Making sense of reAKTive oxygen species

The association of cellular redox states with a variety of physiological and pathophysiological states is becoming increasingly appreciated in biology. Recent studies report on advances in our ability to measure redox changes and exploit them for therapeutic benefit.

The investigation of changes in cellular redox is technically challenging. Redox couples, such as GSH:GSSG or NADPH:NADP+, change dynamically in response to oxidative challenges and the ratio of these molecules can vary significantly in subcellular compartments. The development of genetically encoded biosensors, which give a read-out of hydrogen peroxide or the GSH:GSSG redox couple in real time, has advanced our ability to assess changes in redox homeostasis within the cell. However, existing redox biosensors have their limitations—while they are able monitor changes in the antioxidant state after oxidative insults, they lack the sensitivity required to measure basal, unstimulated H₂O₂ levels. To overcome these challenges, Morgan et al.¹ developed a new ultrasensitive, genetically encoded H₂O₂ sensor based on a redox relay between Tsa2, a 2-Cys peroxidredoxin from S accharomyces cerevisiae, and roGFP2, a redox-sensitive fluorescent probe. The authors observed that existing sensors, such as HyPer² and roGFP2-Orp1,³ react with H₂O₂ 100-fold more slowly than 2-Cys peroxiredoxins, the most efficient thiol peroxidases. By screening all eight yeast thiol peroxidases for their ability to transfer electrons from H₂O₂ to roGFP2, the authors found that the roGFP2-Tsa2 fusion showed greater and more prolonged roGFP2 oxidation after H₂O₂ exposure than the existing roGFP2-Orp1 sensor.

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