Plasma membrane coenzyme Q: evidence for a role in autism.

BACKGROUND: The Voltage Dependent Anion Channel (VDAC) is involved in control of autism. Treatments, including coenzyme Q, have had some success on autism control. DATA SOURCES: Correlation of porin redox activity and expression of autism is based on extensive literature, especially studies of antibodies, identification of cytosolic nicotinamide adenine dinucleotide reduced (NADH) dehydrogenase activity in the VDAC, and evidence for extreme sensitivity of the dehydrogenase to a mercurial. Evidence for a coenzyme Q requirement came from extraction and analog inhibition of NADH ferricyanide reductase in the erythrocyte plasma membrane, done in 1994, and reinterpreted when it was identified in VDAC in 2004. The effects of ubiquinol (the QH2 - reduced form of coenzyme Q) in children with autism were studied. RESULTS: A new role for coenzyme Q in the porin channels has implications on autism. Ubiquinol, the more active form of coenzyme Q, produces favorable response in children with autism. Agents which affected electron transport in porin show parallel effects in autism. CONCLUSION: We propose a hypothesis that autism is controlled by a coenzyme Q-dependent redox system in the porin channels; this conclusion is based on the effects of agents that positively or negatively affect electron transport and the symptoms of autism. The full understanding of the mechanism of their control needs to be established.

Evidence for a relation between plasma membrane coenzyme Q and autism.

Voltage Dependent Anion Channel (VDAC) in the cell membrane transports important molecules and ions across the cell membrane. It was recently shown that VDAC also acts as a trans membrane NADH dehydrogenase. A recent study showed that autistic children have increased antibodies to VDAC proteins and such a binding inhibits both the transport and dehydrogenase activities of VDAC. The derived function of VDAC, therefore, might underlie the development of autism. It has also recently been shown that the dehydrogenase in erythrocyte membranes requires coenzyme Q. Since the plasma membrane oxidase is not in erythrocyte membranes, the coenzyme Q requirement must be for VDAC. This is consistent with sensitivity of the dehydrogenase to SH inhibitors. This is a novel site for coenzyme Q function but it has an analogy with the Q requirement for the mitochondrial uncoupler protein and the permeability transition pore.

Sirtuin activation: a role for plasma membrane in the cell growth puzzle.

For more than 20 years, the observation that impermeable oxidants can stimulate cell growth has not been satisfactorily explained. The discovery of sirtuins provides a logical answer to the puzzle. The NADH-dependent transplasma membrane electron transport system, which is stimulated by growth factors and interventions such as calorie restriction, can transfer electrons to external acceptors and protect against stress-induced apoptosis. We hypothesize that the activation of plasma membrane electron transport contributes to the cytosolic NAD(+) pool required for sirtuin to activate transcription factors necessary for cell growth and survival.

Putting together a plasma membrane NADH oxidase: a tale of three laboratories.

The observation that high cellular concentrations of NADH were associated with low adenylate cyclase activity led to a search for the mechanism of the effect. Since cyclase is in the plasma membrane, we considered the membrane might have a site for NADH action, and that NADH might be oxidized at that site. A test for NADH oxidase showed very low activity, which could be increased by adding growth factors. The plasma membrane oxidase was not inhibited by inhibitors of mitochondrial NADH oxidase such as cyanide, rotenone or antimycin. Stimulation of the plasma membrane oxidase by iso-proterenol or triiodothyronine was different from lack of stimulation in endoplasmic reticulum. After 25 years of research, three components of a trans membrane NADH oxidase have been discovered. Flavoprotein NADH coenzyme Q reductases (NADH cytochrome b reductase) on the inside, coenzyme Q in the middle, and a coenzyme Q oxidase on the outside as a terminal oxidase. The external oxidase segment is a copper protein with unique properties in timekeeping, protein disulfide isomerase and endogenous NADH oxidase activity, which affords a mechanism for control of cell growth by the overall NADH oxidase and the remarkable inhibition of oxidase activity and growth of cancer cells by a wide range of anti-tumor drugs. A second trans plasma membrane electron transport system has been found in voltage dependent anion channel (VDAC), which has NADH ferricyanide reductase activity. This activity must be considered in relation to ferricyanide stimulation of growth and increased VDAC antibodies in patients with autism.

The oxidative function of diferric transferrin.

There is evidence for an unexpected role of diferric transferrin as a terminal oxidase for the transplasma membrane oxidation of cytosolic NADH. In the original studies which showed the reduction of iron in transferrin by the plasma membranes NADH oxidase, the possible role of the reduction on iron uptake was emphasized. The rapid reoxidation of transferrin iron under aerobic conditions precludes a role for surface reduction at neutral pH for release of iron for uptake at the plasma membrane. The stimulation of cytosolic NADH oxidation by diferric transferrin indicates that the transferrin can act as a terminal oxidase for the transplasma membrane NADH oxidase or can bind to a site which activates the oxidase. Since plasma membrane NADH oxidases clearly play a role in cell signaling, the relation of ferric transferrin stimulation of NADH oxidase to cell control should be considered, especially in relation to the growth promotion by transferrin not related to iron uptake. The oxidase can also contribute to control of cytosolic NAD concentration, and thereby can activate sirtuins for control of ageing and growth.

Plasma membrane redox and control of sirtuin.

We consider possible contributions of plasma membrane redox systems to Aging control by sirtuin (SIR). Reported changes in plasma membrane redox introduced by calorie restriction (CR) may lead to activation of SIR. The most obvious effect would lie in the increase of NAD+ as a result of NADH oxidation. So the question arises, do the observed changes herald an increase in NADH oxidase under CR? The other possibility is an increase in expression of SIR by activation of plasma membrane oxidase. Previous experiments have shown that activation of the plasma membrane redox system can increase cellular NAD+ concentration. The plasma membrane redox systems are also involved in control of protein kinase activity through oxygen radical generation. This activity may be related to control of SIR expression.