Saturday, September 05, 2015

Protons (36) Glycolysis to lactate

Before we can even begin to think about metformin and mtG3Pdh we have to re examine lactate and glycolysis. It's difficult to over emphasise how interesting this hypothesis is:

Schurr, A. Lactate: the ultimate cerebral oxidative energy substrate?

I've no idea who Avital Schurr is. But he appears to be an anaesthetist, always a plus point, and he has a view of glycolysis which I really like.

I've blogged before on the astrocyte-neuron lactate shuttle and why I, from my own personal viewpoint, consider lactate to be the ideal mitochondrial fuel when reverse electron transport through complex I is best avoided. It behaves like glucose but without easy access to mtG3Pdh. With the exclusion of fatty acids from neurons the only reduction in the CoQ couple other than complex I then comes from complex II, part of the TCA. There is no input from ETFdh or mtG3Pdh. Pure acetyl-CoA, driving mostly through complex I.

The lactate shuttle is controversial.

Many years ago I recall a sketch on a comedy program, probably on Radio 4, where two politicians of irreconcilable views were invited in to the studio to debate the finer points of some policy by throwing half-bricks at each other.

I never really realised this at the time but the lactate shuttle polarises people. Lactate is viewed by many as an utterly useless, rather toxic end product of anaerobic glycolysis. It is a surrogate for hypoxia, hypoperfusion or mitochondrial failure. It is remarkably unacceptable to almost all physiologists that lactate can be a super fuel or even a fuel of any sort at all. Schurr goes through the arguments and the people and the papers and the logical fallacies and how two groups can look at the same data and draw radically differing conclusions. Think LCer vs vegan vs potato head. You look at the same studies but see different explanations......... And you know, we can't all be correct. Lactophobia is an emotional response. Schurr's words are ‘glucoseniks’ vs ‘lactatians’. You really have to read the paper!

The basic argument is that glycolysis always goes to lactate through pyruvate via cytoplasmic LDH 5. Whatever the oxygen availability. It's energetically favourable.

Lactate is then transfered to the mitochondria via a monocarboxylate transporter and fuels the TCA via pyruvate generated from the intra mitochondrial LDH, putatively LDH 1.

Partly this is redox related. Traditionally, using pyruvate:

Glucose + 2 NAD+ + 2 ADP + 2 Pi → 2 Pyruvate + 2 NADH + 2 H+ + 2 ATP + 2 H2O

Obviously, when you run out of NAD+ glycolysis would grind to a halt. But just look at how neat things become if you take glycolysis through to lactate:

Glycolysis, if it runs to lactate, is self sustaining. There is no deficit of NAD+, just an NAD+:NADH cycle. There is no need for the glycerol-3-phosphate shuttle, not for NAD+ regeneration anyway. Obviously, once lactate enters the mitochondrion it gets converted back to pyruvate with the generation of NADH. But this NADH is where it's needed, in the mitochondrial matrix, well away from the nucleus, ready to be processed by complex I.

How neat is that? Edward Edmonds suggested "elegant" as the descriptor. Yes, some hypotheses are so elegant the really have to be correct.

If it is correct you can then start asking questions about what mtG3Pdh is doing (if it's not regenerating NAD+) and how this might fit in with metformin. We're also back to what controls insulin sensitivity and how a cell regulates energy throughput. And fructose. And hyperglycaemia. Lots to think about.