How the cell prioritizes and targets organelles and protein aggregates for degradation by autophagy

How the cell prioritizes and targets organelles and protein aggregates for degradation by autophagy

[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, face 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 neutrons,
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]: 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 ubiquity relation, 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 the performance and the 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.


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