Mitochondria are best known as the energy producers of the cell, but they also regulate metabolism, gene expression, and cell survival, all essential for healthy aging. One key mitochondrial protein, Mitofusin 2 (MFN2), has long been recognized for its role in mitochondrial fusion. Now, a study led by Dr. Mafalda Escobar at the Institute of Genetics has uncovered an additional, unexpected function of MFN2 in maintaining protein quality within cells.
“We’ve uncovered a hidden function of MFN2 in protein quality control,” says Dr. Escobar. “This new understanding helps us separate MFN2’s well-known role in mitochondria from its link to CMT, opening up new treatment possibilities. We are very thankful to the many sponsors of our study.”
The research team, collaborating with partners in Germany, France, and Italy, found that MFN2 interacts with the proteasome and chaperones—cellular systems that prevent newly produced proteins from forming toxic aggregates. Further analysis of skin cells from CMT patients confirmed that when MFN2 is mutated, this protective function is lost, leading to harmful protein clumping.
“Although MFN2 is a leading causative gene in Charcot-Marie-Tooth, most other genes linked to the disease do not encode mitochondrial proteins,” explains Mariana Joaquim, one of the study’s first authors. “This makes it less surprising that MFN2’s connection to CMT is independent of its primary function in mitochondrial dynamics.”
To understand MFN2’s unique role, the researchers compared it to its closely related counterpart, MFN1. While hundreds of mutations in MFN2 are known to cause CMT, MFN1 has not been linked to the disease. By generating human cell lines lacking either MFN1 or MFN2, they found that only MFN2 interacts with the proteasome and prevents harmful protein accumulation. This highlights MFN2’s specialized role in cellular health.
“Seeing these protein aggregates in CMT patient cells was a real eye-opener for me,” says Maria-Bianca Bulimaga, a PhD student at the Aging Graduate School in Cologne. “It reinforced how mitochondria are deeply involved in balancing protein synthesis and degradation. It’s something I’m eager to explore further.”
The findings also raise broader questions about MFN2’s role in other health conditions. “This 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,” says Tânia Simões, another author on the study.
For Selver Altin, a former PhD student involved in the early stages of the research, the study represents an important milestone. “It is immensely rewarding to see the results of this work, which I helped initiate during my PhD.”
This discovery is a key step in understanding how mitochondria contribute to cellular health. As research continues, Dr. Escobar sees potential for 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,” she says.
With its fusion-independent role in maintaining protein quality, MFN2 is emerging as a critical player in cellular protection. This research paves the way for new strategies to address CMT and other neurodegenerative diseases.
Scientific contact person:
Dr. Mafalda Escobar
E-Mail: mafalda.escobar[at]uni-koeln.de
Tel: +49 0221 478 84257
Press and Communications Team:
Dr. Tanio Calabrese
E-Mail: g.calabrese[at]uni-koeln.de
Original publication:
https://www.nature.com/articles/s41467-025-56673-5