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The Acid Gate in the Lysosome.

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Scientists identified TMEM175 as a proton channel crucial for lysosomal pH balance. This discovery offers a new target for treating lysosomal dysfunction and Parkinson disease.

Keywords:
H+ leakProton channelTMEM175acidificationlysosome

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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.