HMN 2026: How Mitochondria reveal built-in speed control for protein production

Researchers at the University Medical Center Göttingen (UMG) and the Max Planck Institute (MPI) for Multidisciplinary Sciences have elucidated how the production of certain proteins and their insertion into the inner membrane of mitochondria are coordinated.

This process ensures energy production in living cells, and if it malfunctions, can cause serious diseases in humans. The new regulatory mechanism provides a better understanding of the causes of neuromuscular diseases. The results have been published in the journal Nature Structural & Molecular Biology.

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 Prof. Dr. Peter Rehling, director of the Department of Cellular Biochemistry at the University Medical Center Göttingen (UMG), and Dr. 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 Dr. Thomas Schöndorf, first author and a postdoctoral researcher in Prof. Rehling’s team.

In collaboration with Dr. Ilgin Kotan and Dr. 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-froze them at temperatures below minus 180 degrees Celsius for cryo-electron microscopy. This allowed Dr. Valentyn Petrychenko, co-first author and postdoctoral researcher in Dr. 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 Dr. Fischer.

Prof. 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.”

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