How the cell prioritizes and targets organelles and protein aggregates for degradation by autophagy
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Autophagy is a cellular defense mechanism that gathers protein aggregates, pathogens, and damaged or dysfunctional organelles into vesicles within the cell and then delivers them for destruction. Subsequently, proteins, fats, carbohydrates, and nucleic acids are released for energy and re-use. The process of autophagy is activated by cellular stressors such as nutrient depletion, hypoxia, and the presence of toxins. It performs a general housekeeping role and maintains cellular quality control, but it can also respond to cues from damaged organelles, pathogens, or protein aggregates that demarcate them for destruction. In this way, it serves as a targeted cleansing program that removes slightly damaged or aging parts of the cell. In this clip, Dr. Guido Kroemer describes the cellular process of autophagy and what factors trigger its activation.
- Rhonda: So maybe we can kind of talk, shift a little bit into the general role that autophagy plays in some of these age-related diseases, like neurodegenerative disease, cardiovascular disease, and cancer. Talk a little bit about the microautophagy, or is that what you call it, like, when you're talking about the specific degradation of organelles like mitochondria or protein aggregates?
- Dr. Kroemer: So normally, when we refer to autophagy, we talk about macroautophagy, which is the phenomenon that you can see easily by microscopy. Because of the formation of the autophagosomes that are big enough to be seen by conventional microscopy, phase contrast, and especially of course when you enhance a solution by immunofluorescence or similar technologies. So, there are other types of autophagy that are less well studied. Like, chaperone-mediated autophagy or microautophagy where basically proteins or portions of the cytosol are introduced directly into lysosomes. So you don't need the mouth of the process or autophagosome, you just need the lysosome. And they are much less studied. And then there's a special case among different kinds of macroautophagy. So to be very simple in the dichotomy, there is the case that autophagy is dictated by general stress or general absence of nutrients, which means that it is dictated by demand. So the cell needs to eat some portions of itself to adapt to nutrient stress, and the other kind of autophagy is dictated by the offers. So a damaged organelle will change the composition of its surface in a way that it is decorated by signals for stimulating its engulfment by the autophagosome. And so, it's another kind of autophagy that then can be specific. Specific for organelles of different types like mitochondria, and it is called mitophagy, or for peroxisomes, and it is called pexophagy, for the endoplasmic reticulum, and it's called reticulophagy, specific for ribosomes, ribophagy. Perfect, yes. And specific for viruses, and it is called virophagy. And the two processes may also interact in a way. So when you stimulate general autophagy by activating the nutrient sensors, AMP kinase, inhibition of mTOR, or by provoking deacetylation, then you increase the demand, and the autophagy machinery actually prefers in a way to sequester and to destroy those organelles that are already slightly marked for destruction. The protein aggregates that are not yet harmful enough to emit a signal per se but they are there. And so it's a sort of preferential cleaning of the slightly damaged and slightly aging portions of the cell. And this may actually explain why stimulation of autophagy in cells, when they are monocellular organisms or at the organismal level at different organs, can be a sort of device against aging.
- Rhonda: Wow, that was very beautiful explanation. It actually answered a question I was going to ask you which was, you know, the difference between the signal, for example, nutrient generalized autophagy, when you have the nutrient sensing-stress that even that can, to some degree, selectively degrade mitochondria, for example, but the actual signal that really does activate mitophagy...when you're talking about mitophagy, it's a little different, right? It's the actual mitochondrial damage, the membrane potential...
- Dr. Kroemer: Yes. So when a mitochondrion is suboptimal in its function, it will decrease its mitochondrial transmembrane potential. And this is a signal to activate enzymes on the surface of the mitochondria that cause ubiquitination, recruitment of autophagy adapters, and leads at the end to autophagy because of the organelles or the organelle in a way offers itself, it proclaims its sacrifice by autophagy. And so, of course, this is not an all-or-nothing phenomenon. So mitochondria can be aging in the cell, and as they age, they gradually decrease their performance and their mitochondrial transmembrane potential. So, those mitochondria that are most dysfunctional, they will be eaten first if you increase the demand for autophagy.
- Rhonda: That is very cool.
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 aqueous component of the cytoplasm of a cell, within which various organelles and particles are suspended.
A type of organelle in the cells of eukaryotic organisms that forms as interconnected network of flattened, membrane-enclosed sacs or tube-like structures known as cisternae. Rough ER is studded with ribosomes and is the site of protein synthesis, whereas smooth ER functions in lipid manufacture and metabolism.
Any of a group of complex proteins or conjugated proteins that are produced by living cells and act as catalyst in specific biochemical reactions.
Macroautophagy is used primarily to eradicate damaged cell organelles or unused and/or damaged proteins. This involves the formation of a double membrane known as an autophagosome around the organelle marked for destruction before delivering it to a lysosome. Microautophagy, on the other hand, involves direct engulfment of cytoplasmic material by the lysosome via a process of invagination, meaning the inward folding of the lysosomal membrane.
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.
Tiny organelles inside cells that produce energy in the presence of oxygen. Mitochondria are referred to as the "powerhouses of the cell" because of their role in the production of ATP (adenosine triphosphate). Mitochondria are continuously undergoing a process of self-renewal known as mitophagy in order to repair damage that occurs during their energy-generating activities.
The selective degradation of mitochondria by autophagy. It often occurs in defective mitochondria following damage or stress. Mitophagy is key in keeping the cell healthy. It promotes turnover of mitochondria and prevents accumulation of dysfunctional mitochondria, which can lead to cellular degeneration.
A broad range of disorders caused by the progressive death of neurons in the central and peripheral nervous systems. Common neurodegenerative diseases include Alzheimer's disease, Parkinson's disease, Huntington’s disease, and multiple sclerosis. Although treatments are available for some neurodegenerative diseases, there are currently no cures.
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.
Ubiquitin is a small regulatory protein found in most tissues of eukaryotic organisms (e.g. ubiquitously). Ubiquitination refers to the the process by which ubiquitin proteins are added to cytosolic proteins in order to: alter their cellular location, mark them for degradation via the proteasome, and promote or prevent protein interactions.
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