In his recent Journal of Biological Chemistry minireview, Helmut Sies of the Heinrich Heine University Düsseldorf in Germany provides a comprehensive review on the dual roles of metabolic hydrogen peroxide production in animal physiology. As the originator of the concept “oxidative stress” and a pioneer in this field, Sies provides an expert account with a focus on the methods used to measure intracellular concentrations of hydrogen peroxide (he was the first to demonstrate H2O2 as a normal metabolite in mammalian tissue); the primary biological modes by which it is produced or neutralized; and its significance in both redox signaling and oxidative stress pathways.
The toxic effects of hydrogen peroxide — a reactive oxygen species produced during cellular processes, such as aerobic respiration in mitochondria, or as a defense mechanism within phagocytes — long have been associated with a plethora of biological processes and disorders including aging, cancer, diabetes and inflammation. Research now indicates that hydrogen peroxide also serves as an important redox-signaling compound to indicate oxidative stress (i.e., an imbalance in the ratio of oxidants to antioxidants), thus posing as a transcription-independent second messenger in a number of pathways including insulin signaling and ROS-defense mechanisms.
The redox-signaling function likely results from the direct oxidation of reactive protein thiols, causing post-translational modifications that affect a large number of proteins within the redox proteome. One major unanswered question that remains is the concentration at which hydrogen peroxide is a) a useful redox signal to keep cells in a ready state to respond to oxidative stress or b) a toxic substance that causes detrimental molecular damage. Sies advocates for the advancement of noninvasive cell biology methods toward quantitative, real-time analyses to address this issue of “redox optimization” in future research. However, he concludes, “The threshold from signaling to excessive toxic levels will be challenging to further identify. The precise transition points for these cellular responses may vary due to cell type and metabolic conditions.”
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