A new study sheds light on the organization of proteins within mitochondria.

Mitochondria, the “powerhouses” of cells, play a crucial role in the energy production of organisms and are involved in various metabolic and signaling processes. Researchers from the University Hospital Bonn and the University of Freiburg have now gained a systematic understanding of the organization of proteins within mitochondria.

The protein map of mitochondria represents a critical foundation for further exploring the functions of these cellular powerhouses, and holds implications for disease understanding. The new research has recently been published in the prestigious journal Nature.

Mitochondria are essential components of cells and are surrounded by a double membrane that separates them from the rest of the cell. They produce the majority of the energy needed to sustain these activities. Beyond energy production, mitochondria play key roles in metabolism and signaling, serving as a surface for inflammation processes and programmed cell death.

Defects in mitochondria lead to numerous diseases, especially of the nervous system. Therefore, the molecular understanding of mitochondrial processes is of the highest relevance for basic medical research. The molecular workers in the cell are usually proteins.

Mitochondria can contain around 1,000 or more different proteins. To execute functions, several of these molecules often work together and form a protein machine, also called a protein complex. Proteins also interact in the execution and regulation of molecular processes. Yet little is known about the organization of mitochondrial proteins in such complexes.

Precision in the analysis of dynamic protein machines

The research groups of Prof. Thomas Becker and Dr. Fabian den Brave at the UKB, together with the research groups of Prof. Bernd Fakler, Dr. Uwe Schulte, and Prof. Nikolaus Pfanner at the University of Freiburg, have created a high-resolution image of the organization of proteins in protein complexes, known as MitCOM. This involved a specific method known as complexome profiling to record the fingerprints of individual proteins at an unprecedented resolution.

MitCOM reveals the organization into protein complexes of more than 90 percent of the mitochondrial proteins from baker’s yeast. This allows to the identification of new protein-protein interactions and protein complexes – important information for further studies.

Quality control in the mitochondrial entry gate TOM as an example

Researchers at UKB in cooperation with Collaborative Research Center 1218 “Regulation of cellular function by mitochondria,” have shown how this dataset can be used to elucidate new processes. Mitochondria import 99 percent of their proteins from the liquid portion of the cell, known as cytosol. In this process, a protein machinery called the TOM complex enables the uptake of these proteins through the membrane into the mitochondria.

However, it is largely unclear how proteins are removed from the TOM complex when they get stuck during the transport process. To elucidate this, the team led by Prof. Becker and Dr. den Brave used information from the MitCOM dataset. It was shown that non-imported proteins are specifically tagged for cellular degradation.

Research by Ph.D. student Arushi Gupta further revealed a pathway by which these tagged proteins are subsequently targeted for degradation. Understanding these processes is important because defects in protein import can lead to cellular damage and neurological diseases.

“The example from our study demonstrates the great potential of the MitCOM dataset to elucidate new mechanisms and pathways. Thus, this map of proteins represents an important source of information for further studies that will help us to understand the functions and origin of the cell’s powerhouse,” says Prof. Becker, director of the Institute of Biochemistry and Molecular Biology at UKB.