Roles of MFN2 in proteostasis management. Credit score: Nature Communications (2025). DOI: 10.1038/s41467-025-56673-5
Researchers from Cologne, Bochum, Padova and Angers have found a novel connection between mitochondrial operate, protein high quality management and mobile well being, whose failure could possibly be the main reason behind the at present incurable neurological illness Charcot-Marie-Tooth (CMT).
The examine led by Mafalda Escobar on the College of Cologne’s Institute of Genetics, CECAD Cluster of Excellence in Getting older Analysis and Middle for Molecular Drugs Cologne (CMMC), uncovered an surprising operate of the protein Mitofusin 2 (MFN2) in mitochondria. It might have far-reaching implications for the therapy of CMT and comparable circumstances.
The work, “Mitofusin 2 displays fusion-independent roles in proteostasis surveillance,” is printed in Nature Communications.
Mitochondria are greatest often called the power producers of the cell, however additionally they regulate metabolism, gene expression and cell survival, all important for wholesome getting old. MFN2 has lengthy been acknowledged for its position in mitochondrial fusion.
The researchers now uncovered an extra, surprising operate of MFN2 in sustaining protein high quality inside cells. The crew discovered that MFN2 interacts with the proteasome and chaperones—mobile techniques that forestall newly produced proteins from forming poisonous aggregates, which may result in neurodegeneration.
Unexpectedly, MFN2 shares this protecting operate. Additional evaluation of pores and skin cells from CMT sufferers confirmed that when MFN2 is mutated, this novel operate is misplaced, resulting in dangerous protein clumping. This discovery opens new prospects for treating illnesses like CMT.
“Although MFN2 is a leading causative gene in Charcot-Marie-Tooth, most other genes linked to the disease do not encode mitochondrial proteins. This makes it less surprising that MFN2’s connection to CMT is independent of its primary function in mitochondrial dynamics,” defined Mariana Joaquim, one of many first authors.
MFN2 controls mitochondrial mass and composition. Credit score: Nature Communications (2025). DOI: 10.1038/s41467-025-56673-5
To know MFN2’s distinctive position, the researchers in contrast it to its carefully associated counterpart, MFN1. Whereas lots of of mutations in MFN2 are recognized to trigger CMT, MFN1 has not been linked to the illness. By producing human cell traces missing both MFN1 or MFN2, they discovered that solely MFN2 interacts with the proteasome and prevents dangerous protein accumulation. This highlights MFN2’s specialised position in mobile well being.
The authors used a mixture of state-of-the-art proteomics, microscopy and biochemistry methods, primarily because of services at CECAD, because of help from the CMMC and largely benefiting from the mitochondria and proteostasis analysis communities in Cologne.
Doctoral researchers from the Cologne Graduate College of Ageing Analysis (CGA) had been concerned within the discovery. The CGA is a three way partnership of CECAD, College Hospital Cologne, the Max Planck Institute for Biology of Ageing and the Max Planck Institute for Metabolism Analysis.
Doctoral researcher Maria-Bianca Bulimaga shared her pleasure concerning the outcomes: “Seeing these aggregates in CMT patients’ cells was a real eye-opener for me. It reinforced how mitochondria are deeply involved in balancing protein synthesis and degradation. It’s something I’m eager to explore further.”
“The study suggests that MFN2’s function in protein quality control could also be relevant for diseases like obesity, where cellular stress and protein misfolding play a major role,” stated Tânia Simões, one other creator on the examine.
Selver Altin, a former doctoral pupil, stated, “It is immensely rewarding to see the results of this work, which I helped initiate during my doctoral work.”
In keeping with the researchers, this discovery is a key step in uncovering how mitochondria contribute to mobile well being. The crew now sees potential for brand spanking new therapeutic approaches.
“By understanding how MFN2 interacts with the cellular machinery that maintains protein health, we may be able to develop treatments that prevent harmful protein aggregation and protect neuronal function in CMT and perhaps other neurodegenerative diseases. We are very thankful to the many sponsors of our study, including the German Research Foundation (DFG) as well as the Fritz Thyssen, Boehringer Ingelheim and Bayer Foundations,” added Escobar.
Extra info:
Mariana Joaquim et al, Mitofusin 2 shows fusion-independent roles in proteostasis surveillance, Nature Communications (2025). DOI: 10.1038/s41467-025-56673-5
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A mitochondrial protein’s protecting position gives new hope for Charcot-Marie-Tooth illness (2025, February 14)
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