Critical Role of Electron Leak from Mitochondrial Electron Transport Chain Complex I in Oxygen Sensing in the Rabbit Ductus Arteriosus
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Authors
Read, Austin
Date
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thesis
Language
eng
Keyword
Ductus Arteriosus , Reactive oxygen species , Oxygen sensing , Electron leak suppressor , Patent Ductus Arteriosus
Alternative Title
Abstract
Background: The ductus arteriosus (DA) connects the pulmonary trunk to the descending thoracic aorta, allowing placentally oxygenated blood to bypass the non-ventilated fetal lungs and enter the systemic circulation. The fetus’ systemic arterial oxygen tension (pO2) is <40 mmHg, maintaining the DA in a state of hypoxic vasodilation. As pO2 rises with the first breath, the DA constricts and becomes functionally closed within minutes. The oxygen sensor responsible for initiating this vasoconstrictor effect resides within the mitochondria of DA smooth muscle cells (DASMC). At birth, increased pO2 leads to increased reactive oxygen species (ROS) production by complexes I and III of the electron transport chain (ETC). These ROS act as diffusible signaling molecules and inhibit redox sensitive potassium channels causing DASMC depolarization and vasoconstriction. Complex I and III inhibitors, rotenone and antimycin A, relax the DA ex vivo by decreasing normoxic ROS production by the mitochondria, but also alter mitochondrial respiration. A new generation of electron leak suppressors, S1QEL and S3QEL, which decrease electron leak from complexes I and III respectively, can selectively decrease ROS production without inhibiting the metabolic function of the ETC complexes. These new leak suppressors may offer better understanding of the physiology of O2 sensing in the DA and also offer new therapeutic avenues for controlling DA tone in vivo.
Methods/Results: DA tissues were obtained from term rabbit kits. Using the ring bath model for measuring vessel tone ex vivo, we have shown that S1QEL causes a vasodilatory effect in oxygen induced pre-constricted DAs. In rabbit DASMC, S1QEL decreases oxygen consumption rates (OCR), while maintaining key parameters related to mitochondrial respiration. In DASMC isolated from humans, S1QEL blunts oxygen induced increases in superoxide generation. In vivo, S1QEL reverses oxygen induced constriction of the DA in term rabbit kits.
Conclusions: S1QEL, but not S3QEL, causes reversal of DA constriction both ex vivo and in vivo, suggesting an importance for Complex I electron leak during DA oxygen sensing. S1QEL decreases superoxide production in DASMC exposed to normoxia, but maintains key parameters of mitochondrial respiration, confirming the importance of ROS produced by Complex I in DA oxygen signaling.
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ProQuest PhD and Master's Theses International Dissemination Agreement
Intellectual Property Guidelines at Queen's University
Copying and Preserving Your Thesis
This publication is made available by the authority of the copyright owner solely for the purpose of private study and research and may not be copied or reproduced except as permitted by the copyright laws without written authority from the copyright owner.