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.