D-Amino acid oxidase-derived chemogenetic oxidative stress: Unraveling the multi-omic responses to in vivo redox stress

Chemogenetic approaches have been developed to define the mechanisms whereby the intracellular oxidant hydrogen peroxide (H₂O₂) modulates both physiological and pathological responses. Recombinant yeast D-amino acid oxidase (DAAO) can be exploited to modulate H₂O₂ in target cells and tissues. In vitro studies using cultured cells expressing recombinant DAAO have provided critical new information on the intracellular transport and metabolism of H₂O₂ with great temporal and spatial resolution. In contrast, in vivo studies using chemogenetic/transgenic animal models have explored the pathological effects of chronically elevated H₂O₂ in tissues. Coupled with transcriptomic, proteomic, and metabolomic methods, in vivo chemogenetic approaches are providing new insights into the adaptations to oxidative stress. This review of chemogenetic applications focuses on new models of heart failure and neurodegeneration that leverage in vivo chemogenetic modulation of oxidative stress in target tissues to identify new therapeutic targets.