One protein and several at the same time

Recent research solves the puzzle of the interconnection of organelles within cells.

A research team made up of, among others, Dr. Antonio Zorzano, from the Barcelona Institute for Research in Biomedicine (IRB Barcelona), and the University of Barcelona, ​​Dr. Luca Scorrano, from the Veneto Institute of Molecular Medicine (VIMM) in Padua and the University of Padua, in Italy, and Dr. Deborah Naón, from IRB Barcelona and VIMM, has discovered the existence of different “variants” of the Mitofusin 2 protein, called ERMIT2 and ERMIN2. These variants are generated through “alternative splicing,” a process in which segments of the gene called “exons” are rearranged to generate different proteins from the same DNA sequence. Surprisingly, ERMIN2 and ERMIT2, derived from the mitochondrial protein Mitofusin 2, do not localize in the mitochondria themselves, but rather in the endoplasmic reticulum.

“Our extensive investigation found ERMIN2 and ERMIT2 in a wide range of human cells and tissues, including adipose tissue, muscle, and liver. These findings underscore the role of these proteins in maintaining optimal cellular functionality,” explains Dr. Zorzano. , leader of the Complex Metabolic Diseases and Mitochondria laboratory at IRB Barcelona.

He co-led the study with Dr. Scorrano, Professor of Biochemistry, Department of Biology, University of Padua, Principal Investigator and former VIMM Scientific Director, who states: “Our research uncovered 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. This bridge facilitates the exchange of signals and lipids between these crucial cellular structures.”

Alternative and complementary variants

Genes contain the instructions for making specific proteins within cells. However, some genes undergo a process called “alternative splicing,” in which cells selectively combine gene fragments to generate multiple protein variants. This mechanism increases the complexity and adaptability of our bodies, playing a fundamental role in the functioning of living organisms.

In the case of Mitofusin 2, a mitochondrial protein, the research team has discovered two hitherto unknown variants, called ERMIT2 and ERMIN2, that reside in the endoplasmic reticulum. ERMIT2, by interacting with Mitofusin 2, establishes the critical connection between mitochondria and the endoplasmic reticulum, while ERMIN2 regulates the structure of the latter.

“This study represents one of the few cases in which these alternative mitochondrial protein variants have been observed. Consequently, the interaction and mechanism of action that we describe in this study is highly innovative,” says Deborah Naón. Dr. Naón started her project during her doctoral studies at IRB Barcelona and continued it during her postdoctoral stage at VIMM and the University of Padua.

Dr. Zorzano and Dr. Naón. (Photo: IRB Barcelona)

Metabolic and neuromuscular diseases

Facilitated by Mitofusin 2 and its variant ERMIT2, the interaction between the endoplasmic reticulum and mitochondria is vital for lipid metabolism, general metabolic regulation, and the functioning of both mitochondria (the powerhouses of the cell) and the endoplasmic reticulum ( the protein and lipid synthesis factory). When this interaction between organelles is compromised, a condition known as “endoplasmic reticulum stress” occurs, with deleterious effects on cells, tissues and the organism.

In fact, in 2019 Dr. Zorzano’s group discovered that the altered interaction between these two organelles contributes to non-alcoholic steatohepatitis, a serious liver complication associated with metabolic disorders. Now, the team has been able to improve liver function in models of non-alcoholic steatohepatitis simply by stimulating the production of the bridging protein ERMIT2.

“The interaction between mitochondria and the endoplasmic reticulum is also altered in insulin-resistant syndromes such as diabetes and obesity. Therefore, this finding presents a potential therapeutic strategy worth exploring,” explains Dr. Zorzano, who is also Professor at the Faculty of Biology of the University of Barcelona (UB) and member of the Center for Biomedical Research in Diabetes and Associated Metabolic Diseases Network (CIBERDEM) in Spain.

In addition, mutations in the Mitofusin 2 gene cause Charcot-Marie-Tooth 2A, a genetic peripheral neuropathy characterized by severe muscle weakness in the legs. The resulting ambulatory difficulties often require the use of a wheelchair. “The discovery of ERMIN2 and ERMIT2 opens the possibility that alterations in the endoplasmic reticulum and the communication of this organelle with mitochondria contribute to the clinical manifestations of this disease. If so, we could currently explore new therapeutic strategies specific to this disorder. intractable,” adds Dr. Scorrano.

“Our future efforts will focus on understanding the regulation of this gene ‘processing’ to determine the production of specific protein variants. The team will also look at the delicate balance of this process in various physiological and pathological problems, including metabolic and neurological disorders.” Dr. Naón.

The study had the collaboration of other IRB Barcelona laboratories, including those directed by Dr. Manuel Palacín and Dr. Modesto Orozco, who played a crucial role in the discussion of the interaction mechanisms and in the analysis of the results. . In addition, research groups from the Institute of Neurosciences of the Autonomous University of Barcelona (UAB), the Rovira i Virgili University (URV) in Tarragona, the Joan XXIII Hospital in Tarragona and the Parc Sanitari Sant Joan de Déu, with centers in Sant Boi and other locations.

The study is titled “Splice variants of mitofusin 2 shape the endoplasmic reticulum and tether it to mitochondria”. And it has been published in the academic journal Science. (Source: IRB Barcelona)