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Metformin delays neurological symptom onset in a mouse model of neuronal complex I deficiency
Susana Peralta, … , Francisca Diaz, Carlos T. Moraes
Susana Peralta, … , Francisca Diaz, Carlos T. Moraes
Published November 5, 2020
Citation Information: JCI Insight. 2020;5(21):e141183. https://doi.org/10.1172/jci.insight.141183.
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Research Article Genetics

Metformin delays neurological symptom onset in a mouse model of neuronal complex I deficiency

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Abstract

Complex I (also known as NADH-ubiquinone oxidoreductase) deficiency is the most frequent mitochondrial disorder present in childhood. NADH-ubiquinone oxidoreductase iron-sulfur protein 3 (NDUFS3) is a catalytic subunit of the mitochondrial complex I; NDUFS3 is conserved from bacteria and essential for complex I function. Mutations affecting complex I, including in the Ndufs3 gene, cause fatal neurodegenerative diseases, such as Leigh syndrome. No treatment is available for these conditions. We developed and performed a detailed molecular characterization of a neuron-specific Ndufs3 conditional KO mouse model. We showed that deletion of Ndufs3 in forebrain neurons reduced complex I activity, altered brain energy metabolism, and increased locomotor activity with impaired motor coordination, balance, and stereotyped behavior. Metabolomics analyses showed an increase of glycolysis intermediates, suggesting an adaptive response to the complex I defect. Administration of metformin to these mice delayed the onset of the neurological symptoms but not of neuronal loss. This improvement was likely related to enhancement of glucose uptake and utilization, which are known effects of metformin in the brain. Despite reports that metformin inhibits complex I activity, our findings did not show worsening a complex I defect nor increases in lactic acid, suggesting that metformin should be further evaluated for use in patients with mitochondrial encephalopathies.

Authors

Susana Peralta, Milena Pinto, Tania Arguello, Sofia Garcia, Francisca Diaz, Carlos T. Moraes

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Figure 5

Metformin treatment delays the onset of the phenotype in Ndufs3 nKO mice.

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Metformin treatment delays the onset of the phenotype in Ndufs3 nKO mice...
(A) Schematic representation of the protocol used for metformin treatment. (B) Representative images of 4-month-old vehicle-treated Ndufs3 nKO female mice and metformin-treated Ndfus3 nKO female mice. (C) Body weight comparison over time of female mice: vehicle-treated Ndufs3 nKO (pink circles; n = 4); metformin-treated Ndufs3 nKO (red circles; n = 5), vehicle-treated controls (light gray circles, n = 6), and metformin-treated controls (dark gray circles, n = 3). (D) Body weight comparison over time of male mice: vehicle-treated Ndufs3 nKO (pink squares; n = 6), metformin-treated Ndufs3 nKO (red squares; n = 3), vehicle-treated controls (light gray squares, n = 7), and metformin-treated controls (dark gray squares, n = 5). (E and F) Rotarod performance of control and Ndufs3 nKO female mice (E) and male mice (F) of 2, 3, and 4 months of age (n = 3–5/group). Statistical significance was determined using 1-way ANOVA. Pairwise Bonferroni’s post tests were used to compare different groups in all panels. Data are presented as mean ± SEM. *P < 0.05, **P < 0.01, ***P < 0.001.

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