TMEM175 does not function as a proton-selective ion channel to prevent lysosomal over-acidification

Area of Science:

• Cell Biology
• Ion Transport
• Neurodegenerative Diseases

Background:

• Lysosomes maintain an acidic pH via the V-ATPase proton pump.
• Mechanisms preventing lysosomal hyper-acidification are not fully understood.
• TMEM175, linked to Parkinson's disease (PD), was hypothesized as a proton leak channel.

Purpose of the Study:

• To rigorously evaluate TMEM175's function as a proton-selective channel in lysosomes.
• To investigate the role of TMEM175 in regulating lysosomal pH and preventing hyper-acidification.
• To clarify TMEM175's contribution to Parkinson's disease pathology.

Main Methods:

• Electrophysiological recordings in lysosomes.
• Analysis of lysosomal pH in cells with and without TMEM175.
• Cellular manipulations to induce hyper-acidification.

Main Results:

• TMEM175 predominantly conducts potassium (K+) ions, not protons (H+).
• Lysosomal proton leak is minimal, inconsistent with a major channel contribution.
• TMEM175 deficiency leads to lysosomal alkalinization, supporting K+ conductance.
• Lysosomes can be hyper-acidified regardless of TMEM175 presence.

Conclusions:

• TMEM175 functions as a K+ channel, not a H+-selective leak channel in lysosomes.
• Findings challenge the model of TMEM175 preventing hyper-acidification via proton leak.
• TMEM175's K+ conductance influences lysosomal pH homeostasis and PD pathology.