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CABD researchers discover new cellular mechanism with therapeutic potential in neurodegenerative diseases

This study paves the way for new medical approaches focused on modulating the fluidity of cell membranes.

A study developed in the laboratory of Pablo de Olavide University professor Juan Jiménez, at the Centro Andaluz de Biología del Desarrollo (CABD) -a joint center of the UPO, the CSIC and the Junta de Andalucía-, has unveiled a key mechanism that links the rigidity of cell membranes with the accumulation of misfolded proteins and mitochondrial stress, fundamental factors in neurodegenerative and mitochondrial pathologies. This finding, recently published in the journals iScience and Yeasts, opens the door to new therapeutic strategies based on the modulation of cell membrane fluidity.



Scheme relating altered proteostasis and mitochondrial function to membrane fluidity homeostasis regulated by ergosterol levels in cells.

Neurodegenerative diseases, such as Alzheimer's or Parkinson's, present common cellular alterations, such as protein misfolding, mitochondrial dysfunction and changes in the lipid composition of cell membranes. Until now, the relationship between these processes was not clear. However, the research team has shown that the EMC chaperone, an endoplasmic reticulum complex responsible for inserting proteins into cell membranes, plays an essential role in the regulation of cholesterol (ergosterol in yeast).

Key in this process is the Lam6/Ltc1 protein, whose function is to eliminate excess ergosterol from cell membranes. Without EMC, Lam6/Ltc1 stops working and the ergosterol accumulates, stiffening the membranes. “It's like trying to stick an umbrella into a rock instead of sand on the beach. When the membrane is fluid, proteins can be easily inserted, but when it becomes rigid, many are misfolded and cannot fulfill their function,” explains Juan Jiménez, Professor of Genetics at the UPO.



Cells with impaired respiration in the absence of EMC.

Possible therapeutic applications

Experiments performed with EMC-deficient yeast showed that the accumulation of ergosterol hardens cell membranes and causes the retention of misfolded proteins, which end up moving to the mitochondria, overloading them to the point of causing atrophy and loss of respiratory function. However, the researchers found that these effects can be reversed by two strategies: inhibiting ergosterol synthesis with ketoconazole or treating the cells with the emulsifier tween20 (E432), which restores membrane fluidity.
Since EMC and Lam6/Ltc1 are universal proteins in eukaryotes, the results of this study in yeast could be extrapolated to human cells. “Although still speculative, this discovery suggests that compounds that modulate membrane fluidity, such as certain food emulsifiers or cholesterol-lowering drugs, could have therapeutic applications in human pathologies caused by mutations in EMC, as well as in mitochondrial and neurodegenerative diseases, opening an unexpected avenue for the development of innovative therapies,” adds Juan Jiménez.

This work is part of Modesto Berraquero's doctoral thesis, co-directed by UPO Genetics Area professors Víctor Álvarez-Tallada and Juan Jiménez, and has been published in iScience (DOI: 10.1016/j.isci.2025.112096) and Yeasts (https://doi: 10.1002/yea.3998).

Work of reference:

Modesto Berraquero, Víctor A. Tallada, Juan Jiménez. Ltc1 localization by EMC regulates cell membrane fluidity to facilitate membrane protein biogenesis. iScience 2025. https://doi.org/10.1016/j.isci.2025.112096

Modesto Berraquero, Víctor A. Tallada, Juan Jiménez. A Key Role of the EMC Complex for Mitochondrial Respiration and Quiescence in Fission Yeasts. Yeast 2025 https://doi: 10.1002/yea.3998



This press release was written in collaboration with the Unit od Communication of UPO.