Scientists reveal intracellular signaling pathway: mitofusin 2 is the lock and key

• Today, an international team of scientists from VIMM, University of Padua, IRB Barcelona and University of Barcelona have published their findings in this journal. Science.
• Their research shows that the mitochondrial protein Mitofusin 2 is produced in different ways and this acts as a lock and key on the bridge between the mitochondria, the power house of the cell, and the factory, the endoplasmic reticulum.
• Mitofusin 2 plays an important role in Charcot-Marie-Tooth IIA neuropathies and is decreased in metabolic disorders such as diabetes and non-alcoholic fatty liver disease.
• This remarkable discovery provides a way to understand how these cells work and provides possible insights into the development of therapeutic strategies that target these disorders.

Researchers at IRB Barcelona, ​​​​University of Barcelona (UB), VIMM, and University of Padua have revealed the important role of cell-produced Mitofusin 2 in connecting organelles within cells. As important structures with specialized functions, these organelles rely on complex connections to connect seamlessly. Among the organelles, the mitochondria (called cell powerhouses) and the endoplasmic reticulum (in charge of protein and lipid synthesis) carry out important exchanges.

The research team led by Dr. Antonio Zorzano at IRB Barcelona and UB, Dr. Luca Scorrano at VIMM and the University of Padua and Dr. Deborah Naon, a member of both groups, has now revealed the existence of different “different” versions of the Mitofusin 2 protein, called ERMIT2 and ERMIN2 respectively. These genes are produced through a different process, a process in which sections of the gene called “exons” are rearranged to produce different proteins from the same DNA. Surprisingly, ERMIN2 and ERMIT2, derivatives of the mitochondrial protein Mitofusin 2, are not localized to the mitochondria but instead to the endoplasmic reticulum.

In 2008, the group took the lead Dr. Luca Scorrano, Professor of Biochemistry at the Department of Biology of the University of Padua, Principal Investigator, and former Scientific Director of VIMM, discovered that the mitochondrial protein Mitofusin 2, which is altered in peripheral neuropathy Charcot-Marie-Tooth IIA and reduced in metabolism. Diseases such as diabetes and fatty liver disease contribute significantly to this relationship. However, the associated proteins in the endoplasmic reticulum have not been identified.

“Our extensive research found ERMIN2 and ERMIT2 in many human cells and tissues, including adipose tissue, muscles, and liver. These findings emphasize the participation of these proteins to maintain their optimal function,” he explains. Dr. Antonio Zorzanohead of the laboratory of Complex Metabolic Diseases and Mitochondria at IRB Barcelona.

He led one lesson Dr. Scorranowho says, “Our study revealed the regulatory role of ERMIN2 in the formation of the endoplasmic reticulum, while ERMIT2 interacts with Mitofusin 2, forming a bridge between the mitochondria and the endoplasmic reticulum.”.

Other changes and additions

Genes contain instructions for making specific proteins in cells. However, some genes undergo a process called “alternative splicing,” in which cells choose to combine gene fragments to make different types of proteins. The system allows our bodies to be flexible and flexible, which is very important for the functioning of living organisms.

In the case of Mitofusin 2, a mitochondrial protein, the research team has found two previously unknown types called ERMIT2 and ERMIN2, which reside in the endoplasmic reticulum. ERMIT2, in association with Mitofusin 2, establishes a strong connection between mitochondria and the endoplasmic reticulum, while ERMIN2 controls its final structure.

“This study represents one of the rare cases where certain types of mitochondrial proteins have been observed. Therefore, the connection with the methods we describe in this study is a new development,” he says. Dr. Deborah Naonfirst & co-author of this study. Dr. with them started this project during his doctoral studies at IRB and continued during his doctoral studies at VIMM and the University of Padova.

Metabolic and neuromuscular diseases

With the help of Mitofusin 2 and its type ERMIT2, the interaction between the endoplasmic reticulum and mitochondria is important for lipid metabolism, metabolic control, and the functioning of mitochondria (cell powerhouses) and endoplasmic reticulum (protein and lipid synthesis factory) . When this interaction between organelles is disrupted, a condition known as “endoplasmic reticulum stress” begins, which leads to harmful effects on cells, tissues, and organisms.

Yes, in 2019 dr. ZorzanoThe team discovered that the disruption of communication between these two organs contributes to the development of non-alcoholic steatohepatitis, a serious liver disease associated with metabolic disorders. Now, the team has been able to improve liver function in models of non-alcoholic steatohepatitis by simply stimulating the production of the bridge protein ERMIT2. “The relationship between mitochondria and endoplasmic reticulum is also altered in syndromes that show insulin resistance, such as diabetes and obesity. Therefore, this provides a therapeutic approach that can be investigated,” he explains. dr. Zorzanowho is also a Professor at the Faculty of Biology of the University of Barcelona (UB) and a member of CIBERDEM.

In addition, mutations in the Mitofusin 2 gene cause Charcot-Marie-Tooth IIa, a genetic peripheral neuropathy characterized by severe weakness of the leg muscles. As a result, driving difficulties often require the use of a wheelchair. “The discovery of ERMIN2 and ERMIT2 opens the possibility that the disruption of the endoplasmic reticulum and the communication of this organelle with mitochondria contributes to the clinical manifestations of this disease. This disease is currently incurable,” he added. Dr. Scorrano.

“The future efforts of the research group are focused on understanding the control of the “processing” of the gene in order to determine the production of different types of proteins. The group will also evaluate the maintenance of this process in various physiological and pathological diseases, including metabolic and neurological diseases”, he reveals. . Dr. with them.

This extraordinary work was carried out within the framework of projects supported by the ‘la Caixa’ Foundation, the Spanish Ministry of Science and Innovation, the Carlos III Health Institute, the European Research Council, the Muscular Dystrophy Association (MDA), the Italian Ministry of Health. University and Research, and the Italian National Recovery and Resilience Plan (NRRP), Mission 4, Component 2, Investment 1.2, supported by the European Union – NextGenerationEU.

The research involved collaboration with other laboratories at IRB Barcelona, ​​including those led by Dr. Manuel Palacin and Dr. Modesto Orozco, who played an important role in discussing the communication process and analyzing the results. In addition, research teams from the Institute of Neurosciences of the Autonomous University of Barcelona, ​​Rovira i Virgili University, Joan XXIII Hospital, and Parc Sanitari Sant Joan de Déu contributed to the research.

Related article:
Different types of Mitofusin 2 form the endoplasmic reticulum and connect it to mitochondria.
There are many ways to get the best results from your results, but the most important thing is to find the right one for you Vendrel, Jorge Joven, Modesto Orozco, Antonio Zorzano and Luca Scorrano.
Science (2022) DOI: 10.1126/science.adh9351