Catherine Pasquier Memorial Award Lecture (shared): The adventure of detecting subtle signals (such as protein nitrosothiols and superoxide) among cell traffic jams (from proteomics to hypoxia)

Abstract

Like big human cities, cells are crowded environments with a lot of inhabitants, where a myriad of signals try to orchestrate how each component can do its best among the crowd, and how the whole system respond to changes in the environment. Some signals are robust and stable, so they can be easily studied by life science researchers. However, free radical researchers know well that other molecular signals are short-lived and unstable. I have been involved in several studies that can be seen as adventures searching for those subtle signals, overcoming the difficulties that appear in the way. One is the reliable proteomic identification of protein S-nitrosylation (or S-nitrosation), and of other reversible oxidations of cysteines, in physiological scenarios where they can act as signals (not just in nitrosative, oxidative or similar stresses). Different techniques have been used for that purpose (called “thiol redox proteomics”), with technical developments still ongoing. A related adventure is the study of the functional relevance of these modifications in individual proteins, and of the particularities of these modes of signalling. Another adventure deals with the role of reactive oxygen species production in hypoxia sensing and adaptation, on which a debate has been maintained for a long time. We have measured superoxide production in acute hypoxia, showing there is a fast burst at the first minutes of acute hypoxia, and we are currently studying its molecular mechanism, implying mitochondrial complex I and the sodium/calcium exchanger. This can be a common signal to different cell types that produces diverse effects depending on the signalling cascades and effectors of each cell type. Thiol redox proteomics can help in identifying the specific protein cysteine residues that can be affected by reversible oxidation and take part in those signals.