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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 2

NDUFS3 expression and complex I deficiency.

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NDUFS3 expression and complex I deficiency.
(A–C) Western blots of corte...
(A–C) Western blots of cortex homogenates of control (CTR) and Ndufs3 nKO male mice at different ages (2, 3, and 4 months, respectively) using antibodies against NDUFS3, NDUFB8, NDUFA9, and NDUFS4 (complex I subunits); SDHA (complex II subunit); UQCRC2 (complex III subunit); COX1 (complex IV subunit); ATP5A (complex V subunit); and VDAC1, Tim23, and β-actin [β-actin (a) for NDUFS3, SDHA, and NDUFS4; β-actin (b) for NDUFB8 and COXI; β-actin (c) for NDUFA9 and ATP5A; and β-actin (d) for UQCRC2, VDAC1, and Tim23]. The dashed line in C indicates that the gel image was cropped to remove lanes not relevant to the analysis. (D–I) Quantification of the Western blots in A–C. Data are represented as mean ± SEM (n = 4–5/group). P values were determined by Student’s t test. (J) mtDNA levels measured by RT-PCR in DNA extracted from cortices of 4-month-old control and Ndufs3 nKO male mice (n = 4–5/group). (K) Spectrophotometric complex I/citrate synthase, complex III/citrate synthase, and complex IV/citrate synthase activity ratios were measured in cortex homogenates from 1-, 2-, 3-, and 4-month-old male mice. Complex I activity in Ndufs3 nKO animals was decreased in comparison with that in control mice. Data are represented as mean ± SEM (n = 3–8/group). P values were determined by Student’s t test. (L) Steady-state levels of complex I and III measured by BN-PAGE in homogenates from cortices of control and Ndufs3 nKO mice at 4 months of age using antibodies against NDUFS4 (complex I) and UQCRC2 (complex III) subunits and relative mitochondrial content (Western blot of the same homogenates using antibody against VDAC1). *P < 0.05, **P < 0.01, ***P < 0.001

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