Metformin delays neurological symptom onset in a mouse model of neuronal complex I deficiency
Susana Peralta, Milena Pinto, Tania Arguello, Sofia Garcia, Francisca Diaz, Carlos T. Moraes
Susana Peralta, Milena Pinto, Tania Arguello, Sofia Garcia, Francisca Diaz, Carlos T. Moraes
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Research Article Genetics

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

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 1

Characterization of Ndufs3 nKO mice.

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Characterization of Ndufs3 nKO mice. (A) Body weight comparison over tim...
(A) Body weight comparison over time of Ndufs3 nKO male mice (pink squares; n = 6), age-matched control male mice (gray squares; n = 7), Ndufs3 nKO female mice (pink circles; n = 6), and age-matched control female mice (gray circles; n = 6). P values were calculated by Student’s t test. (B) Representative image of a 4- to 4.5-month-old Ndfus3 nKO mouse and a control (CTR) littermate, showing decreased body weight and kyphosis. (C) Survival curve of Ndufs3 nKO female mice (red line) and male mice (blue line). P values were calculated using log-rank (Mantel-Cox) test. P = 0.0038 for male mice (n = 15); P < 0.0001 for female mice (n = 14). Survival was reduced in the Ndufs3 nKO mice: all Ndfus3 nKO male mice died before 5 months of age, all Ndfus3 nKO female mice died before 6 months of age. (D) Nocturnal ambulatory activity of 4-month-old Ndufs3 nKO female mice (pink circles; n = 11), control female mice (gray circles n = 14), Ndufs3 nKO male mice (pink squares; n = 7), control male mice (gray squares; n = 6). P values were calculated by Student’s t test. (E) Stereotypical time of 3- and 4-month-old Ndufs3 nKO and control male and female mice (n = 4–8/group). (F) Representative image of a tail suspension test of 4-month-old Ndfus3 nKO and control littermate. Ndfus3 nKO mice clasped the 4 limbs, while control mice extended the legs in preparation for the contact. (G) Rotarod performed by Ndufs3 nKO and control mice at 2, 3, and 4 months of age (n = 4–10). Data are represented as mean ± SEM. P values were calculated by Student’s t test to determine the level of statistical difference. *P < 0.05, **P < 0.01, ***P < 0.0001.