image: Mitochondrial DNA stress (in red) triggers the inflammatory response in mouse muscle cells devoid of Opa1 (nuclei in green). view more
Credit: Aida Rodríguez, IRB Barcelona
The link between mitochondria and inflammation is still unclear. But it is known is that, for example, the accumulation of defective mitochondria, which should have been removed, causes inflammation. Scientists at the Institute for Research in Biomedicine (IRB Barcelona) headed by Antonio Zorzano, also full professor of the University of Barcelona and researcher in the CIBERDEM programme, now demonstrate that the removal of a single mitochondrial protein in mouse muscle leads to severe inflammation throughout the body, causing the premature death of the animal. This study has been published today in the EMBO Journal.
Opa1 and inflammation
Opa1 is a mitochondrial fusion protein. It serves to fuse the internal membranes of mitochondria. Although present in all cells and tissues (except white blood cells), mitochondria are particularly abundant in muscle and liver, and their main function is to convert the energy in food into energy for cells. Mitochondria are highly dynamic; they join and separate, and grow and shrink constantly. These processes are known as mitochondrial dynamics.
Mitochondrial dynamics is one of the research lines addressed in Antonio Zorzano's Complex Metabolic Diseases and Mitochondria Lab. To study this process, the scientists examine the proteins involved in mitochondrial membrane fusion, namely Mitofusin 1 and 2, and Opa1.
Authored by 24 researchers from various centres and involving a significant contribution by Aida Rodríguez-Nuevo, Angels Díaz-Ramos and Eduardo Noguera from Zorzano's lab, this study focuses on the protein Opa1. To examine its functions, the researchers generated a mouse deficient in Opa1 only in skeletal muscle. "It was surprising to see how small they were and that they died after only a few months," explains Zorzano.
The article describes the animal phenotype and explains that the removal of Opa1 exclusively from skeletal muscle fibre triggers a severe inflammatory process that spreads from the muscle fibre throughout the body. The inflammatory response halts growth and shortens the lifespan of the animal. The scientists also describe the main molecular components of the cell signalling pathway that activates the inflammatory response in muscle.
"This is the first time that we've seen that the lack of a muscle mitochondrial protein triggers an inflammatory response of this magnitude, and these observations give us further information on the relation between mitochondria and inflammation," says Zorzano.
The head of the study explains that these results are of biomedical relevance. There is a set of diseases known as inflammatory myopathies, of unknown origin, in which patients show chronic muscle inflammation accompanied by muscle weakness. "The results of this study suggest that mitochondrial alterations may underlie inflammatory myopathies. More research is now needed to address this possible link," says the scientist.
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Reference article:
Aida Rodríguez-Nuevo, Angels Díaz-Ramos, Eduard Noguera, Francisco Díaz-Sáez, Xavier Duran, Juan Pablo Muñoza, Montserrat Romero, Natàlia Plana, David Sebastián, Caterina Tezze, Vanina Romanello, Francesc Ribas, Jordi Seco, Evarist Planet, Susan R. Doctrow, Javier González, Miquel Borràs, Marc Liesa, Manuel Palacín, Joan Vendrell, Francesc Villarroya, Marco Sandri, Orian Shirihai, Antonio Zorzano Mitochondrial DNA and TLR9 drive muscle inflammation upon Opa1 deficiency EMBO Journal (2018) doi: 10.15252/embj.201796553
About IRB Barcelona
Created in 2005 by the Generalitat de Catalunya (Government of Catalonia) and University of Barcelona, IRB Barcelona is a Severo Ochoa Centre of Excellence, a seal that was awarded in 2011. The institute is devoted to conducting research of excellence in biomedicine and to transferring results to clinical practice, thus improving people's quality of life, while simultaneously promoting the training of outstanding researchers, technology transfer, and public communication of science. Its 25 laboratories and seven core facilities address basic questions in biology and are orientated to diseases such as cancer, metastasis, Alzheimer's, diabetes, and rare conditions. IRB Barcelona is an international centre that hosts 400 employees and 32 nationalities. It is located in the Barcelona Science Park. IRB Barcelona forms part of the Barcelona Institute of Science and Technology (BIST) and the "Xarxa de Centres de Recerca de Catalunya" (CERCA).
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Journal
The EMBO Journal