Malate-Aspartate shuttle

[Phloston]

Quick question:

During gluconeogenesis, after pyruvate goes to oxaloacetate, via pyruvate carboxylase in the mitochondria, is it malate or aspartate that OAA is converted to before moving back into the cytosol?

I had the impression that it is generally aspartate that goes mitochondria --> cytosol and malate that goes cytosol --> mitochondria, but GT says malate for mitochondria --> cytosol.

Does anyone have any thoughts here?

As a refresher:

OAA + glutamate <---> alpha-KG + aspartate

OAA + NADH + H+ <---> malate + NAD+

Cheers,

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[JackShephard MD]

Quick question:

During gluconeogenesis, after pyruvate goes to oxaloacetate, via pyruvate carboxylase in the mitochondria, is it malate or aspartate that OAA is converted to before moving back into the cytosol?

Hmmm, the point of the shuttle is to make use of NADH in the mitochondria (--> ATP). Gluconeogenesis doesn't shuttle things back and forth, you just move malate out of the mitochondria to make glucose (GT is correct, it is malate that moves out to the cytosol).

I had the impression that it is generally aspartate that goes mitochondria --> cytosol and malate that goes cytosol --> mitochondria, but GT says malate for mitochondria --> cytosol.

Does anyone have any thoughts here?

So I guess this is where the confusion is, malate does move out of the mitochondria to the cytosol in gluconeogensis because your purpose is to take that molecule (opposite the "shuttle" direction), convert it to pyruvate and then into glucose. The shuttle as you are describing is used to make use of NADH in the cytosol, i.e. take OAA in the cytosol, turn it into malate (so it can go into mitochondria) and then use the reduced malate to convert NAD to NADH in the mito. So your impressions are right because you're thinking of the shuttle in the traditional sense.

As a refresher:

OAA + glutamate <---> alpha-KG + aspartate

OAA + NADH + H+ <---> malate + NAD+

Cheers,

yeah, that's correct.

OAA + glutamate <---> aspartate + alpha-KG

OAA + NADH + H+ <---> malate + NAD+

 

[usmlesuccess]

correct me if I am wrong, but my understanding is that the malate-aspartate shuttle is only used for carrying over some of the by products of glycolysis into the mitochondria.

However, for gluconeogensis, I distinctly remember from my first year biochem, surprisingly, that it's just pyruvate-oxaloacetate-malate-oxaloacetate . the intermediate is just malate, which gets transferred to the cytosol, and then gets oxidized again before continuing the gluconeogenesis pathway.

 

[JackShephard MD]

correct me if I am wrong, but my understanding is that the malate-aspartate shuttle is only used for carrying over some of the by products of glycolysis into the mitochondria.

However, for gluconeogensis, I distinctly remember from my first year biochem, surprisingly, that it's just pyruvate-oxaloacetate-malate-oxaloacetate . the intermediate is just malate, which gets transferred to the cytosol, and then gets oxidized again before continuing the gluconeogenesis pathway.

👍 You're correct. But also the malate shuttle is used to move OAA --> malate ---> shuttle (mito-->cytosol) --> malate ---> OAA --> pyruvate

 

[Phloston]

It makes sense that when OAA is moving from the cytosol to mitochondria not during gluconeogenesis, that the cytosolic conversion to malate, followed by conversion of malate back to OAA in the mitochondria, would produce intra-mitochondrial NADH, and therefore ATP.

However, it doesn't make sense that the mitochondria would use NADH to get OAA to malate (i.e. not use it for ATP synthesis), when they could essentially, free of charge, convert it to aspartate. With the latter, the NADH isn't simply converted back to NAD+, but instead is used to make ATP in order to get back to NAD+. The pathways are the same, but the OAA --> aspartate conversion is metabolically more beneficial because ATP is produced from the NADH having instead been used in the transport chain. This ATP produced via producing aspartate, instead of malate, cancels out the GTP used when OAA --> PEP. Bingo.

Are you catching my drift?

 

[JackShephard MD]

It makes sense that when OAA is moving from the cytosol to mitochondria not during gluconeogenesis, that the cytosolic conversion to malate, followed by conversion of malate back to OAA in the mitochondria, would produce intra-mitochondrial NADH, and therefore ATP.

However, it doesn't make sense that the mitochondria would use NADH to get OAA to malate (i.e. not use it for ATP synthesis), when they could essentially, free of charge, convert it to aspartate. With the latter, the NADH isn't simply converted back to NAD+, but instead is used to make ATP in order to get back to NAD+. The pathways are the same, but the OAA --> aspartate conversion is metabolically more beneficial because ATP is produced from the NADH having instead been used in the transport chain. This ATP produced via producing aspartate, instead of malate, cancels out the GTP used when OAA --> PEP. Bingo.

Are you catching my drift?

I see your point and had to think about this for a second. There is no "cost" to reduce OAA to malate, the NADH is essentially conserved in the cytosol when malate is convered back to OAA yielding NADH. So, yes the NADH is now displaced but you didn't lose it.

I don't see why one couldn't use the mechanism you've proposed though, who knows, maybe it happens sometimes. The aminotransferases are in enough tissues that it's a plausible explanation. This question goes beyond my understanding.

The only thing I could think of was the speed of the rxn being more beneficial via malate or possible by-products, but that AST rxn doesn't really involve much.

Edit: fortunately for you, I think you understand this concept well enough to answer any Step 1 Q about it correctly.