Control of Cell Growth by Plasma Membrane NADH Oxidation

Most cells that have been tested have two trans plasma membrane electron transport systems for the oxidation of cytosolic NADH. The first is an oxidase which transfers electrons from NADH to oxygen through dehydrogenases to coenzyme Q and a terminal reduced coenzyme Q oxidase. The second system for trans membrane electrontransport from NADH is a protein complex called porin or Voltage Dependent Anion Channel (VDAC). It transfers electrons across the 32 F. L. Crane et al. membrane on a pair of SH groups which line the channel. It does not react directly with oxygen but transfers electrons to an external artificial acceptor such as ferricyanide. The natural acceptor is most likely to be semidehydroascorbic acid which would be reduced to ascorbate which can be oxidized by ascorbate oxidase acting as the terminal oxidase. Activation of NADH oxidation in serum deficient media stimulates growth of cultured cells. Which oxidase contributes to the growth stimulation has not been determined. Here we consider inhibitors which can help define which NADH oxidation controls growth Growth stimulation is much greater with transformed tumor cells than with untransformed cells. Inhibitors of transmembrane electron transport inhibit growth and a wide group of well known anti tumor drugs are excellent inhibitors of the transmembrane electron transport in tumor cells and are less inhibitory in untransformed cells. The terminal oxidase copper protein, referred to as tNOX or ECTO-NOX, appears to be modified with cell transformation so that it is less firmly attached to the outer surface of the cell and is released into the sera more than c NOX.1 Activation of the trans membrane electron transport increases the NAD+ concentration inside the cell by oxidation of NADH. Since the reduction of pyruvate , which also increases cytosolic NAD, can stimulate growth a function of NAD in growth control is indicated which could involve activation of sirtuin 1 by NAD in the cytoplasm. Sirtuin 1 is known to control the cell cycle and apoptosis.