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

Erika Riederer1, Vedrana Mikusevic2, Tuoxian Tang1

  • 1Department of Biology, University of Pennsylvania, Philadelphia, PA, USA.

The Journal of Cell Biology
|October 24, 2025
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TMEM175 is not a proton channel in lysosomes, contrary to previous proposals. This Parkinson's disease-associated protein conducts potassium ions, influencing lysosomal pH and offering new insights into disease mechanisms.

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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.