Role of ROS and mitochondria during the hyperglycemic shift from apoptosis to necroptosis

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Issue Date
2020-07
Authors
Haluska, Robert J., Jr. '20
Degree
MS in Molecular Biosciences
Advisor
LaRocca, Timothy J.
Committee Members
Malik, Meenakshi
Sharifi, H. John
Singh, Vir
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Abstract
Eukaryotes undergo two distinct principal modes of cell death, apoptosis and necroptosis. Apoptosis is non-inflammatory whereas necroptosis is highly inflammatory. Previously we showed that there is a shift in cell death mechanisms toward necroptosis during hyperglycemia. In addition, we showed that the hyperglycemic shift to necroptosis exacerbated neonatal hypoxia-ischemia (HI) brain injury in vivo. However, the underlying mechanism of this novel shift in cell death modalities is not well understood. Cell death proteins serve different roles depending upon the cellular compartment in which they are found. During necroptosis, in particular, factors including RIP1, RIP3, and MLKL have distinct roles when they are found in the membrane vs. the mitochondria vs. the cytoplasm. Trafficking of RIP1, RIP3, and MLKL to the mitochondria leads to ROS production during canonical necroptosis. We will analyze cellular compartmentalization of these factors during the hyperglycemic shift to necroptosis using density gradient ultracentrifugation. We will also be exploring the impact of ROS in the absence of death receptor engagement.
Citation
Haluska RJ. Role of ros and mitochondria during the hyperglycemic shift from apoptosis to necroptosis [thesis]. Ann Arbor (MI): Proquest LLC; 2020. 53 p.
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