NADH oxidase of plasma membranes.

NADH oxidase is a cyanide-resistant and hormone-responsive oxidase intrinsic to the plasma membrane of both plant and animal cells. The activity has many unique characteristics that distinguish it from other oxidases and oxidoreductases of both organelles and internal membranes and from other oxidoreductases of the plasma membrane. Among these are resistance to inhibition by cyanide, catalase, superoxide dismutase, and phenylchloromercuribenzoate. Activity is stimulated by hormones and growth factors and inhibited by quinone analogs such as piercidin, the flavin antagonist atebrin, and growth inhibiting gangliosides such as GM3. In marked contact to the NADH-ferricyanide oxidoreductase of the plasma membrane, the NADH oxidase is activated by lysophospholipids and fatty acids, products of phospholipase A2 action, in a time-dependent manner suggestive of stabilization of an activated form of the enzyme. The hormone-responsive NADH oxidase of the plasma membrane is not a peroxidase and may function as a terminal oxidase to link transfer of electrons from NADH to oxygen at the plasma membrane. The functional significance of the NADH oxidase of the plasma membrane is unknown but some relationship to growth or growth control is indicated. In both animal and plant plasma membranes, the oxidase is activated by growth factors and hormones to which the cells or tissues of origin have functional hormone or growth factor receptors. In addition, substances that inhibit the oxidase, the associated transmembrane reductase or both, inhibit growth. In transformed cells and tissues, the hormone and growth factor responsiveness of the NADH oxidase is reduced or absent. With human keratinocytes which exhibit an increased sensitivity to the antiproliferative action of both retinoic acid and calcitriol, the NADH oxidase of the plasma membrane is strongly inhibited by these agents and shows the same increased sensitivity. If transfer of electrons from NADH to oxygen across or within the eukaryotic plasma membrane is an important aspect of growth or growth control, then the hormone- and growth factor-responsive NADH oxidase associated with the plasma membrane could be of fundamental importance. Because of its low basal activity, stimulation by growth factors and hormones, and the inhibition of growth in direct proportion to inhibition of the oxidase, the activity is a candidate as a rate-limiting step in the growth process. Completely unknown is the mechanism whereby NADH oxidation and growth or growth control may be coupled. This, together with further characterization of the activity and the mechanism of loss of control with neoplastic transformation, represent important challenges for future investigations.