A new scientific study led by Carlos III University of Madrid (UC3M) describes a mechanochemical mechanism by which the acidity of the cellular environment destabilizes microtubules, the “channels” that organize traffic inside cells. This discovery is key to understanding pathological conditions such as cancer, diabetes, or certain infectious processes where extracellular acidosis is a tissue feature.
A cell’s cytoskeleton is essentially its framework or engine. It is composed of three major structures: intermediate filaments (which provide mechanical and stress resistance), actin filaments (which control cell shape and movement), and microtubules.
Intracellular microtubules are the equivalent of the main streets of a big city, as they act as routes for almost all transport that occurs within a cell. ”
One of the study authors, Armando del Rio, is a researcher in the Department of Neuroscience and Biomedical Sciences and the Dean’s Representative for the Development and Implementation of the UC3M School of Health Sciences.
pH is extremely important to cells because it affects nearly all of the cells’ internal biochemical processes. Until now, studies on the effects of pH on microtubules have been carried out in vitro using structures isolated from whole cell lysates, and it has only been possible to observe the direct effects of internal pH changes. However, cells have highly sophisticated systems that keep their internal pH neutral and constant. It was unclear how external pH (the acidity of the environment surrounding the cell) could indirectly control this system.
A team of researchers from UC3M, in collaboration with colleagues from the Autonomous University of Madrid and the University of Tampere (Finland), uncovered this mystery in a study published in the latest issue of the scientific journal Journal of the American Chemical Society (JACS). This study describes a novel molecular mechanism linking extracellular acidosis to microtubule stability and organization of critical organelles such as the Golgi apparatus. “The importance of our study lies in discovering how extracellular acidity directly interferes with the cell’s internal transport systems,” points out Ander Bastida Urkiza, another author from UC3M’s Department of Neuroscience and Biomedical Sciences.
Given that extracellular acidosis is a hallmark of multiple diseases in which metabolic imbalance alters normal cellular function, this discovery is not only a milestone in basic cell biology, but also opens important avenues for clinical medicine. For example, in cancer, the tissue surrounding the tumor nucleus becomes highly acidic due to the high metabolic rate of tumor cells and poor oxygen supply. Chronic diseases such as diabetes alter pH balance systemically. Additionally, certain infectious processes induce anaerobic metabolism in affected tissues, leading to lactic acidosis.
Molecular “switches” and signal transduction pathways
The main finding of this study is that a cell surface protein called β1 integrin has been shown to function as a pH-sensitive receptor. Thanks to advanced computer simulations, Finnish professor Vesa Hytonen’s team was able 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 in this protein (amino acid Asp138), flipping an alarm switch. This change activates β1 integrin, which triggers a “domino effect” toward the inside of the cell, transmitting signals through chains of proteins (called RhoA, ROCK, and CRMP-2) that act as messengers of pH changes. The end result is microtubule destabilization.
“Continuing with the analogy I mentioned earlier, external acidity destroys the asphalt of the city streets through which internal cellular traffic flows. When these pathways collapse, cellular components have nowhere to go, and the Golgi apparatus, the cell’s ‘logistics and packaging center,’ shifts and loses its shape, disrupting internal delivery,” explains the study’s other author, Dariush Rachowski from the Department of Neuroscience and Biomedical Sciences. UC3M.
Advanced technology and multidisciplinary collaboration
This interdisciplinary project combines various advanced experimental approaches. To investigate the mechanisms involved in microtubule dynamics, the researchers employed total internal reflection fluorescence microscopy and protein comet tracking techniques. In addition, a newly created magneto-mechanical actuation device developed by another UC3M research team led by Daniel García González was utilized. This tool allows us to precisely mimic the various mechanical properties inherent in living tissues, linking acidosis processes and cellular mechanical transduction for the first time.
The results of this study raise a huge number of questions for basic research, including determining the precise effects this acidity produces on the molecular motors (the proteins kinesin and dynein) responsible for transporting vesicles along microtubules. In the long term, the researchers say, the discovery of this mechanochemical mechanism will advance our knowledge of cell trafficking and serve as a model or guide to explore potential therapeutic targets to develop new drugs that protect internal cellular systems in pathological settings.
sauce:
Carlos III University of Madrid – OIDCI
Reference magazines:
Lachowski, D. others. (2026). Acidosis regulates microtubule dynamics through the β1 integrin/RhoA/CRMP-2 axis. Journal of the American Chemical Society. DOI::10.1021/jacs.5c20041. https://pubs.acs.org/doi/10.1021/jacs.5c20041
