{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,5]],"date-time":"2026-11-05T15:22:28Z","timestamp":1793892148269,"version":"4.8.0"},"reference-count":55,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"12","funder":[{"DOI":"10.13039\/100000062","name":"National Institute of Diabetes and Digestive and Kidney Diseases","doi-asserted-by":"publisher","award":["R01 DK090242"],"award-info":[{"award-number":["R01 DK090242"]}],"id":[{"id":"10.13039\/100000062","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["1S10 OD016281"],"award-info":[{"award-number":["1S10 OD016281"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100001642","name":"Glenn Foundation for Medical Research","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100001642","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000968","name":"American Heart Association","doi-asserted-by":"publisher","award":["17POST33670685"],"award-info":[{"award-number":["17POST33670685"]}],"id":[{"id":"10.13039\/100000968","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JASN"],"published-print":{"date-parts":[[2019,12]]},"abstract":"<jats:sec>\n                    <jats:title>Significance Statement<\/jats:title>\n                    <jats:p>\n                      Proximal tubular epithelial cells, a primary site of injury in AKI, are rich in mitochondria and peroxisomes, the two organelles that mediate fatty acid oxidation. Deletion of\n                      <jats:italic toggle=\"yes\">Sirtuin 5<\/jats:italic>\n                      (\n                      <jats:italic toggle=\"yes\">Sirt5<\/jats:italic>\n                      ) reverses posttranslational lysine acylation of several enzymes involved in fatty acid oxidation. The authors demonstrate that mice lacking Sirt5 had significantly improved kidney function and less tissue damage following either ischemia-induced or cisplatin-induced AKI compared with wild-type mice. These differences coincided with higher peroxisomal fatty acid oxidation compared with mitochondria fatty acid oxidation in the Sirt5-deficient proximal tubular epithelial cells. Their findings indicate that Sirt5 regulates the balance of mitochondrial versus peroxisomal fatty acid oxidation in proximal tubular epithelial cells to protect against injury in AKI. This novel mechanism has potential therapeutic implications for treating AKI.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>The primary site of damage during AKI, proximal tubular epithelial cells, are highly metabolically active, relying on fatty acids to meet their energy demands. These cells are rich in mitochondria and peroxisomes, the two organelles that mediate fatty acid oxidation. Emerging evidence shows that both fatty acid pathways are regulated by reversible posttranslational modifications, particularly by lysine acylation. Sirtuin 5 (Sirt5), which localizes to both mitochondria and peroxisomes, reverses post-translational lysine acylation on several enzymes involved in fatty acid oxidation. However, the role of the Sirt5 in regulating kidney energy metabolism has yet to be determined.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We subjected male Sirt5-deficient mice (either +\/\u2212 or \u2212\/\u2212) and wild-type controls, as well as isolated proximal tubule cells, to two different AKI models (ischemia-induced or cisplatin-induced AKI). We assessed kidney function and injury with standard techniques and measured fatty acid oxidation by the catabolism of\n                      <jats:sup>14<\/jats:sup>\n                      C-labeled palmitate to\n                      <jats:sup>14<\/jats:sup>\n                      CO\n                      <jats:sub>2<\/jats:sub>\n                      .\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Sirt5 was highly expressed in proximal tubular epithelial cells. At baseline,\n                      <jats:italic toggle=\"yes\">Sirt5<\/jats:italic>\n                      knockout (\n                      <jats:italic toggle=\"yes\">Sirt5\u2212\/\u2212<\/jats:italic>\n                      ) mice had modestly decreased mitochondrial function but significantly increased fatty acid oxidation, which was localized to the peroxisome. Although no overt kidney phenotype was observed in\n                      <jats:italic toggle=\"yes\">Sirt5\u2212\/\u2212<\/jats:italic>\n                      mice,\n                      <jats:italic toggle=\"yes\">Sirt5\u2212\/\u2212<\/jats:italic>\n                      mice had significantly improved kidney function and less tissue damage compared with controls after either ischemia-induced or cisplatin-induced AKI. This coincided with higher peroxisomal fatty acid oxidation compared with mitochondria fatty acid oxidation in the\n                      <jats:italic toggle=\"yes\">Sirt5\u2212\/\u2212<\/jats:italic>\n                      proximal tubular epithelial cells.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Our findings indicate that Sirt5 regulates the balance of mitochondrial versus peroxisomal fatty acid oxidation in proximal tubular epithelial cells to protect against injury in AKI. This novel mechanism might be leveraged for developing AKI therapies.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1681\/asn.2019020163","type":"journal-article","created":{"date-parts":[[2019,10,1]],"date-time":"2019-10-01T18:25:12Z","timestamp":1569954312000},"page":"2384-2398","source":"Crossref","is-referenced-by-count":136,"title":["Sirtuin 5 Regulates Proximal Tubule Fatty Acid Oxidation to Protect against AKI"],"prefix":"10.1681","volume":"30","author":[{"given":"Takuto","family":"Chiba","sequence":"first","affiliation":[{"name":"Department of Pediatrics, University of Pittsburgh School of Medicine, University of Pittsburgh Medical Center Children\u2019s Hospital of Pittsburgh, University of Pittsburgh, Pittsburgh, Pennsylvania; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3409-9008","authenticated-orcid":false,"given":"Kevin D.","family":"Peasley","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, University of Pittsburgh School of Medicine, University of Pittsburgh Medical Center Children\u2019s Hospital of Pittsburgh, University of Pittsburgh, Pittsburgh, Pennsylvania; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kasey R.","family":"Cargill","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, University of Pittsburgh School of Medicine, University of Pittsburgh Medical Center Children\u2019s Hospital of Pittsburgh, University of Pittsburgh, Pittsburgh, Pennsylvania; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katherine V.","family":"Maringer","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, University of Pittsburgh School of Medicine, University of Pittsburgh Medical Center Children\u2019s Hospital of Pittsburgh, University of Pittsburgh, Pittsburgh, Pennsylvania; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sivakama S.","family":"Bharathi","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, University of Pittsburgh School of Medicine, University of Pittsburgh Medical Center Children\u2019s Hospital of Pittsburgh, University of Pittsburgh, Pittsburgh, Pennsylvania; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elina","family":"Mukherjee","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, University of Pittsburgh School of Medicine, University of Pittsburgh Medical Center Children\u2019s Hospital of Pittsburgh, University of Pittsburgh, Pittsburgh, Pennsylvania; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6682-012X","authenticated-orcid":false,"given":"Yuxun","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, University of Pittsburgh School of Medicine, University of Pittsburgh Medical Center Children\u2019s Hospital of Pittsburgh, University of Pittsburgh, Pittsburgh, Pennsylvania; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9856-002X","authenticated-orcid":false,"given":"Anja","family":"Holtz","sequence":"additional","affiliation":[{"name":"Buck Institute for Research on Aging, Novato, California"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6173-1139","authenticated-orcid":false,"given":"Nathan","family":"Basisty","sequence":"additional","affiliation":[{"name":"Buck Institute for Research on Aging, Novato, California"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shiva D.","family":"Yagobian","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, University of Pittsburgh School of Medicine, University of Pittsburgh Medical Center Children\u2019s Hospital of Pittsburgh, University of Pittsburgh, Pittsburgh, Pennsylvania; 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