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The cytoskeleton of cells is, essentially, like their framework and engine. It is composed of three main structures: intermediate filaments (which provide mechanical and stress resistance), actin filaments (which control cell shape and movement), and microtubules. “One could say that microtubules in cells are equivalent to avenues in a large city, as they serve as routes for practically all the transport that occurs inside them,” explains one of the study's authors, Armando del Río, a researcher at the Department of Neuroscience and Biomedical Sciences and the Rector's delegate for the development and implementation of the Faculty of Health Sciences at UC3M.

pH is of vital importance for cells, as it affects nearly all of their internal biochemical processes. Until now, studies on the effect of pH on microtubules were conducted in vitro using isolated structures from whole-cell lysates, which only allowed for the observation of the direct effect of internal pH changes. However, cells possess a highly sophisticated system that keeps their internal pH neutral and constant. It was unknown how external pH (the acidity of the environment surrounding the cell) could indirectly take control of this system.

This team of researchers from UC3M, in collaboration with colleagues from the Universidad Autónoma de Madrid and the University of Tampere (in Finland), has unveiled this mystery in a study published in the latest issue of the scientific journal Journal of the American Chemical Society (JACS). In this work, they describe a new molecular mechanism that connects extracellular acidosis with microtubule stability and the organization of key organelles, such as the Golgi apparatus. “The importance of our work lies in discovering how extracellular acidity can directly interfere with the cell's internal transport system,” points out another author, Ander Bastida Urkiza, from the Department of Neuroscience and Biomedical Sciences at UC3M.

This discovery not only represents a milestone in basic cell biology but also opens up important avenues in clinical medicine, given that extracellular acidosis is a hallmark of multiple diseases that alter normal cellular function due to metabolic imbalances. For instance, in cancer, tumor cells exhibit high metabolic rates and a deficient oxygen supply, causing the tissue surrounding the tumor core to be highly acidic. Chronic diseases like diabetes systemically alter pH balance. Additionally, certain infectious processes induce anaerobic metabolism in affected tissues, generating lactic acidosis.

The molecular "switch" and the signaling pathway

The main finding of this research points to a cell surface protein called β1 integrin, which has been shown to act as a pH-sensitive receptor. Thanks to advanced computer simulations, Professor Vesa Hytönen's team in Finland managed to detect the exact moment when “the magic” happens: when the cell's environment becomes acidic, a small chemical change occurs at a very specific point on this protein (the amino acid Asp138), flipping an alarm switch. This change activates the β1 integrin, and from there, a "domino effect" is triggered toward the inside of the cell, transmitting the signal through a chain of proteins (called RhoA, ROCK, and CRMP-2) that act as messengers of the pH change. The final result is the destabilization of the microtubules.

“Continuing with the analogy we mentioned, external acidity destroys the asphalt of the streets through which internal cell traffic flows. As these pathways collapse, cellular components lose their way, and the Golgi apparatus—the cell's 'logistics and packaging center'—becomes displaced and loses its shape, disrupting internal deliveries,” explains another author of the study, Dariusz Lachowski, from the Department of Neuroscience and Biomedical Sciences at UC3M.

Advanced technology and multidisciplinary collaboration

This multidisciplinary project combined various advanced experimental approaches. To explore the mechanisms involved in microtubule dynamics, the researchers employed total internal reflection fluorescence microscopy and protein comet tracking techniques. Furthermore, a newly created magneto-mechanical actuation device developed by another UC3M research team, led by Daniel García González, was utilized. This tool has enabled the precise mimicry of the different mechanical properties inherent to living tissues, linking acidosis processes with cellular mechanotransduction for the first time.

The results of this study open up a vast number of questions for basic research, such as determining the exact effect that this acidity produces on the molecular motors (the proteins kinesin and dynein) responsible for transporting vesicles along microtubules. In the long term, according to the researchers, the discovery of this mechano-chemical mechanism will serve as a model or guide to advance knowledge of cellular transport and to explore potential therapeutic targets for developing new drugs that protect the internal cellular system in pathological environments.

Bibliographic reference:Lachowski, Dariusz; Cortes, Ernesto;  Mykuliak, Vasyl; Fernandez-de la Torre, Miguel; Bastida Urkiza, Ander;  Muñoz-Barrutia, Arrate; Garcia-Gonzalez, Daniel;  Hytonen, Vesa; del Rio Hernandez, Armando (2026). Acidosis Regulates Microtubule Dynamics via the β1 Integrin/RhoA/CRMP-2 Axis. J. Am. Chem. Soc. https://doi.org/10.1021/jacs.5c20041 e-arhivo: https://hdl.handle.net/10016/50129  

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