NADPH oxidases: redox regulation of cell homeostasis and disease

The redox signaling network in mammals has garnered enormous interest and taken on major biological significance in recent years as the scope of NADPH oxidases (NOXs) as regulators of physiological signaling and cellular degeneration has grown exponentially. All NOX isoforms have in common the capacity to generate reactive oxygen species (ROS) superoxide anion (O₂^•-) and/or hydrogen peroxide (H₂O₂). A baseline, normal level of ROS formation supports a wide range of processes under physiological conditions. A disruption in redox balance caused by either the suppression or "super" induction of NOX off balance with antioxidant systems is associated with myriad diseases and cell/tissue damage. Over the past two to three decades, our understanding of NOXs has progressed from almost entirely a phagocyte-, antimicrobial-centered perspective to that of a family of enzymes that is vital to broad cellular function and organismal homeostasis. It is becoming increasingly evident that highly regulated, targeted oxidative protein modifications are elicited in a spatiotemporal manner and initiated at cell membranes in humans by seven NOX isoforms [NOXs 1, 2, 3, 4, 5 and dual oxidases (DUOXs) 1 and 2]. In a sense, this renders NOX-ROS signaling akin to that of other second messenger systems involving localized Ca²⁺ dynamics and tyrosine kinase transactivation. Accordingly, the study of ROS compartmentalization in subcellular organelles has been shown to be crucial to elucidating their role in cell phenotype modulation under physiological and pathophysiological conditions. The NOXs are as distinct in their distribution and activation as they are in their cellular functions, ranging from host defense, second messenger posttranslational modifications (PTMs) to transcriptional, epigenetic, and (de)differentiating effects. This review integrates past knowledge in the field with new focus areas on the leading edge of NOX-centered ROS signaling, including how a new wave of structural information provides insights for NOX biology and targeted therapies.