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Fundamental role of the membrane structure of mitochondria identified

Mitochondria are cell organelles surrounded by a double membrane. In addition to numerous essential functions in the metabolism of the cell, they also play a key role in the integration of signals into the cell, which are critical for the development of cancer and in the immune response.

A study at the Medical Faculty of Heinrich Heine University Düsseldorf (HHU) headed by Professor Dr. Philipp Lang and Professor Dr. Andreas Reichert, which has now been in the journal Cell Reports, has established that changes to the structure of the inner mitochondrial membrane, i.e., the inner wall of the mitochondria, significantly slows down the replication of numerous viruses.

Mitochondria are widely known as the "powerhouse" of the cell, although the term "processor" of the cell is becoming increasingly common and is also more accurate. In addition to playing a role in the integration of signals into the cell, one of their most important activities is the provision and storage of high-energy chemical compounds such as adenosine triphosphate (ATP)—the universal energy source.

To ensure these processes can run smoothly, mitochondria need the help of a specific architectural structure on the inner membrane, the so-called cristae. Whether and how these structures influence the replication of different viruses or how the immune response is modulated by them, has been poorly understood to date.

A study at the Medical Faculty of Heinrich Heine University Düsseldorf headed by Professor Lang (Institute of Molecular Medicine II) and Professor Reichert (Institute of Biochemistry and Molecular Biology I) has now shown that changes to the inner mitochondrial membrane structure significantly slow down the replication of numerous viruses, including the Coronavirus and the Zika virus.

The starting point for the researchers was the observation that treatment with oligomycin, a known inhibitor of ATP synthase, significantly limits virus replication. However, this does not result from a reduction in mitochondrial ATP production, but rather from a change in the structure of the inner mitochondrial membrane.

"These results show the importance of the link between mitochondrial membrane structure, immune metabolism and antiviral immunity," says Professor Lang. The removal of a central sub-unit of the protein complex "Mitochondrial Contact Site and Cristae Organising System" (MICOS), MIC60, which is essential for the formation of a normal membrane structure in mitochondria, also led to a reduction in virus replication. This was proven both in cell cultures and in a mouse model, in which MIC60 was deleted from dendritic cells.

In further experiments, it was demonstrated that these changes also have an effect on the immune metabolism and, e.g., increase the production of the antiviral immune metabolite itaconate. "This knowledge is of great medical significance with regard to understanding our immune system and could lead to the development of new antiviral therapies in the long term," says Professor Reichert.