{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T19:05:16Z","timestamp":1788289516531,"version":"build-2803163510"},"reference-count":51,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2019,4,10]],"date-time":"2019-04-10T00:00:00Z","timestamp":1554854400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100000968","name":"American Heart Association","doi-asserted-by":"publisher","award":["18POST34050049 (GS)"],"award-info":[{"award-number":["18POST34050049 (GS)"]}],"id":[{"id":"10.13039\/100000968","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["analyticalsciencejournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["NMR in Biomedicine"],"published-print":{"date-parts":[[2019,6]]},"abstract":"<jats:p>Mitochondrial dysfunction is considered to be an important component of many metabolic diseases yet there is no reliable imaging biomarker for monitoring mitochondrial damage in vivo. A large prior literature on inter\u2010conversion of \u03b2\u2010hydroxybutyrate and acetoacetate indicates that the process is mitochondrial and that the ratio reflects a specifically mitochondrial redox state. Therefore, the conversion of [1,3\u2010<jats:sup>13<\/jats:sup>C]acetoacetate to [1,3\u2010<jats:sup>13<\/jats:sup>C]\u03b2\u2010hydroxybutyrate is expected to be sensitive to the abnormal redox state present in dysfunctional mitochondria.<\/jats:p><jats:p>In this study, we examined the conversion of hyperpolarized (HP) <jats:sup>13<\/jats:sup>C\u2010acetoacetate (AcAc) to <jats:sup>13<\/jats:sup>C\u2010\u03b2\u2010hydroxybutyrate (\u03b2\u2010HB) as a potential imaging biomarker for mitochondrial redox and dysfunction in perfused rat hearts. Conversion of HP\u2010AcAc to \u03b2\u2010HB was investigated using <jats:sup>13<\/jats:sup>C magnetic resonance spectroscopy in Langendorff\u2010perfused rat hearts in four groups: control, global ischemic reperfusion, low\u2010flow ischemic, and rotenone (mitochondrial complex\u2010I inhibitor)\u2010treated hearts.<\/jats:p><jats:p>We observed that more \u03b2\u2010HB was produced from AcAc in ischemic hearts and the hearts exposed to complex I inhibitor rotenone compared with controls, consistent with the accumulation of excess mitochondrial NADH. The increase in \u03b2\u2010HB, as detected by <jats:sup>13<\/jats:sup>C MRS, was validated by a direct measure of tissue \u03b2\u2010HB by <jats:sup>1<\/jats:sup>H nuclear magnetic resonance in tissue extracts. The redox ratio, NAD<jats:sup>+<\/jats:sup>\/NADH, measured by enzyme assays of homogenized tissue, also paralleled production of \u03b2\u2010HB from AcAc. Transmission electron microscopy of tissues provided direct evidence for abnormal mitochondrial structure in each ischemic tissue model.<\/jats:p><jats:p>The results suggest that conversion of HP\u2010AcAc to HP\u2010\u03b2\u2010HB detected by <jats:sup>13<\/jats:sup>C\u2010MRS may serve as a useful diagnostic marker of mitochondrial redox and dysfunction in heart tissue in vivo.<\/jats:p>","DOI":"10.1002\/nbm.4091","type":"journal-article","created":{"date-parts":[[2019,4,10]],"date-time":"2019-04-10T07:08:11Z","timestamp":1554880091000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":26,"title":["Metabolism of hyperpolarized <sup>13<\/sup>C\u2010acetoacetate to \u03b2\u2010hydroxybutyrate detects real\u2010time mitochondrial redox state and dysfunction in heart tissue"],"prefix":"10.1002","volume":"32","author":[{"given":"Wei","family":"Chen","sequence":"first","affiliation":[{"name":"Advanced Imaging Research Center University of Texas Southwestern Medical Center  Dallas Texas"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1754-7163","authenticated-orcid":false,"given":"Gaurav","family":"Sharma","sequence":"additional","affiliation":[{"name":"Advanced Imaging Research Center University of Texas Southwestern Medical Center  Dallas Texas"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weina","family":"Jiang","sequence":"additional","affiliation":[{"name":"Advanced