A study published in the journal Cell Reports describes new functions of the protein Mitofusin 2 (Mfn2) in macrophages –cells that take part in the defensive and inflammatory response– under immunological stress conditions. The article sheds light on the expression mechanisms of proinflammatory cytokines, molecules that can appear uncontrolledly –known as the cytokine storm– over the course of bacterial and viral infections.
The study is led by Professor Antonio Celada and the lecturer Jorge Lloberas, heads of the Consolidated Research Group on Biology of Macrophage of the UB, located in the Barcelona Science Park (PCB). The study, whose first author is the expert Juan Tur, also member of the Consolidated Research Group on Biology of Macrophage, counts on the participation of Antonio Zorzano, professor at the Faculty of Biology of the UB and head of the Complex Metabolic Diseases and Mitochondria Lab at the Institute of Biomedical Research (IRB Barcelona) and the Diabetes and Associated Metabolic Diseases Networking Biomedical Centre (CIBERDEM).
A determining protein in the mitochondrial metabolism and dynamics
Mitofusin 2 is a protein found in the external membrane of mitochondria, the organelles that work on the energy metabolism of the cell. It plays an important role in physiological processes (mitochondrial dynamics, energy metabolism, embryonal development, cell death, etc.) and its deficiency is related to some metabolic, neurodegenerative, and cardiovascular diseases, apart from cancer and others.
The essential role of Mfn2 is the fusion of mitochondria and the interaction with the endoplasmic reticulum (RE), a system formed by a complex membrane network and related to the synthesis and transport of proteins. This protein is an essential compound of the immune response in macrophages “because, after being activated as a response to immunological stress stimuli, it favours the interaction of mitochondria with the endoplasmic reticulum (RE) and the production of reactive oxygen species (ROS)”, says the lecturer Jorge Lloberas, from the Department of Cell Biology, Physiology and Immunology of the UB.
“ROS are molecules that act as mediators in a high amount of processes related to innate immunity, such as autophagy, a process on which apoptosis and phagocytosis depend. These also take part in the production of cytokines as a response to inflammatory processes, and favour a proper processing and antigenic presentation, the key phases of the connection between innate and adaptive immunity”, notes Lloberas.
Immunometabolism: emerging discipline
This study in the field of the immunometabolism, carried out with knockout laboratory models without Mitofusin 2 expression, enabled researchers to reveal how the mitochondrial protein induces the production of ROS as well as its decisive implications in the immune response.
“In basal conditions of Mdn2 absence, there is no effect. The macrophages’ ability to take and remove any external agent is very low when these are confronted to an immunological stress and do not produce ROS. Also, the lack of Mfn2 in macrophages conditions the processing of the proteins that are caught in the previous phase to the one known as antigenic presentation, which involves the activation of adaptive immunity, that is, the activation of lymphocytes T (cytokine production) and lymphocytes B (antibody production)”, notes the lecturer Lloberas.
In vivo studies in animal models also revealed the key role of this mitochondrial protein in the bactericide response regarding the pathogens Listeria monocytogenes and Mycrobacterium tuberculosis. Apart from inducing the ROS production, Mfn2 favours the identification of bacteria receptors, uptake of pathogens through macrophages (phagocytosis), degradation of bacterial proteins and the activation of adaptive immunity.
Tur, J.; Pereira-Lopes, S.; Vico, T.;Marín, E.; Muñoz, J.P.; Hernández-Alvarez, M.; Cardona, P.J.; Zorzano, A.; Lloberas, J. and Celada, A. “Mitofusin 2 in Macrophages Links Mitochondrial ROS Production, Cytokine Release, Phagocytosis, Autophagy, and Bactericidal Activity“, Cell Reports, agost de 2020. Doi: https://doi.org/10.1016/j.celrep.2020.108079