When pH Gets Out Of Control, Parkinson's Disease Emerges: How a Cellular Channel Controls Brain Acidity

The TMEM175 protein is a channel present in lysosomes that helps control the chemical balance of cells. Although it was previously believed to transport mainly potassium, this study shows that, in acidic environments, the channel primarily conducts protons, rapidly altering the internal pH of lysosomes. This process is regulated by a specific region of the protein that acts as an acidity sensor. Alterations in this channel can impair cellular function and are associated with neurodegenerative diseases, such as Parkinson's disease.

The protein called TMEM175 is a special type of ion channel, that is, a structure that allows the passage of electrically charged particles through cell membranes. It is present in virtually all cells of the body and is mainly located in endosomes and lysosomes, which are cellular compartments responsible for recycling molecules, digesting waste, and maintaining the cell's internal balance.

Endosomes are vesicles (membrane-lined sacs) that receive material entering the cell, while lysosomes are vesicles specialized in degradation. The proper functioning of these compartments depends heavily on adequate pH control, that is, how acidic or basic their interior is.

Alterations in the functioning of TMEM175 have been identified as an important risk factor for neurodegenerative diseases, such as Parkinson's disease. Initially, this protein was described as a channel that primarily allows the passage of potassium ions.

These ions would help maintain the internal pH of lysosomes stable and suitable for their functions. Subsequent studies confirmed that, under neutral pH conditions, TMEM175 actually conducts mainly potassium.

However, new research has shown that when the interior of the lysosome becomes more acidic, which is the normal condition for these compartments, the channel's behavior changes drastically. Under these conditions, the channel's conduction capacity greatly increases, and its selectivity changes, favoring the passage of protons, which are particles associated with acidity.

In other words, the channel begins to conduct mainly hydrogen ions, which can rapidly alter the pH balance within the lysosome.

To better understand this phenomenon, researchers used electrophysiological techniques that measure electrical currents generated by the movement of ions through the channels. One of the parameters analyzed was the so-called reversal potential, which indicates what type of ion is passing through the channel.

Although the results pointed to the conduction of protons, the measured values ​​did not exactly correspond to what would be expected for a channel exclusively selective for protons. This raised doubts about whether the channel would also allow the passage of other larger ions. However, this hypothesis conflicted with the narrow physical structure of the channel pore, which would hardly accommodate large ions.

A more plausible explanation for this discrepancy is related to the technical limitations of the experiments. Accurately measuring proton transport is extremely difficult because protons move very rapidly and at very low concentrations.

Furthermore, when many protons cross the channel at the same time, the pH gradient dissipates rapidly, making the electrical potential measurements unstable. Even the use of concentrated buffer solutions is not sufficient to completely avoid this effect. Similar phenomena have been observed in other proton-transporting systems, indicating that this is a general problem in the electrophysiology of this type of channel.

Taking this into account, the authors of the study investigated how proton conduction through TMEM175 dynamically affects the reversal potential. They observed that acidification of the inner side of the lysosome initially causes a positive shift in the reversal potential, indicating strong proton conduction. Over time, however, this potential returns to values ​​close to zero because the proton flow itself collapses the pH gradient that drives it.

To confirm these findings, the researchers used different experimental approaches, including measurements in whole cells, isolated lysosomes, and artificial membrane systems. These experiments demonstrated that TMEM175 is not exclusively selective for a single type of ion, but exhibits permeability to both potassium and protons, depending on pH conditions.

Furthermore, by analyzing three-dimensional structures of the protein in open and closed states, the authors identified a specific amino acid, histidine at position 57, as a pH sensor located on the inner side of the channel.

This residue acts as a regulator of channel opening and its preference for protons or potassium. When this histidine was genetically modified, the channel's ability to conduct ions decreased significantly, confirming its central role in TMEM175 function.

These results deepen the understanding of how TMEM175 regulates chemical balance within lysosomes and help explain why its dysfunction may contribute to neurodegenerative diseases. Understanding these mechanisms at the molecular level may pave the way for new therapeutic strategies aimed at protecting lysosomal function in diseases such as Parkinson's disease.

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Proton-selective conductance and gating of the lysosomal cation channel TMEM175

Tobias Schulze, Timon Sprave, Carolin Groebe, Jan Hendrik Krumbach, Magnus Behringer, Andre Bazzone, Rocco Zerlotti, Niels Fertig, Mike Althaus, Kay Hamacher, Gerhard Thiel, Christian Grimm, and Oliver Rauh

Proceedings of the National Academy of Sciences. 123 (3) e2503909123. 14 January 2026.DOI: 10.1073/pnas.2503909123

Abstract:

The lysosomal cation channel TMEM175 plays a key role in luminal pH homeostasis and lysosome function, with aberrant activity linked to Parkinson’s disease. Although initially described as a K+-selective channel, TMEM175 exhibits substantial H+ permeability. Here, we dissect complex changes affecting human TMEM175 conductance and ionic properties of TMEM175-mediated current in response to pH shifts on the luminal side of the protein. A drop in pH from 7.4 to 4.7 on the side equivalent to the lysosomal lumen triggers a sustained increase in TMEM175-mediated inward and outward currents, which is accompanied by a transient shift in the reversal potential (Erev) toward the theoretical equilibrium voltage for H+, yet remaining ~100 mV below the expected value even in the absence of K+. This discrepancy, along with low sensitivity of Erev to the concentration gradient for K+, supports a model in which TMEM175-mediated H+ flux rapidly collapses the lysosomal pH-gradient. Molecular dynamics simulations identify H57 as a key residue on the luminal side of the open channel, which forms intra- and intersubunit salt bridges with D279 and E282. Supporting the functional importance of these interactions, the TMEM175 mutant H57Y displayed reduced H+- and K+-conductance and a reduced H+/K+ selectivity in whole-cell and lysosomal electrophysiological analyses. Our findings contribute to a better understanding of TMEM175’s complex electrophysiological properties, thereby expanding the possibilities of understanding the channel’s function in lysosomal physiology and pathophysiology.