[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.