Pyruvate as a final electron acceptor in the electron transport chain

Question

During anaerobic respiration, why are electrons carried by NADH not transferred to the electron transport chain (ETC)? What happens is that lactate dehydrogenase reduces pyruvate to lactate, while removing H⁺ from NADH to form NAD⁺.

Why doesn’t pyruvate simply take the place of O₂ as the final electron acceptor in the ETC during oxidative phosphorylation? Electrons would still be able to flow through the ETC and allow for the regeneration of NAD⁺, wouldn't they?

Answer 1

Someone else may come along later with a definitive answer but I found this question intriguing so here are my thoughts:

The standard redox potentials of the mitochondrial ETC carriers are:

NAD⁺/NADH              -0.32 V
complex I (Fe-S)       -0.27 V
complex II (cyt b₅₆₀)  -0.08 V
complex III ((cyt c₁)  +0.23 V
complex IV (cyt a₃)    +0.38 V
O₂/H₂O                 +0.82 V

Note that electron transport is carried out from negative to positive.

Now, for pyruvate/lactate the standard redox potential is -0.19 V so on the basis of this pyruvate could in theory accept electrons from complex I, but not any further down the chain. However, complex I normally transfers electrons to coenzyme Q within the membrane. The standard redox potential of CoQ is +0.04 V which is already too positive to be able to then reduce pyruvate at the membrane surface. Thus there would have to be a novel way of transferring electrons from the final FeS centre of complex I, which is within the membrane, to pyruvate. Pyruvate is, of course, soluble and is generated by cytoplasmic glycolysis, so this transfer would have be at the membrane surface that faces the intermembrane space of the mitochondria.

If such a scheme had evolved then it might be possible to achieve some proton pumping through the novel version of complex I, which would be energetically advantageous.

Another complication is – assuming that a complex I with pyruvate as electron acceptor had evolved – how would the cell/ mitochondrion regulate electron flow during aerobic respiration? Presumably the pyruvate-accepting version of complex I would have to be kept inactive somehow until needed.

Clearly it is much simpler to have a soluble lactate dehydrogenase to deal with the pyruvate and regenerate NAD⁺.

Answer 2

Summary Answer

In anaerobic respiration the free energy change of the reoxidation of NADH by pyruvate is less than would be required to phosphorylate a molecule of ADP to ATP. The purpose of the electron transport chain is to harness the much greater free energy change in the oxidation of NADH by molecular oxygen. So pyruvate can neither “take the place of O₂ as the final electron acceptor”, nor would there be any point in modifying this complex machinery just so that it could be used by pyruvate to regenerate NAD⁺ when a single cytoplasmic enzyme (lactate dehydrogenase) will do the job.

More detailed numerical answer

This answer is taken from section 18.2 of Berg et al. and involves calculations of free energy changes from the redox potentials of the different half reactions and their relationship to the free energy of hydrolysis of ATP. It is worth careful reading, but I will summarize the key points.

• Both pyruvate and oxygen can oxidize NADH, but the concomitant Standard Gibbs Free Energy change is very different in the two cases. This is the crux of the matter.
• The standard redox potential for NADH → NAD⁺ is +0.32 V
• The standard redox potential for Pyruvate → Lactate is –0.19 V
• The standard redox potential for O₂ → H₂O is +0.82

Combining these half-reaction redox potentials in the two oxidation reactions and then converting to standard free energy change (ΔG˚ʹ):

• Oxidation of NADH by Pyruvate: ΔG˚ʹ = –6.0 kcal/mol
• Oxidation of NADH by Oxygen: ΔG˚ʹ = –52.6 kcal/mol

But ΔG˚ʹ for ADP → ATP = –7.5 kcal/mol

So it can be seen that the energetics of the oxidation of NADH by pyruvate do not yield enough energy to synthesize even a molecule of ATP, never mind the approx. 3 that are obtained from oxygen. The electron transport chain is a device for breaking up this latter oxidation reaction into stages so that the free energy change can be used for generating the proton gradient that is used to generate ATP. It can only work with a powerful enough oxidizing agent.

The oxidation of NADH by pyruvate is useful, but only to regenerate NAD⁺ to allow glycolysis to continue and generate a smaller amount of ATP by substrate-level phosphorylation made possible by the glyceraldehyde 3-phosphate dehydrogenase reaction. For this oxidation only a simple enzyme, lactate dehydrogenase is required. There is certainly no reason to transport the pyruvate into the mitochondria (assuming they exist — think erythrocytes), which process, though incompletely understood, may well have an energetic cost.