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Optical and Microdialysis Monitoring of Succinate Prodrug Treatment in a Rotenone-Induced Model of Mitochondrial Dysfunction in Swine

Lewis, Alistair ; Forti, Rodrigo M. ; Ko, Tiffany S. ; Elmér, Eskil LU orcid ; McManus, Meagan J. ; Yodh, Arjun G. ; Kilbaugh, Todd J. and Baker, Wesley B. (2026) In Metabolites 16(1).
Abstract

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’s 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... (More)

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’s 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 < 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 < 0.01) while OEF decreased (p < 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.

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author
; ; ; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
cerebral oxygen metabolism, complex I dysfunction, cytochrome-c-oxidase, diffuse optical spectroscopy, primary mitochondrial disease
in
Metabolites
volume
16
issue
1
article number
65
publisher
MDPI AG
external identifiers
  • pmid:41590673
  • scopus:105029094509
ISSN
2218-1989
DOI
10.3390/metabo16010065
language
English
LU publication?
yes
id
9ccd9f46-4b74-435d-90bb-eace1aa4f8e6
date added to LUP
2026-02-20 15:25:02
date last changed
2026-05-30 05:48:54
@article{9ccd9f46-4b74-435d-90bb-eace1aa4f8e6,
  abstract     = {{<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’s 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.</p>}},
  author       = {{Lewis, Alistair and Forti, Rodrigo M. and Ko, Tiffany S. and Elmér, Eskil and McManus, Meagan J. and Yodh, Arjun G. and Kilbaugh, Todd J. and Baker, Wesley B.}},
  issn         = {{2218-1989}},
  keywords     = {{cerebral oxygen metabolism; complex I dysfunction; cytochrome-c-oxidase; diffuse optical spectroscopy; primary mitochondrial disease}},
  language     = {{eng}},
  number       = {{1}},
  publisher    = {{MDPI AG}},
  series       = {{Metabolites}},
  title        = {{Optical and Microdialysis Monitoring of Succinate Prodrug Treatment in a Rotenone-Induced Model of Mitochondrial Dysfunction in Swine}},
  url          = {{http://dx.doi.org/10.3390/metabo16010065}},
  doi          = {{10.3390/metabo16010065}},
  volume       = {{16}},
  year         = {{2026}},
}