Plasma Membrane NADH-Oxidoreductase System: A Critical Review of the Structural and Functional Data

Abstract

The observation in the early 1970s that ferricyanide can replace transferrin as a growth factor highlighted the major role plasma membrane proteins can play within a mammalian cell. Ferricyanide, being impermeant to the cell, was assumed to act at the level of the plasma membrane. Since that time, several enzymes isolated from the plasma membrane have been described, which, using NADH as the intracellular electron donor, are capable of reducing ferricyanide. However, their exact modes of action, and their physiological substrates and functions have not been solved to date. Numerous hypotheses have been proposed for the role of such redox enzymes within the plasma membrane. Examples include the regulation of cell signaling, cell growth, apoptosis, proton pumping, and ion channels. All of these roles may be a result of the function of these enzymes as cellular redox sensors. The emergence of many diverse roles for ferricyanide utilizing redox enzymes present in the plasma membrane might also, in part, be due to the numerous redox enzymes present within the membrane; the poor molecular characterization of the enzymes may be the reason for some of the diverging results reported in the literature as various researchers may be working on different enzymes. Here we review the diverse proposals given for structure and function to the plasma membrane NADH-oxidoreductase system(s) with a specific focus on those enzyme activities which can couple ferricyanide and NADH. Although they are still ill-defined enzymes, evidence is rising that they are of utmost significance for cellular regulation.

CNS neurons express two distinct plasma membrane electron transport systems implicated in neuronal viability

“…Although PMOR activity has been associated with many critical cellular functions, such as growth control, apoptosis and bioenergetics, its precise role(s) has been difficult to resolve, possibly due to its overarching role as a redox sensor or as a regulator of the cellular redox environment (Baker and Lawen 2000). Through the transfer of electrons from intracellular NADH to extracellular electron acceptors, including plasma membrane protein disulfides (Morre et al 1998), the PMOR has the ability to regulate both the intracellular (Martinus et al 1993;Larm et al 1994) and plasma membrane redox state to maintain an optimized environment for redox signaling and bioenergetics, both of which play important roles in cellular decisions to live or die (Bowling and Beal 1995;Maher and Schubert 2000).…”

“…Inhibition of the PMOR in q°cells (Larm et al 1994), and other cell lines , causes cell death, highlighting its vital role in redox homeostasis. The PMOR also modulates cellular processes that are redox sensitive, including cell growth, intracellular signaling and apoptosis (reviewed in Baker and Lawen 2000), and it maintains plasma membrane antioxidant systems, preventing oxidative stress-induced cell death (reviewed in Villalba and Navas 2000). Although the PMOR has been extensively studied in non-neuronal cells, to our knowledge, studies of the PMOR in primary CNS neurons have not been reported.…”

Molecular Cloning and Characterization of a Candidate Plant Growth-Related and Time-Keeping Constitutive Cell Surface Hydroquinone (NADH) Oxidase (ENOX1) from <i>Arabidopsis lyrata</i>

“…The high capacity of proliferating mammalian cells to transfer electrons from cytosolic NADH to extracellular acceptors like oxygen via plasma membrane electron transport [45] [46] is now generally regarded as being via a plasma membrane electron transport chain involving reduced quinones as the transmembrane carrier of electrons and protons [3] [47] [48]. The identification and cloning of the constitutive ENOX1 protein of plants whose proposed function is as a terminal oxidase for the plasma membrane electron transport chain [47] rather than superoxide generation, and as a driver of both cell enlargement and of the biological clock represents an important advance in our understanding of these enzyme proteins of the plasma membrane which have, until recently, been largely ill defined [48].…”

Azo Reductase Activity of IntactSaccharomyces cerevisiaeCells Is Dependent on the Fre1p Component of Plasma Membrane Ferric Reductase

“…These systems are linked to several vital cellular functions, including growth control, iron uptake, apoptosis, bioenergetics, transformation, and hormone responses (2,5,28). Some of these roles may be linked to the maintenance of appropriate NAD(P) ϩ /NAD(P)H cytoplasmic ratios.…”