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Permanent link (DOI): https://doi.org/10.7939/R32F7K38V

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Role of Epoxyeicosanoids in Protecting Mitochondria during Cellular Stress Open Access

Descriptions

Other title
Subject/Keyword
Mitochondrial Quality Control
EETs
Mitochondria
Starvation
Mitochondrial Dynamics
epoxyeicosatrienoic acids
Mitochondrial Biogenesis
Type of item
Thesis
Degree grantor
University of Alberta
Author or creator
El-Sikhry, Haitham E
Supervisor and department
Seubert, John (Pharmacy)
Examining committee member and department
Ghosh, Sanjoy (Biology)
Jurasz, Paul (Pharmacy)
Lopaschuk, Gary (Pharmacology)
Simmen, Thomas (Cell Biology)
Seubert, John (Pharmacy)
Department
Faculty of Pharmacy and Pharmaceutical Sciences
Specialization
Pharmaceutical Sciences
Date accepted
2016-03-29T15:03:39Z
Graduation date
2016-06:Spring 2016
Degree
Doctor of Philosophy
Degree level
Doctoral
Abstract
Mitochondria are at the center of cardiac health and disease. These vital organelles provide most of the energy to the contractile apparatus and play a strategic role in cardiomyocyte survival during cellular stress. Cardiovascular diseases and many aging related diseases are often associated with a decline in mitochondrial function. Recent studies suggested that epoxyeicosanoids protect cardiac mitochondria against ischemia and reperfusion-induced damage. Although epoxyeicosatrienoic acids (EETs) have acknowledged cytoprotective and anti-apoptotic properties in several tissues, little is known about their mitochondrial protective effects. Studies presented in this thesis investigated the mechanisms by which EETs influence mitochondrial function and dynamics during different types of cellular stress. Both natural EETs and their synthetic mimetics have been used to examine their effect on mitochondria. Several models of cellular stress, including serum starvation and photodynamic oxidative stress, have been applied to study mitochondrial responses. Live cell microscopy has been utilized to monitor changes in mitochondrial membrane potential and mitochondrial morphological dynamics. Mitochondrial energetic functions have been assessed with respirometry techniques as well as measurement of catalytic activity of key mitochondrial enzymes. DNA-binding experiments were used to assess mitochondrial biogenesis signaling and immunoblotting methods were used to assess expression levels of mitochondrial proteins. Negative control experiments were conducted using the putative EET receptor antagonist 14, 15-EEZE to confirm EET-mediated effects. We found that EETs delayed the collapse of mitochondrial membrane potential and attenuated their fragmentation following acute photodynamic stress. Prolonged serum starvation induced a sustained mitochondrial hyperfusion and a relative increase in mitochondrial protein expression but with a progressive decline in mitochondrial energetic function. EET-treatment induced preservation of mitochondrial function against starvation-induced dysfunction. This was associated with balanced mitochondrial morphological dynamics, enhanced OPA1-dependent stress response, and stimulated mitochondrial biogenesis. Together, studies presented here support a mitochondrial protective effect of EET signaling and provide insight into the strategic role of mitochondria during acute and chronic cellular stress. We discuss the molecular mechanisms that promote mitochondrial quality which can offer a promising therapeutic approach to improve organ function in cardiovascular diseases as well as several other age-related diseases.
Language
English
DOI
doi:10.7939/R32F7K38V
Rights
This thesis is made available by the University of Alberta Libraries with permission of the copyright owner solely for the purpose of private, scholarly or scientific research. This thesis, or any portion thereof, may not otherwise be copied or reproduced without the written consent of the copyright owner, except to the extent permitted by Canadian copyright law.
Citation for previous publication
El-Sikhry, H.E., Miller, G.G., Madiyalakan, M.R. & Seubert, J.M. Sonodynamic and photodynamic mechanisms of action of the novel hypocrellin sonosensitizer, SL017: mitochondrial cell death is attenuated by 11, 12-epoxyeicosatrienoic acid. Invest New Drugs 29, 1328-1336 (2011).

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