...explores our secretive mitochondrial ’roommates’
Since the end of last year, Hauke Hillen has led a double life: He is professor of protein biochemistry at the University Medical Center Göttingen (UMG) and heads a research group at the Max Planck Institute (MPI) for Biophysical Chemistry. In this portrait, he revealed how he found his profession, what his research focuses on, and how he combines both affiliations.
“When I was younger, I never would have thought that one day I will become a biochemist and structural biologist. After all, I dropped biology after 10th grade,” Hillen laughs. It was a part-time job in a laboratory at the end of his school years that awakened his fascination for natural sciences. His father, a chemist himself, encouraged him to study biochemistry in Tübingen. During this time, he worked as an intern and research assistant at the MPI for Developmental Biology and spent a semester abroad at the University of California Berkley (USA) in the department of later Nobel Prize awardee Jennifer Doudna. These experiences quickly brought the scientist from Erlangen into contact with his research topic: structures and functions of molecular machines in higher cells.
Of molecular machines and strange mitochondria
Like clockwork gears, molecular machines are made up of many individual molecules that fit, move, and work together to perform different functions. These structures in our cells enable, for example, muscle contractions, are essential to produce energy for our bodies, and are significantly involved in what is called gene expression. In the latter process, proteins are built according to the genetic information on the DNA. To read the ’building instructions’ for the proteins off the DNA, a molecular copying machine called RNA polymerase transcribes them precisely. This process of copying is the first phase of gene expression – transcription. In the final phase, translation, proteins are formed according to the instructions. ”I conducted my doctoral thesis with Patrick Cramer, whose research revolves around RNA polymerases and the molecular processes and structures involved in transcription,” Hillen says. ”However, thematically I was already a bit of an ‘outsider‘ in the group since I studied transcription in mitochondria and not in the cell nucleus.”
Mitochondria are commonly known as the ’powerhouse of our cells‘ as they enable the body to generate energy through respiration. They are part of all higher cells but have their own genetic material and all the molecular machinery to read out those genes. This so-called mitochondrial gene expression is essential for survival because without it the cell organelles cannot fulfill their function as powerhouses. Why mitochondria are equipped with their own genes seems to be resolved. Most likely, their ancestors are alphaproteobacteria, which at some point were swallowed but not digested by archaebacteria. In the course of evolution, a vital interdependence arose between the two and the alphaproteobacteria evolved into cell organelles of their hosts. This process is now considered the founding stone for the development of higher, multicellular organisms such as animals and plants. After all, even today mitochondria are permanent roommates in our bodies.
”The exciting thing about mitochondria is that some of their molecular machinery for gene expression is completely different, not only compared to the nucleus but also compared to those in bacteria, their presumed ancestors,” the group leader explains enthusiastically. For example, mitochondrial RNA polymerase is most similar to the corresponding enzyme in viruses (bacteriophages, to be precise). It remains unclear how individual processes of the mitochondrial gene expression work, how they are coordinated with nuclear gene expression, or what other molecular machines might be involved. Yet, from a medical point of view, it is important to unravel these processes. Functional mitochondrial disorders belong to the most common hereditary diseases and can affect different organs individually, simultaneously, or sequentially. Cardiac muscle weakness, visual disturbances, and epilepsy are just some possible consequences. However, there remains a lack of mechanistic understanding of the causes of mitochondrial diseases, which makes therapies difficult, if not impossible.
Two positions that complement each other perfectly
By studying the molecular structures and mechanisms of mitochondrial transcription during his PhD, Hillen developed his fascination for mitochondrial gene expression that kept him loyal to MPI-BPC for years. ”I initially wanted to get to know institutes abroad after my PhD. But to carry out my experiments, I need a certain repertoire of equipment and expertise, and that’s where the MPI-BPC is really world-class,” the biochemist tells us. ”In addition, there are many experts here and at UMG with whom I can exchange great ideas. Eventually, the choice was not difficult.” Hence, he initially worked as a postdoc in Cramer’s department but was quickly given his own project group. In 2020, he successfully applied for a junior professorship at UMG, and in parallel started an independent research group at the MPI-BPC, for which he is currently recruiting team members. The two positions complement each other perfectly: At both UMG and MPI-BPC, the scientist can consult with colleagues who are researching other aspects of mitochondria. At the MPI-BPC, he also benefits from the exchange and collaboration with other groups working in the field of structural and cell biology. And so, he commutes back and forth between the two institutions on his bike almost every day.
Combining established and new methods
To uncover the secrets of mitochondria, Hillen and his research group want to find out more about the processes of mitochondrial gene expression and the structures of the involved molecular machines. To do so, he relies on two approaches. ”In our bottom-up approach, we purify individual components of molecular complexes using bacterial orinsect cells and then assemble the machines piece by piece in the test tube,” the scientist explains. ”Then we examine their functions with biochemical experiments and determine their structures using X-ray crystallography or cryo-electron microscopy.” In cryo-electron microscopy, samples are snap-frozen and then examined under an electron microscope. This often involves taking thousands of highly magnified images in which the protein complexes are visible as individual particles. With the help of computers, a three-dimensional structure of the individual components can then be calculated.
In addition to working with artificial samples, in a top-down approach the research group wants to isolate molecular machines directly from cells to investigate their structures. Methodologically, research with such natural samples is more difficult but offers better and more realistic insights into the actual environment of the molecular complexes. Moreover, the group leader hopes to be able to look at whole mitochondria instead of just individual components at the molecular level in future. This would provide many new insights into mitochondrial gene expression. The required technique for this novel approach is called cryo-electron tomography and it already draws quite some interest in the scientific world, but also retains a lot of development potential.
For the next years, Hillen and his team will investigate our mysterious cellular roommates in Göttingen, and so he will continue to cycle up the Fassberg – powered by mitochondria. (kr)
Five questions to Hauke Hillen
Which other job could you imagine doing?
I sometimes dreamed of becoming a pilot. However, I am more than happy with my choice of job. It really is a privilege when you can turn your interests into a profession!
Which country would you like to visit?
I have never been to Africa, so a trip through countries like South Africa and Namibia, for example, would be very appealing to me. I am also very fascinated by Scandinavia because it has large sparsely populated areas and offers lots of nature.
What would you do if you had more time?
I would use the time to travel more and visit family as well as friends who now live scattered throughout Europe and the world. These contacts are very important to me, but it is not always easy to find the time to meet regularly and stay in touch.
How do you recharge your batteries after a tough day?
My balance to all the brainwork is sports. I really enjoy jogging and I also cycle a lot. I used to play squash regularly but, unfortunately, this is not possible at the moment due to the pandemic. I also draw a lot of strength from the time I spend with family and friends.
You are waiting for the discovery/invention of...?
Beaming – like in Star Trek! I travel a lot, both professionally and privately, so it would be great to be able to skip the long train rides!