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Undergraduate Research Opportunities Program

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Expansion of Mitochondrial and Nuclear Heme Sensor Library

2019-05 , Atuluru, Pranusha

The long-term objective of the work in the lab is to determine the mechanisms by which cells sense and respond to the utilization of heme, an essential nutrient. Heme is an iron-containing compound of the porphyrin class that enables proteins to carry out an array of functions. Heme-dependent processes require that heme be dynamically mobilized to hemoproteins in almost every subcellular compartment. Although it is understood that the cytotoxicity and hydrophobicity of heme requires heme be tightly regulated by the cell, the method by which this is done is unknown [1]. The primary factor that limits the understanding of heme mobilization and trafficking is the lack of tools available to sense heme, more specifically labile heme. The Reddi lab is working to develop ratiometric fluorescent sensors to offer better insight into subcellular labile heme pools relevant for heme trafficking and signaling. HS1 (Heme Sensor 1) is mutated at either the His or Met in the heme-binding coordinating bundle of cytochrome to create sensors of different affinity. Ten new mutant sensors were created from the original HS1 and HS1-M7A, and it is seen that two sensors, H102C and H102C-M7H, are the most suitable sensors to be used in the mitochondria, nucleus and cytosol. With the use of these sensors, different pathways of heme trafficking and signaling can be studied in the cell.

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Probing Heme Trafficking Factors via Organellar Contact Points Using Genetically Encoded Fluorescent Heme Sensors

2019-05 , Saini, Arushi

Heme is an important protein cofactor and signaling molecule that plays diverse roles in biological systems. The hydrophobicity and cytotoxicity of heme necessitates that it is transported and trafficked in a regulated manner. However, the molecules and mechanisms responsible for mediating heme trafficking remain poorly understood. Until recently, the tools to study heme in vivo did not exist, but the emergence of genetically encoded fluorescent sensors has enabled comprehensive real time analysis of heme in model organisms such as Saccharomyces cerevisiae. This study showcases a new a protocol that allows investigation of heme trafficking from its site of synthesis in the matrix side of the mitochondrial inner membrane to the outer matrix, cytosol, and nucleus over time. The method allows for the simultaneous examination of heme re-population in three cellular compartments after chemically depleting it. The study revealed that mitochondrial contact points play central roles in regulating heme availability and illuminates novel approaches to heme trafficking. These methods have the potential to be adapted to more inclusive compartmental analyses and enable a better understanding of heme trafficking which can empower innovative approaches to study infectious diseases, neurodegenerative disorders, and anemias associated with perturbations in heme cellular dynamics.

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Utilization of Cytochrome b562 as a Localized Labile Heme Chelator

2019-05 , Jenkin, Bryan

Heme is an essential, but toxic cofactor required for virtually all aerobic life. As a consequence, cells are challenged to safely traffic heme to hemoproteins that reside in every subcellular compartment. However, the mechanisms underlying heme transport and trafficking are largely unknown. Moreover, it is unclear how various subcellular compartments communicate their requirement for heme to the mitochondria, where heme is synthesized. In order to determine how different subcellular compartments sense and respond to heme deficiency, I have been developing a heme chelator to induce local heme deficiencies. Once this is achieved, we can employ transcriptome and proteome profiling to determine pathways that enable various organelles to adapt to heme deficiency. Altogether, we seek to better understand how cells appropriate and distribute heme to diverse compartments that require this essential nutrient.

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