What happens to the NADH produced by lactate oxidation?

Question

I first want to note that I'm a layman attempting to gain an understanding of metabolism by reading resources on the internet with only a little understanding of chemistry. I've hit a snag:

Oxidation of lactate into pyruvate reduces NAD+ to NADH. Subsequent glyconeogenesis can then turn two pyruvate into a new glucose molecule at the cost of 6 ATP. However, the NADH is presumably used to generate ATP via oxidative phosphorylation producing ~2.5ATP, making an overall reaction of 2 lactate -> 1 glucose cost only ~1ATP. This clashes with other things I have read - that glyconeogenesis costs 3x the energy glycolysis produces - as this would seem to discount the reduction of NAD+ to NADH in glycolysis. I feel I am clearly misunderstanding something, but I'm not sure where.

Answer 1

What you have read about the direct energy costs/benefits of glycolysis and gluconeogenesis is not wrong. Glycolysis produces 2 ATP and gluconeogenesis consumes 6 ATP.

The net reaction for coversion of glucose $\ce{C6H12O6}$ into pyruvate $\ce{C3H3O3-}$ by glycolysis is (note that I am keeping track of the charges and the magnesium counterion/cofactor on ADP/ATP):

$$\ce{C6H12O6 + 2NAD+ + 2[MgADP]- + 2HPO4^{2-} ->}$$ $$\ce{ 2C3H3O3- + 2NADH + 2[MgATP]^{2-} + 2H+ + 2H2O}$$

For conversion of pyruvate back to glucose by gluconeogenesis (note that gluconeogenesis usually uses 4ATP and 2GTP - for simiplicity let's consider that a GTP has about the energy equivalence to an ATP):

$$\ce{2C3H3O- + 2NADH + 4[MgATP]^{2-} + 2[MgGTP]^{2-} + 6 H2O ->}$$ $$\ce{C6H12O6 + 2NAD+ + 4[MgADP]- + 2[MgGDP]- + 6HPO4^{2-} +2H+} $$

If you compare the two processes directly, in absence of the source/fate of any of the components, you see that gluconeogenesis consumes 6 ATP/GTP and 2 NADH while glycolysis produces 2ATP and 2NADH. The NADH consumption and production is balanced out.

Why would we compare these two directly and not worry about coupled processes?

1. Not all organisms undergo oxidative phosphorylation. Most do, but not all.
2. More importantly, in the context of your question, NADH can do other things. Not all NADH goes to oxidative phosphorylation.
3. Most importantly, the direct comparison is carbon balanced with the same organic species: glucose and pyruvate. If we try to include all possible variations and coupled processes we find ourselves eventually trying to do a general chemistry level stoichiometric and thermochemical analysis of an entire life-form. I'd rather not. There are lots of feed stocks into gluconeogenesis besides lactate and pyruvate. An amino acid or lipid that can be catabolized into acetyl-CoA can be fed into gluconeogenesis.

As for lactate...

True, pyruvate can be generated from lactate $\ce{C3H5O3-}$, which also produces NADH:

$$\ce{C3H5O3- + NAD+ -> C3H3O3- + NADH + H+}$$

If we start with lactate, we have no net generation of NADH in gluconeogenesis. However, we are also no longer comparing the interconversion of the same carbon species. Lactate is produced from pyruvate (consuming NADH), so we are back to square one. Including lactate in the comparison instead of pyruvate leads to no net NADH production/consumption.