Scientists discover “overflow valve” in cells linked to Parkinson’s Disease

Just like sinks and bathtubs have overflow drains to prevent spills, human cells appear to have a similar built-in safeguard. A new study by scientists from Bonn-Rhein-Sieg University of Applied Sciences (H-BRS), LMU Munich, TU Darmstadt, and Nanion Technologies, published in PNAS (Proceedings of the National Academy of Sciences), reveals this protective system. Led by Professor Christian Grimm (LMU Munich) and Dr. Oliver Rauh (H-BRS), the team decoded the long-debated function of the ion channel TMEM175. Their findings suggest that inside lysosomes, this channel acts like an overflow valve, preventing the environment from becoming too acidic.

Lysosomes and the Control of Cellular Acidity

Lysosomes are small compartments enclosed by membranes that serve as the cell’s recycling centers. They break down large molecules into simpler building blocks that the cell can reuse. For this process to work properly, lysosomes must maintain an acidic environment.

pH measures the concentration of protons (H+) in a solution, and lower pH values indicate higher proton levels. A specialized protein pumps protons into lysosomes to create this acidity. However, maintaining the right balance requires additional proteins embedded in the lysosomal membrane. The study highlights TMEM175 as a key player in fine-tuning this balance.

The researchers believe that in healthy cells, TMEM175 helps maintain the ideal acidity level, allowing waste breakdown to proceed efficiently. When mutations disrupt this channel, pH regulation is impaired. As a result, proteins are not properly degraded, which can lead to the death of nerve cells. Previous research has linked problems in lysosomal function to aging and neurodegenerative diseases such as Parkinson’s. “Our study establishes that the ion channel TMEM175 plays a decisive role here,” says Dr. Oliver Rauh.

TMEM175 Ion Channel Transports Potassium and Protons

For years, scientists were unsure where TMEM175 was located in cells or what it actually did. Its simple name, which stands for transmembrane protein 175, reflects how little was initially known. Over time, interest in TMEM175 grew as evidence connected it to neurodegenerative diseases, especially Parkinson’s.

Researchers eventually confirmed that TMEM175 is an ion channel that moves charged particles across the lysosomal membrane. However, there was ongoing debate about whether it mainly transported potassium ions or protons, and how those movements affected cell function in both healthy and diseased states.

A pH Sensor That Adjusts Proton Flow

“I’ve worked on many ion channels, and TMEM175 is by far the strangest of them all,” says Dr. Oliver Rauh, who moved from TU Darmstadt to H-BRS to work in the research collaboration CytoTransport. “When we started on the project around six years ago, it was assumed that TMEM175 was a potassium channel. Its function was completely unknown. We’ve now been able to demonstrate that TMEM175 not only conducts potassium ions, but also protons, and is thus directly involved in the regulation of pH — that is, the proton concentration — in the interior of lysosomes.”

“Most of the experiments were conducted using the patch clamp method,” explains Christian Grimm, an expert in techniques that measure electrical activity in lysosomal membranes. This method allowed the team to analyze how the channel behaves under different conditions. Their results show that TMEM175 can detect when acidity reaches a critical level and adjust the flow of protons accordingly.

“Our findings create an important foundation for a better understanding of functional processes in lysosomes and the function of the TMEM175 channel, which was contested before now,” say the authors. “At the same time, our insights into the protein TMEM175 offer a promising target structure for the development of drugs to treat or prevent neurodegenerative diseases like Parkinson’s.”