An interesting paper was published recently. Intracellular metabolic gradients dictate dependence on exogenous pyruvate This was from the same lab as the excellent paper A non-canonical tricarboxylic acid cycle underlies cellular identity.
An interesting question that the paper answers is what drives the need for external pyruvate. The paper concludes "The requirement for pyruvate over lactate can be partially rescued by NAD+, suggesting that at least part of the role of pyruvate in development is regulation of cellular redox62. ". What I find particularly interesting about the link to NAD+ is that Complex 1 (which is reduced in stem cells) has a major role in maintaining NAD+ levels. Hence if it is to be inhibited in some form then something else needs to be done to maintain NAD+ levels. Although Complex 1 maintains mitochondrial NAD+ rather than cytosolic NAD+, depletion in the Mitochondria will block the Malate-Aspartate shuttle affecting the cytosol
Pyruvate in the cytosol can be used to accept electrons from NADH to create Lactate and NAD+ using lactate dehydrogenase.
What is particularly interesting is comparing the way naive stem cells behave and oocytes. In those situations Complex 1 is inhibited thereby reducing ROS from the Electron Transport Chain and acting to protect mitochondrial DNA from the damage that would occur with higher Complex 1 activity levels.
It turns out the research has already been done finding that pyruvate uptake is higher in oocytes as well as Stem cells.
I suppose it should not be surprising that Stem cells also try to protect mitochondrial DNA when they are being quiescent in some form.
I think it is also becoming clearer what happens in each step as Stem cells differentiate. They start out in a relatively dormant state. Exogenous Pyruvate is needed to maintain NAD+ levels because Complex 1 is inhibited in some way. Then they move out of the stem cell hypoxic niche, this has the effect of turning up levels of the citrate carrier (SLC25A1) via Nuclear Factor kappa B responding to a change in oxygen levels. This causes the process of differentiation to occur as cytosolic levels of acetyl-CoA increase and the substrate is available for histone acetylation (and other aspects of acetylation).
An interesting question that the paper answers is what drives the need for external pyruvate. The paper concludes "The requirement for pyruvate over lactate can be partially rescued by NAD+, suggesting that at least part of the role of pyruvate in development is regulation of cellular redox62. ". What I find particularly interesting about the link to NAD+ is that Complex 1 (which is reduced in stem cells) has a major role in maintaining NAD+ levels. Hence if it is to be inhibited in some form then something else needs to be done to maintain NAD+ levels. Although Complex 1 maintains mitochondrial NAD+ rather than cytosolic NAD+, depletion in the Mitochondria will block the Malate-Aspartate shuttle affecting the cytosol
Pyruvate in the cytosol can be used to accept electrons from NADH to create Lactate and NAD+ using lactate dehydrogenase.
What is particularly interesting is comparing the way naive stem cells behave and oocytes. In those situations Complex 1 is inhibited thereby reducing ROS from the Electron Transport Chain and acting to protect mitochondrial DNA from the damage that would occur with higher Complex 1 activity levels.
It turns out the research has already been done finding that pyruvate uptake is higher in oocytes as well as Stem cells.
I suppose it should not be surprising that Stem cells also try to protect mitochondrial DNA when they are being quiescent in some form.
I think it is also becoming clearer what happens in each step as Stem cells differentiate. They start out in a relatively dormant state. Exogenous Pyruvate is needed to maintain NAD+ levels because Complex 1 is inhibited in some way. Then they move out of the stem cell hypoxic niche, this has the effect of turning up levels of the citrate carrier (SLC25A1) via Nuclear Factor kappa B responding to a change in oxygen levels. This causes the process of differentiation to occur as cytosolic levels of acetyl-CoA increase and the substrate is available for histone acetylation (and other aspects of acetylation).
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