{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T06:21:24Z","timestamp":1790230884971,"version":"4.1.0"},"reference-count":44,"publisher":"National Academy of Sciences","issue":"1","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2012,1,3]]},"abstract":"<jats:p>\n                    Radiolabeled diacetylbis(4-methylthiosemicarbazonato)copper\n                    <jats:sup>II<\/jats:sup>\n                    [Cu\n                    <jats:sup>II<\/jats:sup>\n                    (atsm)] is an effective positron-emission tomography imaging agent for myocardial ischemia, hypoxic tumors, and brain disorders with regionalized oxidative stress, such as mitochondrial myopathy, encephalopathy, and lactic acidosis with stroke-like episodes (MELAS) and Parkinson\u2019s disease. An excessively elevated reductive state is common to these conditions and has been proposed as an important mechanism affecting cellular retention of Cu from Cu\n                    <jats:sup>II<\/jats:sup>\n                    (atsm). However, data from whole-cell models to demonstrate this mechanism have not yet been provided. The present study used a unique cell culture model, mitochondrial xenocybrids, to provide whole-cell mechanistic data on cellular retention of Cu from Cu\n                    <jats:sup>II<\/jats:sup>\n                    (atsm). Genetic incompatibility between nuclear and mitochondrial encoded subunits of the mitochondrial electron transport chain (ETC) in xenocybrid cells compromises normal function of the ETC. As a consequence of this impairment to the ETC we show xenocybrid cells upregulate glycolytic ATP production and accumulate NADH. Compared to control cells the xenocybrid cells retained more Cu after being treated with Cu\n                    <jats:sup>II<\/jats:sup>\n                    (atsm). By transfecting the cells with a metal-responsive element reporter construct the increase in Cu retention was shown to involve a Cu\n                    <jats:sup>II<\/jats:sup>\n                    (atsm)-induced increase in intracellular bioavailable Cu specifically within the xenocybrid cells. Parallel experiments using cells grown under hypoxic conditions confirmed that a compromised ETC and elevated NADH levels contribute to increased cellular retention of Cu from Cu\n                    <jats:sup>II<\/jats:sup>\n                    (atsm). Using these cell culture models our data demonstrate that compromised ETC function, due to the absence of O\n                    <jats:sub>2<\/jats:sub>\n                    as the terminal electron acceptor or dysfunction of individual components of the ETC, is an important determinant in driving the intracellular dissociation of Cu\n                    <jats:sup>II<\/jats:sup>\n                    (atsm) that increases cellular retention of the Cu.\n                  <\/jats:p>","DOI":"10.1073\/pnas.1116227108","type":"journal-article","created":{"date-parts":[[2011,12,16]],"date-time":"2011-12-16T01:26:42Z","timestamp":1323998802000},"page":"47-52","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":105,"title":["An impaired mitochondrial electron transport chain increases retention of the hypoxia imaging agent diacetylbis(4-methylthiosemicarbazonato)copper\n                    <sup>II<\/sup>"],"prefix":"10.1073","volume":"109","author":[{"given":"Paul S.","family":"Donnelly","sequence":"first","affiliation":[{"name":"School of Chemistry, University of Melbourne, Victoria 3010, Australia;"},{"name":"Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Victoria 3010, Australia;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffrey R.","family":"Liddell","sequence":"additional","affiliation":[{"name":"Department of Pathology, University of Melbourne, Victoria 3010, Australia;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"SinChun","family":"Lim","sequence":"additional","affiliation":[{"name":"School of Chemistry, University of Melbourne, Victoria 3010, Australia;"},{"name":"Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Victoria 3010, Australia;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brett M.","family":"Paterson","sequence":"additional","affiliation":[{"name":"School of Chemistry, University of Melbourne, Victoria 3010, Australia;"},{"name":"Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Victoria 3010, Australia;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael A.","family":"Cater","sequence":"additional","affiliation":[{"name":"Peter MacCallum Cancer Center, Victoria 3002, Australia;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria S.","family":"Savva","sequence":"additional","affiliation":[{"name":"Department of Pathology, University of Melbourne, Victoria 3010, Australia;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexandra I.","family":"Mot","sequence":"additional","affiliation":[{"name":"Department of Pathology, University of Melbourne, Victoria 3010, Australia;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Janine L.","family":"James","sequence":"additional","affiliation":[{"name":"Department of Pathology, University of Melbourne, Victoria 3010, Australia;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ian A.","family":"Trounce","sequence":"additional","affiliation":[{"name":"Center for Eye Research Australia, Royal Victorian Eye and Ear Hospital, Victoria 3002, Australia;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anthony R.","family":"White","sequence":"additional","affiliation":[{"name":"Department of Pathology, University of Melbourne, Victoria 3010, Australia;"},{"name":"Center for Neuroscience, University of Melbourne, Victoria 3010, Australia; and"},{"name":"Mental Health Research Institute, Victoria 3052, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter J.","family":"Crouch","sequence":"additional","affiliation":[{"name":"Department of Pathology, University of Melbourne, Victoria 3010, Australia;"},{"name":"Center for Neuroscience, University of Melbourne, Victoria 3010, Australia; and"},{"name":"Mental Health Research Institute, Victoria 3052, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2011,12,15]]},"reference":[{"key":"e_1_3_3_1_2","doi-asserted-by":"publisher","DOI":"10.1016\/0883-2897(87)90162-0"},{"key":"e_1_3_3_2_2","first-page":"1549","article-title":"Copper(II) bis(thiosemicarbazone) complexes as potential tracers for evaluation of cerebral and myocardial blood flow with PET","volume":"29","author":"Green MA","year":"1988","unstructured":"MA Green, DL Klippenstein, JR Tennison, Copper(II) bis(thiosemicarbazone) complexes as potential tracers for evaluation of cerebral and myocardial blood flow with PET. 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