{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,12]],"date-time":"2026-01-12T14:24:37Z","timestamp":1768227877131,"version":"3.49.0"},"reference-count":54,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2026,1,11]],"date-time":"2026-01-11T00:00:00Z","timestamp":1768089600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000065","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01-NS113945"],"award-info":[{"award-number":["R01-NS113945"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000065","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["P41-EB029469"],"award-info":[{"award-number":["P41-EB029469"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000065","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01NS114656"],"award-info":[{"award-number":["R01NS114656"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Children\u2019s Hospital of Philadelphia Frontier Program"},{"DOI":"10.13039\/100000090","name":"Department of Defens","doi-asserted-by":"publisher","award":["PR171698"],"award-info":[{"award-number":["PR171698"]}],"id":[{"id":"10.13039\/100000090","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000968","name":"American Heart Association","doi-asserted-by":"publisher","award":["24SCEFIA1260971"],"award-info":[{"award-number":["24SCEFIA1260971"]}],"id":[{"id":"10.13039\/100000968","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Metabolites"],"abstract":"<jats:p>Background\/Objectives: Mitochondrial dysfunction is a major cause of brain injury in patients with primary mitochondrial disease. New mitochondrial therapeutics and non-invasive tools for efficacy monitoring are urgently needed. To these ends, succinate prodrug NV354 (methyl 3-[(2-acetylaminoethylthio)carbonyl]propionate) and diffuse optical techniques are promising. In this proof-of-concept study, we characterize NV354\u2019s effects on microdialysis metrics of cerebral metabolism in a swine model of mitochondrial dysfunction and assess the associations of diffuse optical metrics with mitochondrial dysfunction and metabolic improvement. Methods: One-month-old swine received a four-hour co-infusion of rotenone with either the succinate prodrug NV354 (n = 5) or placebo (n = 5). Rotenone is a mitochondrial complex I inhibitor. Before and during co-infusion, cerebral metabolism was probed with microdialysis and diffuse optics. Microdialysis acquired interstitial lactate and pyruvate levels invasively, while diffuse optics measured changes in oxygen extraction fraction (OEF) and oxidized cytochrome-c-oxidase concentration (oxCCO). Results: Interstitial lactate continually increased in the placebo group (p &lt; 0.01), but lactate levels plateaued in the NV354 group (p = 0.90). oxCCO also increased in the placebo group (p = 0.05), but OEF remained constant (p = 0.80). In the NV354 group, oxCCO increased (p &lt; 0.01) while OEF decreased (p &lt; 0.01). Conclusions: Microdialysis results suggest that NV354 treatment can increase oxygen metabolism in large animals with mitochondrial dysfunction. The optical oxCCO metric was also sensitive to metabolic changes induced by rotenone and NV354 administration.<\/jats:p>","DOI":"10.3390\/metabo16010065","type":"journal-article","created":{"date-parts":[[2026,1,12]],"date-time":"2026-01-12T09:13:01Z","timestamp":1768209181000},"page":"65","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Optical and Microdialysis Monitoring of Succinate Prodrug Treatment in a Rotenone-Induced Model of Mitochondrial Dysfunction in Swine"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5968-4169","authenticated-orcid":false,"given":"Alistair","family":"Lewis","sequence":"first","affiliation":[{"name":"Department of Chemistry, University of Pennsylvania, Philadelphia, PA 19104, USA"},{"name":"Division of Neurology, Department of Pediatrics, Children\u2019s Hospital of Philadelphia, Philadelphia, PA 19104, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8978-2525","authenticated-orcid":false,"given":"Rodrigo M.","family":"Forti","sequence":"additional","affiliation":[{"name":"Division of Neurology, Department of Pediatrics, Children\u2019s Hospital of Philadelphia, Philadelphia, PA 19104, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5113-0310","authenticated-orcid":false,"given":"Tiffany S.","family":"Ko","sequence":"additional","affiliation":[{"name":"Resuscitation Science Center, Department of Anesthesiology and Critical Care Medicine, Children\u2019s Hospital of Philadelphia, Philadelphia, PA 19104, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7901-1826","authenticated-orcid":false,"given":"Eskil","family":"Elm\u00e9r","sequence":"additional","affiliation":[{"name":"Mitochondrial Medicine and Department of Clinical Sciences, Lund University, 221 00 Lund, Sweden"},{"name":"Abliva AB, 223 63 Lund, Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Meagan J.","family":"McManus","sequence":"additional","affiliation":[{"name":"Resuscitation Science Center, Department of Anesthesiology and Critical Care Medicine, Children\u2019s Hospital of Philadelphia, Philadelphia, PA 19104, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4744-2706","authenticated-orcid":false,"given":"Arjun G.","family":"Yodh","sequence":"additional","affiliation":[{"name":"Department of Physics, University of Pennsylvania, Philadelphia, PA 19104, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4959-3092","authenticated-orcid":false,"given":"Todd J.","family":"Kilbaugh","sequence":"additional","affiliation":[{"name":"Resuscitation Science Center, Department of Anesthesiology and Critical Care Medicine, Children\u2019s Hospital of Philadelphia, Philadelphia, PA 19104, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3025-6061","authenticated-orcid":false,"given":"Wesley B.","family":"Baker","sequence":"additional","affiliation":[{"name":"Division of Neurology, Department of Pediatrics, Children\u2019s Hospital of Philadelphia, Philadelphia, PA 19104, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,1,11]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"122","DOI":"10.1159\/000446586","article-title":"Primary Mitochondrial Disease and Secondary Mitochondrial Dysfunction: Importance of Distinction for Diagnosis and Treatment","volume":"7","author":"Niyazov","year":"2016","journal-title":"Mol. 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