[Rhonda]: ...in terms of the actual external signals that...the main ones that we know
about that cause autophagy, a lot of them have to do with nutrient sensing.
[Dr. Kroemer]: Exactly.
So, perhaps the most physiological way, to induce autophagy that is phylogenetically
conserved from yeast to primitive animals to ourselves is nutrient deprivation, starvation,
hunger.
And so, the idea is that a cell that is deprived from its energetic supply, which can be the
absence of nutrients or the absence of growth factors that are required for these nutrients
to be transported from the outside world into the intercellular space or the absence of
oxygen, all these factors can induce autophagy, and the cells actually will destroy its bioenergetic
reserves, which are macromolecules, proteins, lipids, and ribonucleic acids to generate
energy.
[Rhonda]: In terms of the energy part, I was reading about like three really major pathways
that seem to lead to autophagy.
One, being the actual energetic charge of the cell, like ATP status.
When that lowers, that activates the AMP Kinase pathway.
And then the amino acid sensing pathway, which then when you don't have enough amino acids,
that can basically inhibit mTOR.
And then there's a third one, the protein assimilation pathway, which I'm not as familiar
with essentially how that activates autophagy.
[Dr. Kroemer]: So, it's actually extremely easy.
When you think about basic biochemistry, one of the central metabolites is Acetyl-CoA.
And so, the cytosolic pool of acetyl-CoA determines the level of protein acetylation for the simple
reason that acetyltransferases, which you see acetyl, moiety of Acetyl-CoA, to transfer
it on lysine residues in proteins.
Acetyltransferases are having a low affinity for Acetyl-CoA as compared to kinases which
have a high affinity for ATP.
So if you vary the ATP concentration in the cell, it has little impact on phosphorylation
reactions.
But if you vary acetyl concentrations, it has a major impact on the acetylation level
of cellular proteins.
So that's a major difference.
And so, since Acetyl-CoA is built in the degradation of glucose, a glycolytic pathway, from pure
beta or in the catabolism of branched amino acids, as well as a final product of beta-oxidation.
All major nutrients are actually supplying Acetyl-CoA as an end product.
And taking away glucose or amino acids or fatty acids will cause a reduction in the
Acetyl-CoA pool which is important to note, it is a cytosolic acid Acetyl-Co-A pool that
is accounting for autophagy regulation.
And this reduction of Acetyl-CoA in the cytosol will cause deacetylation at the end of cellular
proteins, hundreds of different proteins, and hence, a sort of multi punked induction
of major subpathways of the apoptotic process.
Autophagy is actually a very complicated process that involves dozens, perhaps hundreds, of
different proteins and is regulated by hundreds, perhaps thousands, of additional proteins.
And so, this common regulation by acetylation is very efficient in stimulating the autophagic
pathway.