Mechanisms and outcomes of the hyperglycemic shift from apoptosis to necroptosis
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Issue Date
2019-07
Authors
Deragon, Matthew '19
Degree
MS in Molecular Biosciences
Advisor
LaRocca, Timothy J
Committee Members
Malik, Meenakshi
Sharifi, H. John
Yager, Eric
Sharifi, H. John
Yager, Eric
Journal Title
Journal ISSN
Volume Title
Abstract
Apoptosis is a non-inflammatory type of programmed cell death (PCD) that is dependent on caspase activation. One type of inflammatory PCD, necroptosis, instead depends on the activation and phosphorylation of the kinases RIP1, RIP3, and MLKL. These three kinases associate with one another to form the necrosome signaling complex. Activation of necroptosis stimulates cellular metabolism and thus increases the production of toxic by-products such as reactive oxygen species (ROS), which leads to cell damage associated with this pathway. Our previous work has shown that hyperglycemic conditions cause a shift in PCD from apoptosis to necroptosis. Here we investigate the role of cellular metabolism and ROS in this high glucose-dependent PCD shift. Through the inhibition of glycolysis, ROS, or superoxide dismutase we show that necroptosis and cellular metabolism/ROS participate in a positive feedback loop, activating one another under hyperglycemic conditions. This work is important due to the clinical relevance of PCD to neonatal hypoxia-ischemia (HI) brain injury. While apoptosis normally predominates during neonatal HI brain injury in euglycemic mice, hyperglycemia induces a PCD shift to necroptosis, resulting in increased tissue damage. Using the mitochondrial ROS scavenger, mitoSNO, we establish that ROS are essential for the exacerbation of neonatal HI-brain injury in hyperglycemic mice. Determining the mechanism by which this shift occurs is critical for the development of therapeutic strategies that might prevent such exacerbation of ischemic injuries in hyperglycemic individuals.
Citation
Deragon MA. Mechanisms and outcomes of the hyperglycemic shift from apoptosis to necroptosis [thesis]. Ann Arbor (MI): Proquest LLC; 2019. 64 p.
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