{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,30]],"date-time":"2026-04-30T00:45:44Z","timestamp":1777509944874,"version":"3.51.4"},"reference-count":40,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"5","license":[{"start":{"date-parts":[[2015,9,1]],"date-time":"2015-09-01T00:00:00Z","timestamp":1441065600000},"content-version":"tdm","delay-in-days":5967,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[1999,5]]},"abstract":"<jats:sec>\n            <jats:title\/>\n            <jats:p>Previously, we showed that the oxidant chemical, <jats:italic toggle=\"yes\">tert<\/jats:italic>\u2013butylhydroperoxide (<jats:italic toggle=\"yes\">t<\/jats:italic>\u2013BuOOH), induces a mitochondrial permeability transition (MPT) in intact hepatocytes, causing lethal cell injury. Here, we investigated the role of mitochondrial free Ca<jats:sup>2+<\/jats:sup> in <jats:italic toggle=\"yes\">t<\/jats:italic>\u2013BuOOH cytotoxicity to 1\u2013day\u2013cultured rat hepatocytes using confocal microscopy of autofluorescence and parameter\u2013indicating fluorophores. <jats:italic toggle=\"yes\">t<\/jats:italic>\u2013BuOOH (100 \u03bcmol\/L) caused an early increase of mitochondrial free Ca<jats:sup>2+<\/jats:sup>, as assessed by confocal microscopy of Rhod\u20132 fluorescence. Increased mitochondrial Ca<jats:sup>2+<\/jats:sup> was followed by onset of the MPT, as evidenced by permeation of cytosolic calcein into mitochondria and loss of the mitochondrial membrane potential-indicating dye, tetramethylrhodamine methylester. Preincubation with an intracellular Ca<jats:sup>2+<\/jats:sup> chelator (BAPTA\u2013AM and its derivatives) partially blocked the late phase of mitochondrial NAD(P)H oxidation after <jats:italic toggle=\"yes\">t<\/jats:italic>\u2013BuOOH, but failed to prevent the early oxidation of mitochondrial NAD(P)H. Ca<jats:sup>2+<\/jats:sup> chelation also prevented the increase of mitochondrial Ca<jats:sup>2+<\/jats:sup>, generation of mitochondrial reactive oxygen species (ROS), onset of the MPT, and subsequent cell death. Confocal images showed that protection occurred when loading of the Ca<jats:sup>2+<\/jats:sup> chelator was predominantly mitochondrial. The antioxidant, desferal, also diminished increased mitochondrial Ca<jats:sup>2+<\/jats:sup> after <jats:italic toggle=\"yes\">t<\/jats:italic>\u2013BuOOH and prevented cell death. We conclude that oxidative stress induced by <jats:italic toggle=\"yes\">t<\/jats:italic>\u2013BuOOH enhances mitochondrial Ca<jats:sup>2+<\/jats:sup> uptake, leading to increased matrix Ca<jats:sup>2+<\/jats:sup>, increased ROS formation, onset of the MPT, and cell death.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1002\/hep.510290521","type":"journal-article","created":{"date-parts":[[2004,7,28]],"date-time":"2004-07-28T07:46:44Z","timestamp":1091000804000},"page":"1523-1531","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":106,"title":["Contribution of Increased Mitochondrial Free Ca2+ to the Mitochondrial Permeability Transition Induced By Tert \u2013Butylhydroperoxide in Rat Hepatocytes"],"prefix":"10.1097","volume":"29","author":[{"given":"Aaron M.","family":"Byrne","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"John 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