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Prof. Maria Hondele on cell organelles of a special kind

Tiny droplets found within the cell have long fascinated Maria Hondele. These structures, known as membraneless organelles, have been well known for a long time, but they are still full of surprises. How they are formed and what their significance is for the cell and for life itself are the questions Maria Hondele is pursuing with her research.

How would you describe membraneless organelles?
Unlike ‘classic’ organelles such as the cell nucleus, these droplet-like structures do not have a membrane separating them from the rest of the cell contents; hence the name membraneless organelles. They were already described about a hundred years ago, for example the nucleolus. About a decade ago, researchers became aware that cells have many more such structures. They are accumulations of proteins and often also nucleic acids which display particular biophysical properties. 

This phenomenon has been known for some time. Where does the research stand today?
For a long time, this research area has received only marginal interest. This has changed in recent years. Today, researchers worldwide are studying this phenomenon. There is a tremendous pioneering spirit, since so much still remains unknown: What are the droplets good for? Why are they important for the cell? Why do the individual components accumulate only at certain locations within the cell? And what can the molecules achieve together that they cannot accomplish alone?

Do we now know how membraneless organelles are formed?
This occurs through a process called biomolecular condensation. In some cases, the phenomenon is also known as phase separation. We have all observed a similar phenomenon in everyday life. For instance, when we mix a salad dressing, we see how the oil drops separate from the vinegar. In principle, a similar thing happens in cells, when proteins and nucleic acids interact and autonomously organize themselves. 

Do the droplets simply arise spontaneously?
Droplet formation is a highly dynamic and regulated process which is also reversible. In the cell, there are some membraneless organelles that are almost always present, for example the nucleolus, but also others that only exist as temporary structures which arise or disappear again depending on the conditions. This depends, among other things, on the state of the cell, for instance starvation or osmotic stress. During my postdoc, we discovered that certain proteins control the formation of membraneless organelles. The cell appears to play an active role in this process.

What are the functions of membraneless organelles?
This is a matter of much discussion and there are many hypotheses. They might serve as storage depots or mini factories, in which biochemical reactions are accelerated. They could also possibly be a new level of gene regulation; this is what is fascinating me. A nice example for this is a recent study by the research groups of Christoph Handschin and Sebastian Hiller, in which they could show that the muscle protein PGC-1alpha forms numerous droplets together with other molecules and thus regulates a complex genetic program. This ensures that the muscles adapt to the demands of endurance training. 

What are the consequences when the droplets do not form properly?
We still know little about this. But impaired droplet formation is linked to neurodegenerative disorders such as Alzheimer’s disease or amyotrophic lateral sclerosis, better known as ALS. There is also another fascinating aspect. It is speculated that membraneless structures are the origins of life – tiny, enclosed reaction chambers in the “primordial soup”.

Research Group Maria Hondele