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A model of lysosomal ion and water fluxes that captures the synchronized, interdependent operation of ion transporters and diffusion enables prediction of organellar responses to external perturbations and supports the design and interpretation of experiments. Particularly with the advent of organelle-targeted rhodopsin-based optogenetics, there is a pressing need to predict cellular outcomes following light-driven, specific ion transport in lysosomes and other organelles. Currently, no models of lysosomal ion balance fully align with existing experimental data or enable simulation of the organelle\u2019s response to stress. Here, we present an updated interactive model that recapitulates appropriate stress responses. We incorporated the functional activities of TPC1 and TMEM165, in addition to the previously included vATPase, ClC-7, TRPML1, and passive ion and water fluxes. The model remains robust during lysosomal maturation, membrane permeabilization, swelling, deacidification induced by vATPase inhibition or additional optogenetics-like proton efflux, and accumulation of weakly basic cationic amphiphilic drugs. Our simulations indicate that lysosomal Ca2+ depletion couples with organellar deacidification triggered by either increased proton leakage or vATPase inhibition, with potential involvement of TMEM165 weakening. Beyond predicting stress\u2013response dynamics, the model enables investigation of highly selective perturbations that can be experimentally induced using optogenetics. Elucidating the mechanisms underlying stable, stress-resilient lysosomal function offers insights for developing anti-disease and antiaging interventions. Further model refinement critically depends on experimental characterization of the lysosomal NHE-like protein mediating sodium influx.<\/jats:p>","DOI":"10.1085\/jgp.202413745","type":"journal-article","created":{"date-parts":[[2026,5,21]],"date-time":"2026-05-21T06:20:41Z","timestamp":1779344441000},"update-policy":"https:\/\/doi.org\/10.1085\/jgp.crossmarkpolicy","source":"Crossref","is-referenced-by-count":0,"title":["Stressed lysosome: A theoretical model of lysosomal pH regulation applied to stress conditions"],"prefix":"10.1085","volume":"158","author":[{"ORCID":"https:\/\/orcid.org\/0009-0005-0259-3377","authenticated-orcid":true,"given":"Sofia F.","family":"Nazarova","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/00v0z9322","id-type":"ROR","asserted-by":"publisher"}],"name":"Research Center for Molecular Mechanisms of Aging and Age-Related Diseases, Moscow Institute of Physics and Technology 1 , Dolgoprudny,","place":["Russia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-8917-8161","authenticated-orcid":true,"given":"Vadim A.","family":"Alekhin","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/00v0z9322","id-type":"ROR","asserted-by":"publisher"}],"name":"Research Center for Molecular Mechanisms of Aging and Age-Related Diseases, Moscow Institute of Physics and Technology 1 , Dolgoprudny,","place":["Russia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-6861-3261","authenticated-orcid":true,"given":"Vladislav V.","family":"Pavlov","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/00v0z9322","id-type":"ROR","asserted-by":"publisher"}],"name":"Research Center for Molecular Mechanisms of Aging and Age-Related Diseases, Moscow Institute of Physics and Technology 1 , Dolgoprudny,","place":["Russia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-7705-1968","authenticated-orcid":true,"given":"Yury S.","family":"Semenov","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/00v0z9322","id-type":"ROR","asserted-by":"publisher"}],"name":"Research Center for Molecular Mechanisms of Aging and Age-Related Diseases, Moscow Institute of Physics and Technology 1 , Dolgoprudny,","place":["Russia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0770-6597","authenticated-orcid":true,"given":"Siarhei M.","family":"Bukhalovich","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/00v0z9322","id-type":"ROR","asserted-by":"publisher"}],"name":"Research Center for Molecular Mechanisms of Aging and Age-Related Diseases, Moscow Institute of Physics and Technology 1 , Dolgoprudny,","place":["Russia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7422-0899","authenticated-orcid":true,"given":"Fedor M.","family":"Tsybrov","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/00v0z9322","id-type":"ROR","asserted-by":"publisher"}],"name":"Research Center for Molecular Mechanisms of Aging and Age-Related Diseases, Moscow Institute of Physics and Technology 1 , Dolgoprudny,","place":["Russia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7589-7823","authenticated-orcid":true,"given":"Andrey O.","family":"Bogorodskiy","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/00v0z9322","id-type":"ROR","asserted-by":"publisher"}],"name":"Research Center for Molecular Mechanisms of Aging and Age-Related Diseases, Moscow Institute of Physics and Technology 1 , Dolgoprudny,","place":["Russia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-0508-5203","authenticated-orcid":true,"given":"Diana F.","family":"Bagaeva","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/00v0z9322","id-type":"ROR","asserted-by":"publisher"}],"name":"Research Center for Molecular Mechanisms of Aging and Age-Related Diseases, Moscow Institute of Physics and Technology 1 , Dolgoprudny,","place":["Russia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2434-2270","authenticated-orcid":true,"given":"Olga V.","family":"Moiseeva","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/00v0z9322","id-type":"ROR","asserted-by":"publisher"}],"name":"Research Center for Molecular Mechanisms of Aging and Age-Related Diseases, Moscow Institute of Physics and Technology 1 , Dolgoprudny,","place":["Russia"]},{"name":"G.K. 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