25.12.2019 | TopNews
Mitochondria need to be able to fuse and let go in order to function properly. The protein Cdc48 is an important coordinator and tears mitochondrial fusion complexes apart, only after the fusion process is completed successfully. Two additional critical steps are now described by the Escobar team at CECAD. The results are published in Life Science Alliance (DOI: 10.26508/lsa.201900476 and 10.26508/lsa.201900491)
Mitochondria are extremely dynamic and constantly change their shape by fusion and fission events. Problems with this process are linked to diseases like Charcot-Marie-Tooth, Alzheimers, cardiopathies and diabetes: “Therefore the fusion of mitochondria is a gatekeeper to a healthy society,” Dr. Escobar-Henriques says. In healthy organisms, mitochondria constantly come together, transmit information and fuse with help of proteins called mitofusins. After the activation, the process needs to be stopped later. As the researchers found, the protein Cdc48 is an important coordinator or “a powerful dismantling machine,” the lead author states. But before this protein can do its job, there need to be a signal to pull the mitofusins apart. Therefore, when changing between the bent or stretched state, they get tagged by a small protein called ubiquitin.
“We need to understand how this functions to intervene the diseases for therapeutic potential,” adds Vincent Anton, the first author in of the two studies. The researchers found that the structure is held by electrical forces. By genetically changing the electric charge using another amino acid, they were able to show that the conformation of the protein complex changes: What used to be negatively charged, was now positive and vice versa. The machinery was still working, but in another arrangement.
Dysregulation of this plasticity can lead to a broad range of aging diseases, including neuropathies and nutrition-linked disorders. Better understanding how mitofusins regulate membrane merging is essential for finding potential therapeutic interventions for these diseases.
“We are happy to provide another piece of the puzzle with our basic research and hope to get closer to therapeutic interventions or new drug discoveries in the end,” Mafalda Escobar-Henriques summarizes.
Dr. Mafalda Escobar-Henriques
Principal Investigator, CECAD, Institute for Genetics
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