Speed control of mitochondrial protein production discovered
Researchers have elucidated how the production of respiratory chain proteins and their incorporation into the inner mitochondrial membrane are coordinated
- Precisely timed choreography: The production of respiratory chain proteins is coordinated with their folding and incorporation into the inner mitochondrial membrane.
- Pauses depending on shape: Depending on the orientation of the newly produced protein in the membrane, mitochondrial ribosomes pause at specific points during translation.
- New regulatory mechanism: The insertion of respiratory chain proteins into the mitochondrial membrane not only follows protein production, but also feeds back into it, contributing to its regulation. This finding improves our understanding of the causes of neuromuscular diseases.
Cells with high energy demands, such as muscle, heart, and nerve cells, contain a particularly large number of them: tiny molecular powerhouses known as mitochondria. These are responsible for the vital energy supply in living cells. Through the mitochondrial respiratory chain — a series of large protein complexes embedded in the inner mitochondrial membrane — they convert nutrients into energy. Mitochondria thus play a central role in metabolism. Dysfunctions can damage the heart and nervous system or lead to neuromuscular diseases such as muscle atrophy.
Human mitochondria are surrounded by two membranes and possess their own genetic material. This contains the blueprints for 13 key proteins of the respiratory chain. These proteins are produced by the mitochondria’s own protein factories, known as mitoribosomes, which use the genetic blueprints stored in the mitochondrial genome to produce the proteins. However, mitoribosomes face a challenge: Already during the production of a respiratory chain protein, the growing protein chain is folded into its functional three-dimensional form and inserted into the inner mitochondrial membrane. How these three processes — production, folding, and insertion — are coordinated and controlled has remained unclear until now.
Precise choreography of the processes
A team led by Peter Rehling, director of the Department of Cellular Biochemistry at the University Medical Center Göttingen (UMG), and Niels Fischer, project group leader at the Max Planck Institute (MPI) for Multidisciplinary Sciences, has now shown that mitoribosomes do not produce membrane proteins at a constant rate, but rather according to a precisely timed choreography. “We have shown when the ribosome pauses,” explains Thomas Schöndorf, first author of the study now published in the journal Nature Structural & Molecular Biology and a postdoctoral researcher in Rehling’s team.
In collaboration with Ilgin Kotan and Günter Kramer from Heidelberg University, the researchers applied a technique known as ribosome profiling. This method allowed the scientists to precisely determine which proteins a cell produces and when. The researchers could thereby identify the specific points at which the mitoribosomes stop during protein production. In addition, the team purified mitoribosomes and flash-frozen them at temperatures below minus 180 degrees Celsius for cryo-electron microscopy. This allowed Valentyn Petrychenko, co-first author and postdoctoral researcher in Fischer’s team, to visualize how mitoribosomes interact with the membrane insertion machinery both during pauses and during active protein production.
New regulatory mechanism in protein production
But what controls the speed of ribosomes? The researchers discovered that how the protein is orientated while being inserted into the membrane is crucial for its production rate. Depending on whether a specific part of the protein protrudes into the mitochondria’s interior or into the space between the inner and outer mitochondrial membrane, pauses of varying lengths occur during its production. This adapts the speed of protein production to the subsequent steps.
“The ribosome, the growing protein chain, and the molecular machinery that inserts the newly produced protein into the mitochondrial membrane work together in a coordinated manner. They slow down protein production at specific points in time to support folding and membrane insertion — important early steps in the formation of the respiratory chain, which are essential for the subsequent energy supply of living cells,” says Fischer. Rehling adds: “This means that membrane insertion and the respiratory chain’s assembly do not simply follow protein production, but rather feed back into it and contribute to its regulation. This is an important new regulatory mechanism that now gives us a better understanding of the causes of neuromuscular diseases.” (cr/nf)
(Joint press release from the University Medical Center Göttingen and the Max Planck Institute
for Multidisciplinary Sciences)
The study was funded by the European Research Council (ERC) through the MiXpress Advanced Grant, as well as from the German Research Foundation (DFG) through the Collaborative Research Centers SFB1565 and SPP245 and the Excellence Strategy (EXC 2067/1).
