Brain cells are cells require one of the highest amount of energy of any cell of body. So why do they use a shuttle which will transfer electrons from NADH produced in glycolysis to FAD(and there by reduce the no of ATP that can be made ) ?

  • $\begingroup$ No that doesn't happen. are you sure ? $\endgroup$
    Sep 5 '13 at 12:53
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    $\begingroup$ @WYSIWYG she is correct. Her question refers to the glycerol phosphate shuttle which is more prominent than the malate asparate shuttle in brain and muscle cells. $\endgroup$ Sep 5 '13 at 13:57
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    $\begingroup$ @SatwikPasani.. Sorry, I didnt know about it so thanks for letting me know. I did a quick check and I could only find this article on G3P shuttle and brain; I couldnt access it right now but the abstract says that G3P shuttle is minimal in neurons and almost zero in astrocytes. $\endgroup$
    Sep 5 '13 at 16:36
  • $\begingroup$ @WYSIWYG Actually, as is already mentioned in the reference abstract you cited, it is not very clear what the distribution of these shuttles is. But the extract refers to pharmaceutical determination studies only. Earlier biochemical studies showed high G3P shuttle prominence in muscles and neuronal tissues but has always been under active controversy. My information was older but Your reference is quite recent and may have solved the issue, but for me it's behind a paywall. $\endgroup$ Sep 6 '13 at 13:54
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    $\begingroup$ I looked at that WYSIWYG's abstract and it doesn't explain the poster's main concern, namely that moving a hydride via NAD has a different energy yield than moving one via FAD. Won't it be irrelevant if the reducing equivalent enters the mitochondrion via glycerol phosphate shuttle vs malate aspartate shuttle? $\endgroup$
    – Ryan
    Sep 15 '13 at 1:53

In the absence of unanimous consensus and sources regarding the actual distribution of these shuttles,(wikipedia favours G3P shuttle abundance) let me try to explain the cause if the glycerol-phosphate shuttle is assumed to be prominent in brain cells. Several possible reasons might lead to this:-

1) The existing metabolic pathways are all intertwined to form a complex metabolic net. This means that invariably, the intermediates of any pathway are the products or intermediates of several other pathways. Therefore, the G3P shuttles require Glycerol-phosphate and Glycerol-phosphate dehydrogenase (I and II) which might be naturally abundant in brain owing to its use in strict lipid metabolic control in nervous tissue. This means that tapping the already high G3P for use as a shuttle compared to synthesising and operating a distinct metabolic shuttle is more profitable. Furthermore, operating Malate aspartate shuttle migh require intermediates whose high concentrations (required to maintain the shuttle) might negatively interfere with existing metabolic pathways like protein synthesis and regulation.

2) This shuttle has much faster operation time than Malate-Aspartate shuttle and hence is very useful in shuttling reducing equivalents fast in muscles and brain. Compared to the malate aspartate shuttle, it is shorter and hence faster and less prone to cessation due to unavailable intermediates or enzymatic disruption. Due to several enzymes working in Malate-aspartate shuttle, it has a narrower pH and temperature optima than the G3P shuttle which is shorter and depends on lesser intermediates, and hence is less prone to disruption.

3)The last and the most far-fetched (but relevant)reason is that the loss of one ATP may not cause much of a problem because of already high respiratory rate, high Oxygen delivery to brain and ability of the body to quickly transfer available energy sources to brain at the cost of other parts, at times of energy stress. This means that replacing the shuttle with a more energetically conserving one may not have a strong driving force for evolution to operate on, and therefore the presence of G3P may be because of something like phylogenetic inertia, that is, the prevalence of an ancestral character just because it is neutral and does not influence the fitness in a considerable manner. Therefore, the ancestral G3P shuttle would just not have been replaced here but this is very unlikely as G3P shuttle is prominent in 2 very high energy-demanding organs, muscles and brain.

Except the last outrageously far-fetched reason, all other reasons should be enough to explain its prominent presence (if it is true) in brain tissues.


Looking at this question, which has resurfaced after five years, I was not really convinced by any of the possibilities suggested in the answer from @stochastic13, commendable attempt though it is. It happens that I have just been consulting the section on these shuttles in Berg, Tymozcko and Stryer where the following is written:

When cytosolic NADH transported by the glycerol 3-phosphate shuttle is oxidized by the respiratory chain, 1.5 rather than 2.5 ATP are formed. The yield is lower because FAD rather than NAD+ is the electron acceptor in mitochondrial glycerol 3-phosphate dehydrogenase. The use of FAD enables electrons from cytosolic NADH to be transported into mitochondria against an NADH concentration gradient. The price of this transport is one molecule of ATP per two electrons. This glycerol 3-phosphate shuttle is especially prominent in muscle and enables it to sustain a very high rate of oxidative phosphorylation.

I know little about brain metabolism, but if the demand for energy in brain is higher than in other tissues (as stated in the question) then the above would seem to provide the explanation: the greater production of ATP by oxidative phosphorylation possible when NADH entry into the mitochondria is independent of its internal concentration more than offsets the price in ATP of that entry.


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