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How lysosomes prevent hyper-acidification by the pump is not well established. Recently, the Parkinson\u2019s 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, \u223c0.02 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.<\/jats:p>","DOI":"10.1083\/jcb.202501145","type":"journal-article","created":{"date-parts":[[2025,10,8]],"date-time":"2025-10-08T06:21:04Z","timestamp":1759904464000},"update-policy":"https:\/\/doi.org\/10.1083\/jcb.crossmarkpolicy","source":"Crossref","is-referenced-by-count":15,"title":["TMEM175 does not function as a proton-selective ion channel to prevent lysosomal over-acidification"],"prefix":"10.1083","volume":"225","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1011-6536","authenticated-orcid":true,"given":"Erika","family":"Riederer","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/00b30xv10","id-type":"ROR","asserted-by":"publisher"}],"name":"University of Pennsylvania 1 Department of Biology, , Philadelphia, PA,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9666-9571","authenticated-orcid":true,"given":"Vedrana","family":"Mikusevic","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/01cwqze88","id-type":"ROR","asserted-by":"publisher"}],"name":"Membrane Transport Biophysics Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health 2 , Bethesda, MD,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6747-461X","authenticated-orcid":true,"given":"Tuoxian","family":"Tang","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/00b30xv10","id-type":"ROR","asserted-by":"publisher"}],"name":"University of Pennsylvania 1 Department of Biology, , Philadelphia, PA,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-0858-7465","authenticated-orcid":true,"given":"Lillian","family":"Martin","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/00b30xv10","id-type":"ROR","asserted-by":"publisher"}],"name":"University of Pennsylvania 1 Department of Biology, , Philadelphia, PA,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6952-8247","authenticated-orcid":true,"given":"Joseph A.","family":"Mindell","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/01cwqze88","id-type":"ROR","asserted-by":"publisher"}],"name":"Membrane Transport Biophysics Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health 2 , Bethesda, MD,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6592-9457","authenticated-orcid":true,"given":"Dejian","family":"Ren","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/00b30xv10","id-type":"ROR","asserted-by":"publisher"}],"name":"University of Pennsylvania 1 Department of Biology, , Philadelphia, PA,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"291","published-online":{"date-parts":[[2025,10,24]]},"reference":[{"key":"2025102410022497600_bib1","doi-asserted-by":"publisher","first-page":"1240","DOI":"10.1126\/science.aaz2924","article-title":"Structure of V-ATPase from the mammalian brain","volume":"367","author":"Abbas","year":"2020","journal-title":"Science"},{"key":"2025102410022497600_bib2","doi-asserted-by":"publisher","first-page":"61","DOI":"10.1085\/jgp.75.1.61","article-title":"Survival of K+ permeability and gating currents in squid axons perfused with K+-free media","volume":"75","author":"Almers","year":"1980","journal-title":"J. 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