ArticleThe Journal of cell biology2026
TMEM175 does not function as a proton-selective ion channel to prevent lysosomal over-acidification.
Article in The Journal of cell biology, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 7 papers.
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Who cites it
7 citing papers in PubMed.
- Lysosomal dysfunction in neurodegenerative disease.Nature reviews. Neurology · 2026Review
- TLDc proteins: Stress-responsive nexus regulators of redox signaling, V-ATPase dynamics, and organellar crosstalk in neurodegeneration.Redox biology · 2026Review
- A nonhydrolyzable candesartan cilexetil analog reveals synergistic activation as a tractable mechanism for TMEM175 modulation.American journal of physiology. Cell physiology · 2026Article
- DNA nanodevices detect an acidic nanolayer on the lysosomal surface.Nature cell biology · 2026Article
- Proton-selective conductance and gating of the lysosomal cation channel TMEM175.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- Autophagy-lysosomal pathway in neurodegeneration.Molecular neurodegeneration advances · 2026Review
- LRRK2 integrates Rab and GABARAP interactions to sense and respond to distinct lysosomal stresses.bioRxiv : the preprint server for biology · 2025Article
Corrections and comments
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Authors and funding
6 authors.
Funding
Abstract
The acidic pH of lysosomes required for function is established by the electrogenic V-ATPase proton pump. How lysosomes prevent hyper-acidification by the pump is not well established. Recently, the Parkinson's disease (PD)-associated protein TMEM175 was proposed as a H+-selective channel to leak protons to counter over-acidification. We rigorously address key findings and predictions of this model and show that, in the lysosome, TMEM175 predominantly conducts K+ and is not a H+-selective channel. The native lysosomal H+ leak is remarkably small, ∼0.02 fA, strongly arguing against major contributions from an ion channel. The predominant effect of TMEM175 deficiencies is lysosomal alkalinization in challenged cells, which is further evidence arguing against TMEM175 as a H+-selective channel and can be explained by K+ conductance through TMEM175. Also, lysosomes can be hyper-acidified by manipulations in the presence or absence of TMEM175. Our studies clarify a basic lysosomal biological problem and provide insights into the working mechanism of TMEM175 and its contribution to PD pathology.
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Registered trials
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