Deprivation of nutrients (starvation) and other signals that play a key role in inducing autophagy
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When a cell is deprived of either its energy supply or the factors that help utilize energy, the cell resorts to drastic measures, sacrificing damaged or unnecessary parts to provide the things it needs to survive. The primary signal that a cell receives indicating that these measures are necessary is the reduction of cellular levels of acetyl-CoA, an end product of nutrient metabolism. Reduced acetyl-CoA levels promote deacetylation of hundreds of cellular proteins that regulate the autophagic process. In this clip, Dr. Guido Kroemer discusses changes that occur within cells that signal the need to induce autophagy.
- Rhonda: But 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 pyruvate 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 cetyl-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-pronged 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.
Acetyl coenzyme A is a molecule that was first discovered to transfer acetyl groups to the citric acid cycle (Krebs cycle) to be oxidized for energy production. Now it is known to be involved in many different pathways including fatty acid metabolism, steroid synthesis, acetylcholine synthesis, acetylation, and melatonin synthesis.
An enzyme that plays multiple roles in cellular energy homeostasis. AMP kinase activation stimulates hepatic fatty acid oxidation, ketogenesis, skeletal muscle fatty acid oxidation, and glucose uptake; inhibits cholesterol synthesis, lipogenesis, triglyceride synthesis, adipocyte lipolysis, and lipogenesis; and modulates insulin secretion by pancreatic beta-cells.
An intracellular degradation system involved in the disassembly and recycling of unnecessary or dysfunctional cellular components. Autophagy participates in cell death, a process known as autophagic dell death. Prolonged fasting is a robust initiator of autophagy and may help protect against cancer and even aging by reducing the burden of abnormal cells.
The relationship between autophagy and cancer is complex, however. Autophagy may prevent the survival of pre-malignant cells, but can also be hijacked as a malignant adaptation by cancer, providing a useful means to scavenge resources needed for further growth.
The process by which fatty acid molecules are broken down. Beta-oxidation occurs in the mitochondria and produces acetyl-CoA, FADH2, NADH, and H+. Under conditions where glucose is limited, beta-oxidation is an important preceding step for producing the acetyl-CoA needed for ketogenesis.
The aqueous component of the cytoplasm of a cell, within which various organelles and particles are suspended.
A molecule composed of carboxylic acid with a long hydrocarbon chain that is either saturated or unsaturated. Fatty acids are important components of cell membranes and are key sources of fuel because they yield large quantities of ATP when metabolized. Most cells can use either glucose or fatty acids for this purpose.
A naturally occurring substance capable of stimulating cellular growth, proliferation, healing, and differentiation. Growth factors typically act as signaling molecules between cells. Examples include cytokines and hormones that bind to specific receptors on the surface of their target cells.
An enzyme that participates in genetic pathways that sense amino acid concentrations and regulate cell growth, cell proliferation, cell motility, cell survival, protein synthesis, autophagy, and transcription. mTOR integrates other pathways including insulin, growth factors (such as IGF-1), and amino acids. It plays key roles in mammalian metabolism and physiology, with important roles in the function of tissues including liver, muscle, white and brown adipose tissue, and the brain. It is dysregulated in many human diseases, such as diabetes, obesity, depression, and certain cancers. mTOR has two subunits, mTORC1 and mTORC2. Also referred to as “mammalian” target of rapamycin.
Rapamycin, the drug for which this pathway is named (and the anti-aging properties of which are the subject of many studies), was discovered in the 1970s and is used as an immunosuppressant in organ donor recipients.
A chemical reaction in which an atom, molecule, or ion loses one or more electrons. Oxidation of biological molecules is associated with oxidative stress, a key driver of many chronic diseases.
A chemical reaction that removes an acetyl functional group from a chemical compound. The presence of the acetyl functional group plays an important role in the synthesis, stability and localization of about 85% of human proteins.[1] During fasting, falling acetyl CoA levels in the cytosol initiate protein deacetylation and initiates autophagy. In general, protein deacetylation, whether from so-called caloric restriction mimetics or nutrient deprivation, is an important general inducer of autophagy.
- ^ Arnesen, Thomas; Van Damme, Petra; Martinho, Rui Gonçalo; Helsens, Kenny; Hole, Kristine; Pimenta-Marques, Ana, et al. (2011). NatF Contributes To An Evolutionary Shift In Protein N-Terminal Acetylation And Is Important For Normal Chromosome Segregation PLOS Genetics 7, 7.
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