Imaging Research Center University of Texas Southwestern Medical Center  Dallas Texas"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nesmine R.","family":"Maptue","sequence":"additional","affiliation":[{"name":"Advanced Imaging Research Center University of Texas Southwestern Medical Center  Dallas Texas"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Craig R.","family":"Malloy","sequence":"additional","affiliation":[{"name":"Advanced Imaging Research Center University of Texas Southwestern Medical Center  Dallas Texas"},{"name":"Department of Radiology University of Texas Southwestern Medical Center  Dallas Texas"},{"name":"Department of Internal Medicine University of Texas Southwestern Medical Center  Dallas Texas"},{"name":"VA North Texas Health Care System  Dallas Texas"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7150-8301","authenticated-orcid":false,"given":"A. Dean","family":"Sherry","sequence":"additional","affiliation":[{"name":"Advanced Imaging Research Center University of Texas Southwestern Medical Center  Dallas Texas"},{"name":"Department of Radiology University of Texas Southwestern Medical Center  Dallas Texas"},{"name":"Department of Chemistry University of Texas at Dallas  Richardson Texas"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1976-8098","authenticated-orcid":false,"given":"Chalermchai","family":"Khemtong","sequence":"additional","affiliation":[{"name":"Advanced Imaging Research Center University of Texas Southwestern Medical Center  Dallas Texas"},{"name":"Department of Radiology University of Texas Southwestern Medical Center  Dallas Texas"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2019,4,10]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-pharmtox-010715-103335"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1104343"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature05292"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.mito.2004.07.027"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1006\/jmcc.2001.1378"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tem.2012.06.005"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.1021\/bi0485124"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.1096\/fasebj.9.8.7768357"},{"key":"e_1_2_7_10_1","doi-asserted-by":"publisher","DOI":"10.1002\/bmb.2006.49403403168"},{"key":"e_1_2_7_11_1","doi-asserted-by":"publisher","DOI":"10.1042\/bj1150609a"},{"key":"e_1_2_7_12_1","doi-asserted-by":"publisher","DOI":"10.1042\/bj1270387"},{"key":"e_1_2_7_13_1","doi-asserted-by":"publisher","DOI":"10.1038\/1951073a0"},{"key":"e_1_2_7_14_1","doi-asserted-by":"publisher","DOI":"10.1038\/195956a0"},{"key":"e_1_2_7_15_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.137.3529.499"},{"key":"e_1_2_7_16_1","article-title":"NADH fluorescence imaging of isolated biventricular working rabbit hearts","volume":"4115","author":"Asfour H","year":"2012","journal-title":"J Vis Exp."},{"key":"e_1_2_7_17_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0070488"},{"key":"e_1_2_7_18_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0805953105"},{"key":"e_1_2_7_19_1","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.3006070"},{"key":"e_1_2_7_20_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.116.309769"},{"key":"e_1_2_7_21_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1733835100"},{"key":"e_1_2_7_22_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M113.498626"},{"key":"e_1_2_7_23_1","doi-asserted-by":"publisher","DOI":"10.1002\/mrm.21998"},{"key":"e_1_2_7_24_1","doi-asserted-by":"publisher","DOI":"10.1002\/mrm.26662"},{"key":"e_1_2_7_25_1","doi-asserted-by":"publisher","DOI":"10.1038\/srep09104"},{"key":"e_1_2_7_26_1","doi-asserted-by":"publisher","DOI":"10.1002\/mrm.25419"},{"key":"e_1_2_7_27_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(19)43389-9"},{"key":"e_1_2_7_28_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI79273"},{"key":"e_1_2_7_29_1","doi-asserted-by":"crossref","first-page":"413","DOI":"10.1016\/S0022-5223(19)37950-4","article-title":"Ultrastructural and cytochemical correlates of myocardial protection by cardiac hypothermia in man","volume":"79","author":"Flameng W","year":"1980","journal-title":"J Thorac Cardiovasc Surg."