Detailed knowledge of the cell powerhouse

Martin Ott has always liked tricky problems, so it is no surprise to him that he is researching into the complicated energy factory in cells – the mitochondria. His goal is to understand how they synthesize proteins, and how proteins are built in the vital respiratory chain. This may ultimately be of importance for diseases caused by non-functioning mitochondria.

Martin Ott

Professor of Biochemistry

Wallenberg Academy Fellow 2013

Institution:
Stockholm University

Research field:
Protein biogenesis

In his youth Martin climbed cliffs and mountains in the majestic alpine landscape of southern Germany. Today he seeks his challenges and insights in the microscopic world of cells. He says that much of what he has learnt from climbing can be put to use in his research.

“To succeed as a climber you have to work hard and with passion. You also have to be stubborn, persistent, flexible, optimistic and analytical. It is also necessary to work methodically and solve numerous small problems along the way to reach the goal. This is why I think climbing shares many aspects with research,” he says.

He developed his passion for mitochondria when attending a course in bioenergetics in his third undergraduate year at university. The moment came when he and his fellow students were using an electron microscope and saw mitochondria for the first time with their very own eyes.

“It was fantastic. I was so impressed. Before then we had only read about mitochondria, but now – wow, there they are! I became almost obsessed, and my fascination has endured.”

Interaction between protein complexes

Given that Martin has always liked challenges and difficult problems, it is no surprise that he plumped for mitochondria. After all, they contain the extraordinarily complicated respiratory chain that is also absolutely vital, since it provides the energy we need to breathe, live and work.

The respiratory chain comprises several large and interactive protein complexes. They transport electrons to react them with oxygen (the reason why we need to breathe) and by this pump protons from the inside of the mitochondria to their exterior. This charges the mitochondrial membrane – plus on one side and minus on the other, like a battery. The charge is used to synthesize energy-carrying molecules of adenosine triphosphate (ATP), which can then be used as an energy source for most of the functions the cells in the body need to perform.

As a Wallenberg Academy Fellow, Martin is using traditional biochemistry and modern genetics to study the biogenesis of the cytochrome bc1 complex – one the large mitochondrial protein complexes in the respiratory chain. It is hoped that this research will provide fundamental knowledge of mitochondrial protein synthesis that will also have general application.

“We are interested in how mitochondria make proteins and how the proteins then combine in the respiratory chain.”

“To receive such a renowned grant is a fantastic honor for me and my research team. It gives us the financial freedom to focus on the big questions, and take risks without being afraid of failing. The grant also means that my family and I can stay in Sweden for good.”

Two kinds of protein

The respiratory protein complex consists of two kinds of protein: protein synthesized inside the mitochondria, and protein produced outside, i.e. in cell cytoplasm. Combining these different proteins to form a protein complex demands advanced co-ordination between protein synthesis inside the mitochondria and the influx of proteins from the cytoplasm.

“It can be compared with an assembly line in an automobile factory: exactly the right quantity of car parts are needed at the various points along the belt for the car to be put together correctly.”

In their previous research, Martin and his team identified a protein complex having precisely this regulatory function. It binds to ribosomes inside the mitochondria, and allows that a specific RNA is translated into the protein cytochrome b. After that it binds to the newly formed protein and helps it to combine with other proteins in the respiratory chain. If the other proteins with which cytochrome b is assembled into a respiratory chain complex are missing, this helper protein remains bound to cytochrome b. This means that it cannot initiate new synthesis of cytochrome b on the ribosomes.

“We now know quite a lot about how the respiratory protein complex is put together. But it is still a mystery how this coordination protein affects ribosomes at the molecular level, and thereby actual influences synthesis of cytochrome b.

Genetically modified yeast

One of the approaches used by Martin and his team to solve this riddle involves genetically modified yeast. This allows detailed study of each tiny individual stage of protein synthesis. They are also using advanced electron microscopy to link protein structure to function. New technology and new methods will also be needed to gain a full insight into this highly complicated process.

“The great challenge is that we are in terra incognita – researching into things that are completely unknown at present. We have some knowledge about some of the components, but we don’t really understand how they work. To make progress we must develop new hypotheses, new technology and new methods,” Martin says, and adds:

“It is like skiing somewhere where no-one has skied before; we can’t follow someone else’s tracks – we have the privilege to define our own ways.”

Martin’s research is fundamental and driven by curiosity, but over the longer term it may also be of benefit to society at large.

“Many diseases, and also ageing, are due to malfunctioning mitochondria. Our research may therefore very well have important medical implications in the future.”

Text Anders Esselin
Translation Maxwell Arding
Photo Magnus Bergström