Regulation of the Nrf2 antioxidant pathway by microRNAs: New players in micromanaging redox homeostasis

MicroRNAs are now thought to play a central role in the regulation of many diverse aspects of cell biology; however, it remains to be fully elucidated how microRNAs can orchestrate cellular redox homeostasis, which plays a central role in a multitude of physiological and pathophysiological processes. The redox-sensitive transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) serves as a "master regulator" of cell survival through the coordinated induction of phase II and antioxidant defense enzymes to counteract oxidative stress and modulate redox signaling events. MicroRNAs are able to "fine-tune" the regulation of processes including those directly interacting with the Nrf2 pathway and the generation of reactive oxygen species (ROS). This review highlights that cellular redox homeostasis can be regulated by microRNAs through their modulation of Nrf2-driven antioxidant gene expression as well as key enzymes that generate ROS, which in turn can alter the biogenesis and processing of microRNAs. Therefore redox sensitive microRNAs or "redoximiRs" add an important regulatory mechanism for redox signaling beyond the well-characterized actions of Nrf2. The potential exists for microRNA-based therapies where diminished antioxidant defenses and dysregulated redox signaling can lead to cardiovascular diseases, cancers, neurodegeneration, and accelerated aging.