},{"key":"e_1_2_7_30_1","doi-asserted-by":"publisher","DOI":"10.1021\/jp302399f"},{"key":"e_1_2_7_31_1","doi-asserted-by":"publisher","DOI":"10.1038\/252285a0"},{"key":"e_1_2_7_32_1","doi-asserted-by":"publisher","DOI":"10.1093\/cvr\/cvp396"},{"key":"e_1_2_7_33_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF00788500"},{"key":"e_1_2_7_34_1","doi-asserted-by":"publisher","DOI":"10.1080\/AC.65.6.2059860"},{"key":"e_1_2_7_35_1","doi-asserted-by":"publisher","DOI":"10.3892\/etm.2017.4124"},{"key":"e_1_2_7_36_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.111.255216"},{"key":"e_1_2_7_37_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.acvd.2015.10.004"},{"key":"e_1_2_7_38_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.yexmp.2006.09.008"},{"key":"e_1_2_7_39_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2015.05.023"},{"key":"e_1_2_7_40_1","doi-asserted-by":"crossref","first-page":"208","DOI":"10.1016\/S0021-9258(18)33242-3","article-title":"Activation of D\u2010Beta\u2010Hydroxybutyrate Apodehydrogenase Using Molecular\u2010Species of Mixed Fatty Acyl Phospholipids","volume":"258","author":"Churchill P","year":"1983","journal-title":"J Biol Chem."},{"key":"e_1_2_7_41_1","doi-asserted-by":"publisher","DOI":"10.1016\/0003-9861(83)90253-9"},{"key":"e_1_2_7_42_1","doi-asserted-by":"publisher","DOI":"10.1021\/bi00613a010"},{"key":"e_1_2_7_43_1","doi-asserted-by":"publisher","DOI":"10.1042\/bj1030514"},{"key":"e_1_2_7_44_1","doi-asserted-by":"publisher","DOI":"10.1002\/ijc.29162"},{"key":"e_1_2_7_45_1","doi-asserted-by":"publisher","DOI":"10.1002\/nbm.3912"},{"key":"e_1_2_7_46_1","article-title":"Metabolism of hyperpolarized 13C\u2010acetoacetate\/\u03b2\u2010hydroxybutyrate reveals mitochondrial redox state in perfused rat hearts","volume":"24","author":"Chen W","year":"2016","journal-title":"Proc Intl Soc Mag Reson Med."},{"key":"e_1_2_7_47_1","doi-asserted-by":"publisher","DOI":"10.1002\/mrm.27054"},{"key":"e_1_2_7_48_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.2001.280.1.H280"},{"key":"e_1_2_7_49_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2013.07.002"},{"key":"e_1_2_7_50_1","doi-asserted-by":"publisher","DOI":"10.1042\/bj1790579"},{"key":"e_1_2_7_51_1","doi-asserted-by":"publisher","DOI":"10.1038\/nm1650"},{"key":"e_1_2_7_52_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-16-0159"}],"container-title":["NMR in Biomedicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/nbm.4091","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/nbm.4091","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/analyticalsciencejournals.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/nbm.4091","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,20]],"date-time":"2025-10-20T08:50:12Z","timestamp":1760950212000},"score":1,"resource":{"primary":{"URL":"https:\/\/analyticalsciencejournals.onlinelibrary.wiley.com\/doi\/10.1002\/nbm.4091"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,4,10]]},"references-count":51,"journal-issue":{"issue":"6","published-print":{"date-parts":[[2019,6]]}},"alternative-id":["10.1002\/nbm.4091"],"URL":"https:\/\/doi.org\/10.1002\/nbm.4091","archive":["Portico"],"relation":{},"ISSN":["0952-3480","1099-1492"],"issn-type":[{"value":"0952-3480","type":"print"},{"value":"1099-1492","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,4,10]]},"assertion":[{"value":"2018-09-20","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2019-02-17","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2019-04-10","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e4091"}}