|Department of Chemistry and Biochemistry|
Office: GSRC 308
Lab: GSRC 305, 803-777-4736
Lab 2: GSRC 306
Lab 3: GSRC 313
Lab 4: GSRC 320
Caryn Outten Group Website
Publications on PubMed
B.S., 1995, College of William and Mary
M.S., 1996, Northwestern University
Ph.D., 2001, Northwestern University
Honors and Awards
Garnet Apple Award for Teaching Innovation, 2016; SC Governor's Young Scientist Award for Excellence in Scientific Research, 2013; University of South Carolina Breakthrough Rising Star, 2011; Presidential Early Career Award for Scientists and Engineers (PECASE), 2009; NIEHS Transition to Independent Positions (K22) Award, 2005-08.
Bioinorganic chemistry; protein biochemistry; characterization of cytosolic and mitochondrial redox homeostasis factors; glutathione metabolism; Fe-S cluster biogenesis; structure-function studies of iron homeostasis proteins in prokaryotic and eukaryotic cells.
Research in the Outten group is focused on two interconnected projects: (1) identifying the mechanisms by which cells maintain adequate levels of the essential metal iron, and (2) characterizing intracellular factors that control mitochondrial redox balance and combat oxidative stress. We take a multidisciplinary approach to tackle these projects, combining biophysical, biochemical, genetic, and molecular and cell biology techniques. For both projects we primarily use the baker's yeast Saccharomyces cerevisiae as a model system since this simple eukaryote is easy to maintain and genetically manipulate in the lab, yet expresses many of the same redox and metal homeostasis systems as human cells.
Project 1: Iron Regulation Mechanisms. Both iron deficiency and iron overload are significant human health issues: iron deficiency is the most common and widespread nutritional disorder in the world, while iron overload disorders are common genetic disorders in the United States. To maintain optimal intracellular iron levels, iron transport and storage is tightly regulated in all eukaryotic cells ranging from yeast to humans. However, there are substantial gaps in our fundamental understanding of iron regulation mechanisms at the cellular and molecular level that require further study, and filling these gaps will be essential for preventing and treating disorders of iron metabolism. Our research program is designed to fill these gaps by providing insight into the basic biology of iron metabolism. In particular, we are focused on monothiol glutaredoxins (Grxs) and BolA-like proteins, which have recently emerged as novel players in iron homeostasis. We are characterizing the structural and functional interactions between these two highly conserved protein families to provide mechanistic insight into their regulatory roles in iron metabolism. We have demonstrated that both yeast and human Grx/BolA proteins form [2Fe-2S]-bridged heterocomplexes with unusual coordination chemistry (Figs. 1-5). In yeast, these complexes inhibit the activity of iron-responsive transcriptional activators that control iron uptake and storage. Overall, our studies are highlighting the essential role that Fe-S clusters play as sensors of cellular iron status in a variety of eukaryotes.
Project 2: Mitochondrial Anti-Oxidant Factors and Redox Control. Iron and redox homeostasis are intimately connected in human health. When left unchecked, excess iron catalyzes formation of reactive oxygen species that disrupt redox homeostasis by oxidatively damaging DNA, proteins, and cell membranes. However, our cells have developed anti-oxidant defense systems that neutralize these reactive by-products and maintain redox balance. The goal of our second research project is to characterize these anti-oxidant defense systems and redox control pathways, especially within the mitochondrion. The mitochondrion is a specialized organelle within cells that houses numerous essential functions, including the respiratory machinery responsible for cellular energy production. Consequently, disruption of mitochondrial redox balance contributes to a host of human disorders, including cancer, neurodegenerative diseases, and aging. A better understanding of the factors controlling mitochondrial oxidative stress and redox homeostasis is required for developing therapies to treat mitochondrial disease and dysfunction. To better characterize redox control pathways in mitochondria, we have targeted green fluorescent protein (GFP)-based redox sensors to the intermembrane space (IMS) and matrix of yeast mitochondria to provide a readout of the subcellular redox environment in live cells (Figs. 6-7). These sensors equilibrate with local glutathione (GSH) pools and register thiol redox changes via disulfide bond formation (Fig. 8). This approach allows us to separately monitor the redox state of the matrix and the IMS, providing a more detailed picture of redox processes in these two compartments (Fig. 9). Our long-term goal is to characterize the subcellular impact of environmental and genetic factors on thiol redox homeostasis to more fully understand their effects on human health and disease.
Dlouhy, A. C.; Beaudoin, J.; Labbé, S.; Outten, C. E. Schizosaccharomyces pombe Grx4 regulates the transcriptional repressor Php4 via [2Fe–2S] cluster binding. Metallomics, 2017, Advance Article. DOI: 10.1039/C7MT00144D.
Dlouhy, A. C.; Li, H.; Albetel; A.-N.; Zhang, B.; Mapolelo, D. T.; Randeniya, S.; Holland, A.; Johnson, M. K.; Outten, C. E. The Escherichia coli BolA protein IbaG forms a histidine-ligated [2Fe-2S] bridged complex with Grx4. Biochemistry, 2016, 55, 6869-79. DOI: 10.1021/acs.biochem.6b00812.
Scian, M., Guttman, M., Bouldin, S. D., Outten, C. E., Atkins, W. M. The myeloablative
drug busulfan converts cysteine to dehydroalanine and lanthionine in redoxins. Biochemistry, 2016, 55, 4720-30.
Ozer, H. K.; Dlouhy, A. C.; Thornton, J. D.; Hu, J.; Liu, Y.; Barycki, J. J.; Balk, J.; Outten, C. E. Cytosolic Fe-S cluster protein maturation and iron regulation are independent of the mitochondrial Erv1/Mia40 import system. J. Biol. Chem., 2015, 290, 27829-27840. DOI: 10.1074/jbc.M115.682179.
Poor, C. B.; Wegner, S. V.; Li, H.; Dlouhy, A. C.; Schuermann, J. P.; Sanishvili, R.; Hinshaw, J. R.; Riggs-Gelasco, P. J.; Outten, C. E.; He, C. Molecular Mechanism and Structure of the Saccharomyces cerevisiae Iron Regulator Aft2. Proc. Natl. Acad. Sci. U.S.A. 2014, 111, 4043 - 4048. DOI: 10.1073/pnas.1318869111.