Scientists Unveil Mechanisms That Cause Intracellular Communication: Mitofusin 2 is the Lock and Key. 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 shown that there are “different” Mitofusin 2 proteins, called ERMIT2 and ERMIN2. These genes are produced through a different process, a process in which parts of the gene called “exons” are rearranged to make different proteins from one. DNA schedule. 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, a group led by 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 modified in the ocean. Neuropathy Charcot-Marie-Tooth IIA and reduced metabolic complications such as diabetes and fatty liver, play an important role in contributing to this interaction. However, the associated proteins in the endoplasmic reticulum have not been identified.
“Our extensive research found ERMIN2 and ERMIT2 in various human cells and tissues, including adipose tissue, muscle, and liver. These results emphasize the participation of these proteins in maintaining optimal cellular function,” says Dr. Antonio Zorzano, head of the Laboratory of Complex Metabolic Diseases and Mitochondria at IRB Barcelona.
He led the study together with Dr. Scorrano, who says, “Our research found the regulatory function of ERMIN2 in the formation of the endoplasmic reticulum, while ERMIT2 interacts with Mitofusin 2, creating a bridge between the mitochondria and the endoplasmic reticulum. This bridge facilitates the exchange of signals and lipids between these important cells”.
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 in which certain types of mitochondrial proteins have been observed. Therefore, the interactions and mechanisms that we describe in this study are innovative,” says Dr. Deborah Naón, first & co-author of this study. Dr Naón started this project during his doctoral studies at the IRB and continued his 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) . This connection between the organelles is disrupted, a problem called “endoplasmic reticulum stress” occurs, which causes harmful effects on cells, tissues, and the organism.
Indeed, in 2019 the group of Dr. Zorzano discovered that a disturbance in the balance between these two groups leads to the development of steatohepatitis, which is 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 interaction between the mitochondria and the endoplasmic reticulum is also altered in syndromes that show insulin resistance, such as diabetes and obesity. Therefore, this discovery provides a therapeutic approach that should be investigated,” explains Dr. Zorzano, who 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 up the possibility that disruption of the endoplasmic reticulum and the communication of this organelle with mitochondria contributes to the clinical manifestation of this disease. If this is true, we can explore new ways to treat this chronic disease,” adds Dr. Scorrano.
“The future efforts of the research team are focused on understanding the regulation of gene “processing” to determine the production of different types of proteins. The team will also evaluate the maintenance of this process in various physiological and pathological conditions, including metabolic and neurological diseases”, he reveals. Dr Naon.
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 study included collaboration with other laboratories at IRB Barcelona, including those led by Dr. Manuel Palacín and Dr. Modesto Orozco, who played an important role in discussing the methods of operation 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.
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