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Succinate prodrugs ...
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Piel, SarahThe Children's Hospital of Philadelphia
(author)
Succinate prodrugs as treatment for acute metabolic crisis during fluoroacetate intoxication in the rat
- Article/chapterEnglish2023
Publisher, publication year, extent ...
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2022-10-25
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Springer Science and Business Media LLC,2023
Numbers
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LIBRIS-ID:oai:lup.lub.lu.se:e5fa13c1-fe9b-4605-a0e9-fe9926fcc8ab
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https://lup.lub.lu.se/record/e5fa13c1-fe9b-4605-a0e9-fe9926fcc8abURI
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https://doi.org/10.1007/s11010-022-04589-9DOI
Supplementary language notes
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Language:English
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Summary in:English
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Subject category:art swepub-publicationtype
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Subject category:ref swepub-contenttype
Notes
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Sodium fluoroacetate (FA) is a metabolic poison that systemically inhibits the tricarboxylic acid (TCA) cycle, causing energy deficiency and ultimately multi-organ failure. It poses a significant threat to society because of its high toxicity, potential use as a chemical weapon and lack of effective antidotal therapy. In this study, we investigated cell-permeable succinate prodrugs as potential treatment for acute FA intoxication. We hypothesized that succinate prodrugs would bypass FA-induced mitochondrial dysfunction, provide metabolic support, and prevent metabolic crisis during acute FA intoxication. To test this hypothesis, rats were exposed to FA (0.75 mg/kg) and treated with the succinate prodrug candidate NV354. Treatment efficacy was evaluated based on cardiac and cerebral mitochondrial respiration, mitochondrial content, metabolic profiles and tissue pathology. In the heart, FA increased concentrations of the TCA metabolite citrate (+ 4.2-fold, p < 0.01) and lowered ATP levels (− 1.9-fold, p < 0.001), confirming the inhibition of the TCA cycle by FA. High-resolution respirometry of cardiac mitochondria further revealed an impairment of mitochondrial complex V (CV)-linked metabolism, as evident by a reduced phosphorylation system control ratio (− 41%, p < 0.05). The inhibition of CV-linked metabolism is a novel mechanism of FA cardiac toxicity, which has implications for drug development and which NV354 was unable to counteract at the given dose. In the brain, FA induced the accumulation of β-hydroxybutyrate (+ 1.4-fold, p < 0.05) and the reduction of mitochondrial complex I (CI)-linked oxidative phosphorylation (OXPHOSCI) (− 20%, p < 0.01), the latter of which was successfully alleviated by NV354. This promising effect of NV354 warrants further investigations to determine its potential neuroprotective effects.
Subject headings and genre
Added entries (persons, corporate bodies, meetings, titles ...)
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Janowska, Joanna I.The Children's Hospital of Philadelphia
(author)
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Ward, J. LaurensonThe Children's Hospital of Philadelphia
(author)
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McManus, Meagan J.The Children's Hospital of Philadelphia
(author)
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Aronowitz, Danielle I.The Children's Hospital of Philadelphia
(author)
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Janowski, Piotr K.The Children's Hospital of Philadelphia
(author)
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Starr, JonathanThe Children's Hospital of Philadelphia
(author)
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Hook, Jordan N.University of Iowa Carver College of Medicine
(author)
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Hefti, Marco M.University of Iowa Carver College of Medicine
(author)
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Clayman, Carly L.The Children's Hospital of Philadelphia
(author)
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Elmér, EskilLund University,Lunds universitet,Klinisk neurofysiologi,Sektion IV,Institutionen för kliniska vetenskaper, Lund,Medicinska fakulteten,Mitokondriell Medicin,Forskargrupper vid Lunds universitet,Clinical Neurophysiology,Section IV,Department of Clinical Sciences, Lund,Faculty of Medicine,Mitochondrial Medicine,Lund University Research Groups,Abliva AB(Swepub:lu)expb-eel
(author)
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Hansson, Magnus J.Lund University,Lunds universitet,Klinisk neurofysiologi,Sektion IV,Institutionen för kliniska vetenskaper, Lund,Medicinska fakulteten,Mitokondriell Medicin,Forskargrupper vid Lunds universitet,Clinical Neurophysiology,Section IV,Department of Clinical Sciences, Lund,Faculty of Medicine,Mitochondrial Medicine,Lund University Research Groups,Abliva AB(Swepub:lu)expb-mha
(author)
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Jang, David H.University of Pennsylvania
(author)
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Karlsson, MichaelCopenhagen University Hospital
(author)
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Ehinger, Johannes K.Lund University,Lunds universitet,Mitokondriell Medicin,Forskargrupper vid Lunds universitet,Mitochondrial Medicine,Lund University Research Groups(Swepub:lu)med-jeg
(author)
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Kilbaugh, Todd J.The Children's Hospital of Philadelphia
(author)
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The Children's Hospital of PhiladelphiaUniversity of Iowa Carver College of Medicine
(creator_code:org_t)
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In:Molecular and Cellular Biochemistry: Springer Science and Business Media LLC478:6, s. 1231-12440300-81771573-4919
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Piel, Sarah
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Janowska, Joanna ...
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Ward, J. Laurens ...
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McManus, Meagan ...
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Aronowitz, Danie ...
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Janowski, Piotr ...
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Starr, Jonathan
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Hook, Jordan N.
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Hefti, Marco M.
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Clayman, Carly L ...
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Elmér, Eskil
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Hansson, Magnus ...
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Jang, David H.
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Karlsson, Michae ...
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Ehinger, Johanne ...
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