{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T16:29:54Z","timestamp":1785428994716,"version":"3.56.0"},"posted":{"date-parts":[[2026,3,4]]},"group-title":"Cell Biology","reference-count":52,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,3,4]],"date-time":"2026-03-04T00:00:00Z","timestamp":1772582400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"award":["R01HL180055"],"award-info":[{"award-number":["R01HL180055"]}],"id":[{"id":"https:\/\/ror.org\/012pb6c26","id-type":"ROR","asserted-by":"publisher"}]},{"award":["H1206"],"award-info":[{"award-number":["H1206"]}],"id":[{"id":"https:\/\/ror.org\/04nv2ya05","id-type":"ROR","asserted-by":"publisher"}]},{"id":[{"id":"https:\/\/ror.org\/05fdb2817","id-type":"ROR","asserted-by":"publisher"}]},{"award":["ARUK-RF2019B-004"],"award-info":[{"award-number":["ARUK-RF2019B-004"]}],"id":[{"id":"https:\/\/ror.org\/02ymzm013","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,3,4]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Mitochondrial Ca\n                  <jats:sup>2+<\/jats:sup>\n                  uptake governs metabolism and cell fate, yet how signals from other organelles shape this remains incompletely defined. Although lysosomes are relatively small Ca\n                  <jats:sup>2+<\/jats:sup>\n                  stores, their strategic positioning at organelle contact sites suggests they may amplify Ca\n                  <jats:sup>2+<\/jats:sup>\n                  transfer within nanodomains. Here, we show that activation of the lysosomal Two-pore channel 2 (TPC2) initiates rapid mitochondrial Ca\n                  <jats:sup>2+<\/jats:sup>\n                  uptake through an endoplasmic reticulum-dependent relay requiring IP\u2083 receptors and the mitochondrial calcium uniporter channel. The extent of mitochondrial Ca\n                  <jats:sup>2+<\/jats:sup>\n                  accumulation scales with TPC2 activity without affecting global Ca\n                  <jats:sup>2+<\/jats:sup>\n                  responses, identifying TPC2 as a specific amplifier of lysosome-mitochondria Ca\n                  <jats:sup>2+<\/jats:sup>\n                  exchange. Moderate TPC2 activation transiently enhances oxidative phosphorylation, whereas sustained enhancement increases susceptibility to Ca\n                  <jats:sup>2+<\/jats:sup>\n                  -induced mitochondrial permeability transition. In stroke models, hyperactivation of TPC2 exacerbates injury, while acute pharmacological inhibition at reperfusion confers neuroprotection, including in human iPSC-derived neurons. Thus, lysosomal Ca\n                  <jats:sup>2+<\/jats:sup>\n                  release acts as an upstream regulator of mitochondrial energetic resilience under stress.\n                <\/jats:p>","DOI":"10.64898\/2026.03.03.709381","type":"posted-content","created":{"date-parts":[[2026,3,5]],"date-time":"2026-03-05T08:55:16Z","timestamp":1772700916000},"source":"Crossref","is-referenced-by-count":0,"title":["Activation of TPC2 amplifies lysosome-mitochondria calcium transfer to regulate energetic stress responses"],"prefix":"10.64898","author":[{"given":"Sadia","family":"Ahmed","sequence":"first","affiliation":[{"name":"Aging + Cardiovascular Discovery Center, Department of Cardiovascular Sciences, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Namratha","family":"Javvaji","sequence":"additional","affiliation":[{"name":"Aging + Cardiovascular Discovery Center, Department of Cardiovascular Sciences, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-4663-671X","authenticated-orcid":false,"given":"Katherine L.","family":"Hammond","sequence":"additional","affiliation":[{"name":"Division of Cardiovascular Medicine, British Heart Foundation Centre of Research Excellence, Radcliffe Department of Medicine, University of Oxford, L6 West Wing, Oxford OX3 9DU, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3734-6075","authenticated-orcid":false,"given":"Kevin M.","family":"Casin","sequence":"additional","affiliation":[{"name":"Aging + Cardiovascular Discovery Center, Department of Cardiovascular Sciences, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, 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