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Dr. Antonio Zorzano and Dr. Deborah Naón (IRB Barcelona)

IRB Barcelona unveils the key role of Mitofusin-2 in guaranteeing vital cell functions in ‘Science’

This protein is produced in different variants that play a vital role in the connections between mitochondria and the endoplasmic reticulum. The work, led by IRB Barcelona, the University of Barcelona, VIMM and the University of Padua, and published in ‘Science’, opens up potential therapeutic strategies in non-alcoholic fatty liver disease or Charcot-Marie-Tooth 2A neuropathy, and in syndromes such as diabetes and obesity.

Mitofusin-2 is a mitochondrial protein that plays a fundamental role in Charcot-Marie-Tooth 2A neuropathy and in metabolic disorders such as diabetes and non-alcoholic fatty liver disease. Now a work co-led by IRB, with headquarters at the Barcelona Science Park, and published in ‘Science’, reveals the key role of cellular Mitofusin-2 in the interconnection of organelles within cells and the existence of different variants of Mitofusin-2: ERMIT2 and ERMIN2.

“Our comprehensive research found ERMIN2 and ERMIT2 in a wide range of human tissues and cells, among them adipose tissue, muscle and liver. These findings underscore the participation of these proteins in maintaining optimal cell function”, explains Dr Antonio Zorzano, head of the Complex Metabolic Diseases and Mitochondria laboratory at IRB Barcelona and co-leader of the study published in ‘Science’.

The work shows that the ERMIN2 variant regulates the structure of the endoplasmic reticulum, and ERMIT2 interacts with Mitofusin-2 forming a bridge between the mitochondria and the endoplasmic reticulum that facilitates the exchange of signals and lipids.

“This study represents one of the few cases in which these alternative variants of mitochondrial proteins have been observed. As a result, the interaction and mechanism of action that we describe in this study are very innovative”, highlights Dr Deborah Naón, the first author and leader of the study, who began the project during her doctoral studies at IRB Barcelona at the Barcelona Science Park, and continued it during her post-doctoral stage at VIMM and the University of Padua.

Potential therapeutic applications

Facilitated by the Mitofusin-2 and its ERMIT2 variant, the interaction between the endoplasmic reticulum and the mitochondria is essential: if it is compromised a condition known as “endoplasmic reticulum stress” occurs leading to detrimental effects on cells, tissues and the organism. In 2019, Dr Zorzano’s group discovered that this altered interaction contributes to non-alcoholic steatohepatitis, a serious liver complication associated with metabolic disorders. Now, researchers have managed to improve the liver function in non-alcoholic steatohepatitis models by stimulating the production of ERMIT2.

“The interaction between mitochondria and the endoplasmic reticulum is also altered in syndromes presenting insulin resistance, such as diabetes and obesity. Therefore, this finding presents a potential therapeutic strategy worth exploring”, explains Dr Zorzano.

On the other hand, mutations to Mitofusin-2 cause Charcot-Marie-Tooth 2A, a genetic peripheral neuropathy characterised by severe muscular weakness in the legs, often requiring the use of a wheelchair. “The discovery of ERMIN2 and ERMIT2 opens up the possibility that alterations in the endoplasmic reticulum and the communication of this organelle with the mitochondria contribute to clinical manifestations of this disease. If this is the case, we could explore new targeted therapeutic strategies for this currently untreatable disorder”, explains Dr Luca Scorrano, Professor of Biochemistry at the Department of Biology of the University of Padua, Principal Investigator and the former Scientific Director of VIMM.

» Link to the article: IRB Barcelona website [+]