The Acid Gate in the Lysosome

Area of Science:

• Cell Biology
• Molecular Biology
• Biochemistry

Background:

• Lysosomes maintain a precise acidic pH (4.5-5.0) essential for macromolecule digestion and metabolite recycling.
• This pH homeostasis relies on proton influx via V-type H⁺-translocating ATPase (V-ATPase) and a poorly understood proton efflux pathway.

Purpose of the Study:

• To identify the molecular identity of the lysosomal proton leak pathway.
• To investigate the role of TMEM175 in lysosomal pH regulation and its connection to Parkinson disease.

Main Methods:

• Candidate expression screening to identify proton channels.
• Electrophysiological recordings of lysosomal currents.
• Cellular assays measuring lysosomal pH and proteolytic degradation.
• Analysis of TMEM175 variants in Parkinson disease patient cells.

Main Results:

• TMEM175 encodes a proton-activated, proton-selective channel (LyPAP) responsible for lysosomal H⁺ leak.
• TMEM175 deficiency leads to lysosomal hyper-acidification and impaired degradation, which are reversible.
• Parkinson disease-associated TMEM175 variants reduce LyPAP currents and cause lysosomal hyper-acidification.

Conclusions:

• TMEM175 is a key component of the lysosomal proton leak pathway, critical for maintaining pH homeostasis.
• Dysfunctional TMEM175 contributes to lysosomal pathologies and Parkinson disease pathogenesis.
• TMEM175 represents a potential therapeutic target for modulating lysosomal function and related diseases.