Sex specific effects of indomethacin-induced inflammatory bowel disease on mitochondrial function

Friday, October 29, 2021


Dr. Kristin Edwards

Department of Cell and Molecular Biology

University of Mississippi Medical Center

Friday, October 29, 2021 at 3:30 PM in Hand 1144

Abstract:
     Inflammatory bowel disease (IBD) is a term used to describe disorders that involve chronic inflammation of the digestive tract, such as Crohn’s Disease and Ulcerative Colitis. IBD currently effects three million people in the United States, with many going undiagnosed. Women appear to have more severe and recurring symptoms of IBD compared to men, most likely due to hormonal fluctuations. A few IBD patient studies have shown alterations in mitochondrial function. Our goal is to determine the role mitochondrial dysfunction and mitochondrial reactive oxygen species (mtROS) in the development of IBD in males and females. Male and female rats 8-10 weeks of age received two injections of indomethacin (7.5 mg/kg) exactly 24 hours apart. Mitochondrial respiration was measured using glutamate/malate, succinate, oleate, or octanoate as substrates. Mitochondrial reactive oxygen species (mtROS) was measured simultaneously with mitochondrial respiration using an Oroboros Fluorespirometer. Activities of individual mitochondrial electron transport complexes were also measured. Citrate synthase activity was measured as a marker for mitochondrial content. In the indomethacin-induced Crohn’s Disease group (CD), rats showed a significant decrease in body weight compared to controls. Females show a 12% loss and males a 6% loss. Female CD rats showed a significant decrease in mitochondrial respiration compared to controls using glutamate/malate (p=0.0014), succinate, oleate, or octanoate. Male CD rats only showed a significant decrease using glutamate/malate and succinate. CD rats showed a significant increase in mtROS production compared to controls. Female CD rats showed a 4-fold increase while males showed a 2.5 fold increase. Female CD rats showed a significant decrease in each of the individual mitochondrial electron transport complex activities while males only showed a significant decrease in complex II, III, and IV activities. Both male and female CD rats showed a significant decrease in mitochondrial content compared to controls. Alterations to mitochondrial function, mtROS production, and mitochondrial content were observed in the indomethacin-induced rat model of Crohn’s Disease suggesting a link between mitochondrial dysfunction and Crohn’s Disease. Females showed more significant changes in body weight and mitochondrial dysfunction compared to males. This may explain the observed differences in symptom severity between men and women. Further research is needed in this area. This study provides a better understanding of the role mitochondria in the development of IBD and an avenue for the development of strategies to re-establish normal mitochondrial function that could provide more options for preventive and therapeutic interventions for IBD.

Bio: Dr. Edwards received her BS degree in biology and chemistry from Jacksonville State University and her PhD in biochemistry from UMMC. Her PhD research focused on the mechanisms by which the echinocandin group of antifungal drugs affect mitochondrial bioenergetics. Her postdoctoral research focused on the deficiency of the mitochondrial inner membrane protein, uncoupling protein 3, and its impairment of cardiac energetics and contractile recovery following ischemia and reperfusion. She has established protocols for isolating mitochondria from various tissues and measuring mitochondrial function, reactive oxygen species production, ATP production, and membrane potential. Her work has led to various awards, including the APS- Cardiovascular Section Research Recognition Award. Dr. Edward’s current research focuses on the role of mitochondrial dysfunction associated with inflammatory bowel disease (IBD); the role of mitochondrial dysfunction in the comorbidities associated with IBD; and how mitochondrial targeted therapeutics are a beneficial treatment option for IBD and other human diseases.


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