NSF/BIO-DFG: Cytochrome c oxidase adaptation to hypoxia in systemic vascular cells - From structure to function

点击翻译按钮获取中文摘要

All cells in oxygen-breathing creatures must react to changes in oxygen levels. This project will examine how stress caused by low oxygen levels causes a key enzyme, COX, to change its protein composition to be able to function more efficiently under that stress. This will be done by determining how the subunits change after short or continuously low levels of oxygen, and the consequences of these changes on the function of energy usage and function of parts of the cell such as mitochondria. Finally, these results will be compared to those caused by other kinds of stress such as heat or changes of temperature. This project will also offer excellent opportunities to engage future scientists at the high school, undergraduate, and graduate student levels. The PIs will especially encourage undergraduate researchers from underfunded communities in the Detroit area who have not participated in research before. Knowledge of how oxygen levels are sensed holds potential for future medical research to provide treatments for diseases and conditions in which cells are compromised due to low oxygen levels caused by stress, pollution, or disease, thereby promoting the well-being of individuals in society.Changes in oxygen levels pose major threats to aerobic organisms, and they accordingly devote considerable resources to counteracting and minimizing the consequent damage. One such recently uncovered mechanism is the reconfiguration of cytochrome c oxidase (COX or complex IV), the final and regulatory electron donor to oxygen of the mitochondrial electron transport chain (ETC). Low oxygen levels induce changing expression of some of the 14 COX subunits, although much remains unknown about this process. This project will investigate the cause and consequences of hypoxia-induced COX remodeling with a focus on previously identified key oxygen-dependent COX subunits in primary cells, and will establish a link of these subunits to redox sensing and signaling. The project will involve: (1) characterization of the dynamic regulation of COX subunit isoform composition in systemic pericytes in response to chronic hypoxia, and comparison to that of systemic vascular cells; (2) characterization of structural consequences of COX remodeling upon chronic hypoxia; (3) characterization of functional consequences of COX remodeling on mitochondrial and cellular health; and (4) comparison of key findings of COX remodeling to responses to other stress stimuli. The project will thus uncover and identify fundamental regulatory mechanisms of mitochondrial oxygen and redox signaling mediated by COX subunit expression.This collaborative US/Germany project is supported by the US National Science Foundation and the German Research Foundation (Deutsche Forschungemeinschaft).This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.