{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,19]],"date-time":"2026-05-19T01:06:53Z","timestamp":1779152813926,"version":"3.51.4"},"reference-count":85,"publisher":"American Society for Clinical Investigation","issue":"7","license":[{"start":{"date-parts":[[2022,4,8]],"date-time":"2022-04-08T00:00:00Z","timestamp":1649376000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000062","name":"NIDDK","doi-asserted-by":"crossref","award":["R01 - DK,115749"],"award-info":[{"award-number":["R01 - DK,115749"]}],"id":[{"id":"10.13039\/100000062","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000062","name":"NIDDK","doi-asserted-by":"crossref","award":["R01-DK103860"],"award-info":[{"award-number":["R01-DK103860"]}],"id":[{"id":"10.13039\/100000062","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000050","name":"NHLBI","doi-asserted-by":"crossref","award":["R01-HL148114"],"award-info":[{"award-number":["R01-HL148114"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000057","name":"NIGMS","doi-asserted-by":"crossref","award":["P20GM135002"],"award-info":[{"award-number":["P20GM135002"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2022,4,8]]},"abstract":"<jats:p>\n                    The importance of healthy mitochondrial function is implicated in the prevention of chronic kidney disease (CKD) and diabetic kidney disease (DKD). Sex differences also play important roles in DKD. Our previous studies revealed that mitochondrial substrate overload (modeled by homozygous deletion of carnitine acetyl-transferase [CrAT]) in proximal tubules causes renal injury. Here, we demonstrate the importance of intact mitochondrial substrate efflux by titrating the amount of overload through the generation of a heterozygous CrAT-KO model (PT-CrAT\n                    <jats:sup>HET<\/jats:sup>\n                    mouse). Intriguingly, these animals developed renal injury similarly to their homozygous counterparts. Mitochondria were structurally and functionally impaired in both sexes. Transcriptomic analyses, however, revealed striking sex differences. Male mice shut down fatty acid oxidation and several other metabolism-related pathways. Female mice had a significantly weaker transcriptional response in metabolism, but activation of inflammatory pathways was prominent. Proximal tubular cells from PT-CrAT\n                    <jats:sup>HET<\/jats:sup>\n                    mice of both sexes exhibited a shift toward a more glycolytic phenotype, but female mice were still able to oxidize fatty acid\u2013based substrates. Our results demonstrate that maintaining mitochondrial substrate metabolism balance is crucial to satisfying proximal tubular energy demand. Our findings have potentially broad implications, as both the glycolytic shift and the sexual dimorphisms discovered herein offer potentially new modalities for future interventions for treating kidney disease.\n                  <\/jats:p>","DOI":"10.1172\/jci.insight.150696","type":"journal-article","created":{"date-parts":[[2022,3,1]],"date-time":"2022-03-01T12:00:53Z","timestamp":1646136053000},"source":"Crossref","is-referenced-by-count":13,"title":["Intact mitochondrial substrate efflux is essential for prevention of tubular injury in a sex-dependent manner"],"prefix":"10.1172","volume":"7","author":[{"given":"Allison","family":"McCrimmon","sequence":"first","affiliation":[{"name":"Oxidative Stress and Disease Laboratory,"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kerin M.","family":"Cahill","sequence":"additional","affiliation":[{"name":"Oxidative Stress and Disease Laboratory,"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Claudia","family":"Kruger","sequence":"additional","affiliation":[{"name":"Oxidative Stress and Disease Laboratory,"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Margaret E.","family":"Mangelli","sequence":"additional","affiliation":[{"name":"Oxidative Stress and Disease Laboratory,"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Emily","family":"Bouffard","sequence":"additional","affiliation":[{"name":"Oxidative Stress and Disease Laboratory,"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Timothy","family":"Dobroski","sequence":"additional","affiliation":[{"name":"Oxidative Stress and Disease Laboratory,"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kelly N.","family":"Michanczyk","sequence":"additional","affiliation":[{"name":"Oxidative Stress and Disease Laboratory,"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Susan J.","family":"Burke","sequence":"additional","affiliation":[{"name":"Immunogenetics Laboratory, and"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Robert C.","family":"Noland","sequence":"additional","affiliation":[{"name":"Skeletal Muscle Metabolism Laboratory, Pennington Biomedical Research Center, Baton Rouge, Louisiana, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4832-4170","authenticated-orcid":true,"given":"Daria V.","family":"Ilatovskaya","sequence":"additional","affiliation":[{"name":"Department of Physiology, Medical College of Georgia, Augusta University, Augusta, Georgia, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Krisztian","family":"Stadler","sequence":"additional","affiliation":[{"name":"Oxidative Stress and Disease Laboratory,"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"232","published-online":{"date-parts":[[2022,4,8]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1001\/jama.298.17.2038"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.7326\/0003-4819-140-3-200402030-00007"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.2337\/db14-0874"},{"key":"B4","doi-asserted-by":"crossref","first-page":"553","DOI":"10.1007\/978-3-319-55330-6_28","article-title":"Mitochondrial dysfunction in the diabetic kidney","volume":"982","author":"Sharma","year":"2017","journal-title":"Adv Exp Med Biol"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.3181\/0705-MR-134"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1172\/JCI71195"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1681\/ASN.2008050514"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.2337\/db08-0057"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1042\/bj1120149"},{"issue":"3 pt 2","key":"B10","first-page":"F407","article-title":"Metabolic substrate utilization by rabbit proximal tubule. 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