个人简介

B.S., 1995, College of William and Mary Ph.D., 2001, Northwestern University Postdoctoral Fellow, 2001-2005, Johns Hopkins University SC Governor's Young Scientist Award for Excellence in Scientific Research, 2013 USC Breakthrough Rising Star, 2011 Presidential Early Career Award for Scientists and Engineers (PECASE), 2009 NIEHS Transition to Independent Positions (K22) Award, 2005-2008

研究领域

Biochemistry

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. Fig. 1. Circular dichroism spectra of [2Fe-2S] cluster-bound human Glrx3 homodimers (blue) titrated with increasing BolA2 protein (red line = 2-fold excess). 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 (Fig 1). 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 Fig. 2. Fluorescence microscopy images of yeast cells expressing cytosol, matrix, or IMS redox sensors. environment in live cells (Fig. 2). These sensors equilibrate with local glutathione (GSH) pools and register thiol redox changes via disulfide bond formation. 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. 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.

近期论文

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Poor CB, Wegner SV, Li H, Dlouhy AC, Schuermann JP, Sanishvili R, Hinshaw JR, Riggs-Gelasco PJ, Outten CE, He C. ""Molecular mechanism and structure of the Saccharomyces cerevisiae iron regulator Aft2."" Proc. Natl. Acad. Sci. U.S.A. 2014, 111, 4043-8. Outten CE, Albetel AN. ""Iron sensing and regulation in Saccharomyces cerevisiae: Ironing out the mechanistic details."" Curr. Opin. Microbiol. 2013, 16, 662-8. Dlouhy AC, Outten CE. ""The iron metallome in eukaryotic organisms."" Met. Ions Life Sci. 2013, 12, 241-78. Mapolelo DT, Zhang B, Randeniya S, Albetel AN, Li H, Couturier J, Outten CE, Rouhier N, Johnson MK. ""Monothiol glutaredoxins and A-type proteins: partners in Fe-S cluster trafficking."" Dalton Trans. 2013, 42, 107-15 Toledano M, Delaunay-Moisan A, Outten CE, Igbaria A. ""Functions and cellular compartmentation of the thioredoxin and glutathione pathways in yeast."" Antioxid. Redox Signal. 2013, 18, 1699-711. Bouldin SD, Darch MA, Hart PJ, Outten CE. ""Redox properties of the disulfide bond of human Cu,Zn superoxide dismutase and the effects of human glutaredoxin 1."" Biochem. J. 2012, 446, 59-67. Li H, Outten CE. ""Monothiol CGFS glutaredoxins and BolA-like proteins: [2Fe-2S] binding partners in iron homeostasis."" Biochemistry, 2012, 51, 4377-89. Dardalhon M, Kumar C, Iraqui I, Vernis L, Kienda G, Banach-Latapy A, He T, Chanet R, Faye G, Outten CE, Huang ME. ""Redox-sensitive YFP sensors monitor dynamic nuclear and cytosolic glutathione redox changes"" Free Rad. Biol. Med. 2012, 52, 2254-65. Li H, Mapolelo DT, Randeniya S, Johnson MK, Outten CE. ""Human glutaredoxin 3 forms [2Fe-2S]-bridged complexes with human BolA2."" Biochemistry. 2012, 51, 1687-96.