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Succinate prodrugs as treatment for acute metabolic crisis during fluoroacetate intoxication in the rat

Piel, Sarah LU orcid ; Janowska, Joanna I. ; Ward, J. Laurenson ; McManus, Meagan J. ; Aronowitz, Danielle I. ; Janowski, Piotr K. ; Starr, Jonathan ; Hook, Jordan N. ; Hefti, Marco M. and Clayman, Carly L. , et al. (2023) In Molecular and Cellular Biochemistry 478(6). p.1231-1244
Abstract

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... (More)

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.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Cell-permeable succinate, Emergency medicine, Fluoroacetate, Mitochondria, Toxicity
in
Molecular and Cellular Biochemistry
volume
478
issue
6
pages
1231 - 1244
publisher
Springer
external identifiers
  • scopus:85140638352
  • pmid:36282352
ISSN
0300-8177
DOI
10.1007/s11010-022-04589-9
project
Mitochondrial dysfunction in drug and chemical toxicity: mechanism, target identification and therapeutic development
language
English
LU publication?
yes
id
e5fa13c1-fe9b-4605-a0e9-fe9926fcc8ab
date added to LUP
2023-01-16 10:33:04
date last changed
2024-06-13 01:30:32
@article{e5fa13c1-fe9b-4605-a0e9-fe9926fcc8ab,
  abstract     = {{<p>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 &lt; 0.01) and lowered ATP levels (− 1.9-fold, p &lt; 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 &lt; 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 &lt; 0.05) and the reduction of mitochondrial complex I (CI)-linked oxidative phosphorylation (OXPHOS<sub>CI</sub>) (− 20%, p &lt; 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.</p>}},
  author       = {{Piel, Sarah and Janowska, Joanna I. and Ward, J. Laurenson and McManus, Meagan J. and Aronowitz, Danielle I. and Janowski, Piotr K. and Starr, Jonathan and Hook, Jordan N. and Hefti, Marco M. and Clayman, Carly L. and Elmér, Eskil and Hansson, Magnus J. and Jang, David H. and Karlsson, Michael and Ehinger, Johannes K. and Kilbaugh, Todd J.}},
  issn         = {{0300-8177}},
  keywords     = {{Cell-permeable succinate; Emergency medicine; Fluoroacetate; Mitochondria; Toxicity}},
  language     = {{eng}},
  number       = {{6}},
  pages        = {{1231--1244}},
  publisher    = {{Springer}},
  series       = {{Molecular and Cellular Biochemistry}},
  title        = {{Succinate prodrugs as treatment for acute metabolic crisis during fluoroacetate intoxication in the rat}},
  url          = {{http://dx.doi.org/10.1007/s11010-022-04589-9}},
  doi          = {{10.1007/s11010-022-04589-9}},
  volume       = {{478}},
  year         = {{2023}},
}