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The succinate prodrug NV354 prevents brain lesions and late-stage motor dysfunction in mitochondrial complex I deficiency

McManus, Meagan J. ; Zhu, Yi ; Alves, Cesar ; Kohli, Neha ; Prada-Dacasa, Patricia ; Sanchez-Benito, Laura ; Sanz, Elisenda ; Yee, Irene LU ; Robinson, Lozen and Sheldon, Malkah , et al. (2026) In iScience 29(2).
Abstract

Leigh syndrome is a fatal pediatric neurodegenerative disease caused by mitochondrial dysfunction, which can be modeled in the Ndufs4 KO mouse with mitochondrial respiratory chain complex I (CI) deficiency. This study explores NV354, a prodrug of succinate with enhanced oral bioavailability and brain uptake, as a potential therapy to counteract this devastating condition. NV354 modulated whole-body respiration and metabolic flexibility, prevented late-stage motor dysfunction, delayed clinical ataxia scores, and improved body weight development, but had otherwise minimal effect on neurobehavior and lifespan of the animals. The succinate prodrug prevented development of the brain stem lesions pathognomonic for Leigh syndrome, attenuated... (More)

Leigh syndrome is a fatal pediatric neurodegenerative disease caused by mitochondrial dysfunction, which can be modeled in the Ndufs4 KO mouse with mitochondrial respiratory chain complex I (CI) deficiency. This study explores NV354, a prodrug of succinate with enhanced oral bioavailability and brain uptake, as a potential therapy to counteract this devastating condition. NV354 modulated whole-body respiration and metabolic flexibility, prevented late-stage motor dysfunction, delayed clinical ataxia scores, and improved body weight development, but had otherwise minimal effect on neurobehavior and lifespan of the animals. The succinate prodrug prevented development of the brain stem lesions pathognomonic for Leigh syndrome, attenuated neuronal loss in the brainstem, diminished activation of astrocytes, blocked hypertrophic microglial accumulation, and reduced reactive oxygen species (ROS) levels in the brain. NV354 also partially alleviated motor symptoms and metabolic decompensation in a rat model of Parkinson disease induced by the CI inhibitor rotenone. In conclusion, the succinate prodrug NV354 shows promise as a potential treatment of mitochondrial CI-related neurodegeneration.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
biochemistry, biological sciences, natural sciences, neuroscience
in
iScience
volume
29
issue
2
article number
114717
publisher
Elsevier
external identifiers
  • pmid:41704780
  • scopus:105029138161
ISSN
2589-0042
DOI
10.1016/j.isci.2026.114717
language
English
LU publication?
yes
id
7bc514ec-1b90-47c4-9aa7-9ac8300e1323
date added to LUP
2026-02-18 13:53:58
date last changed
2026-02-19 03:00:03
@article{7bc514ec-1b90-47c4-9aa7-9ac8300e1323,
  abstract     = {{<p>Leigh syndrome is a fatal pediatric neurodegenerative disease caused by mitochondrial dysfunction, which can be modeled in the Ndufs4 KO mouse with mitochondrial respiratory chain complex I (CI) deficiency. This study explores NV354, a prodrug of succinate with enhanced oral bioavailability and brain uptake, as a potential therapy to counteract this devastating condition. NV354 modulated whole-body respiration and metabolic flexibility, prevented late-stage motor dysfunction, delayed clinical ataxia scores, and improved body weight development, but had otherwise minimal effect on neurobehavior and lifespan of the animals. The succinate prodrug prevented development of the brain stem lesions pathognomonic for Leigh syndrome, attenuated neuronal loss in the brainstem, diminished activation of astrocytes, blocked hypertrophic microglial accumulation, and reduced reactive oxygen species (ROS) levels in the brain. NV354 also partially alleviated motor symptoms and metabolic decompensation in a rat model of Parkinson disease induced by the CI inhibitor rotenone. In conclusion, the succinate prodrug NV354 shows promise as a potential treatment of mitochondrial CI-related neurodegeneration.</p>}},
  author       = {{McManus, Meagan J. and Zhu, Yi and Alves, Cesar and Kohli, Neha and Prada-Dacasa, Patricia and Sanchez-Benito, Laura and Sanz, Elisenda and Yee, Irene and Robinson, Lozen and Sheldon, Malkah and McHugh, Walter J. and Ranganathan, Abhay and Meng, Jennie and Duncan, Nina and Grönberg, Alvar and Wallace, Douglas C. and Piel, Sarah and Karlsson, Michael and Moss, Steven J. and Webster, Lee and Hansson, Magnus J. and Elmér, Eskil and Ehinger, Johannes K. and Quintana, Albert and Kilbaugh, Todd J.}},
  issn         = {{2589-0042}},
  keywords     = {{biochemistry; biological sciences; natural sciences; neuroscience}},
  language     = {{eng}},
  number       = {{2}},
  publisher    = {{Elsevier}},
  series       = {{iScience}},
  title        = {{The succinate prodrug NV354 prevents brain lesions and late-stage motor dysfunction in mitochondrial complex I deficiency}},
  url          = {{http://dx.doi.org/10.1016/j.isci.2026.114717}},
  doi          = {{10.1016/j.isci.2026.114717}},
  volume       = {{29}},
  year         = {{2026}},
}