Mammalian NADPH Oxidases

Reactive oxygen species (ROS) are highly reactive oxygen derivatives. Initially, they were considered as metabolic by-products (of mitochondria in particular), which consistently lead to aging and disease. Over the last decades, however, it became increasingly apparent that virtually all eukaryotic cells possess specifically ROS-producing enzymes, namely, NOX NADPH oxidases. In most mammals, there are seven NOX isoforms: three closely related isoforms, NOX1, 2, 3, which are activated by cytoplasmic subunits; NOX4, which appears to be constitutively active; and the EF-hand-containing Ca2+-activated isoforms NOX5 and DUOX1 and 2. Loss-of-function mutations in NOX genes can lead to serious human disease. NOX2 deficiency leads to primary immune deficiency, while DUOX2 deficiency presents as congenital hypothyroidism. Nox-deficient mice provide important tools to explore the physiological functions of various NADPH oxidases as a loss of function in Nox2, Nox3, and Duox2 leads to a spontaneous phenotype. The genetic absence of Nox1, Nox4, and Duox1 does not result in an obvious mouse phenotype (the NOX5 gene is absent in rodents and can therefore not be studied using knockout mice). Since the discovery of the NOX family at the turn of the millennium, much progress in understanding the biochemistry and the physiology of NOX has been made; however many questions remain unanswered to date. This chapter is an overview of our present knowledge on mammalian NOX/DUOX enzymes.