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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 4

Lack of NDUFS3 in neurons leads to general neuroinflammation and neuronal cell loss in hippocampus.

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Lack of NDUFS3 in neurons leads to general neuroinflammation and neurona...
(A) Gross brain morphology of 4-month-old Ndufs3 nKO mice revealed no changes. (B) Brain weight of 4-month-old Ndufs3 nKO and control (CTR) female and male mice (n = 4–6). (C) H&E staining of cortical regions (first and second rows) of 4-month-old animals showing no apparent difference in morphology between control and Ndufs3 nKO mice. H&E staining of hippocampal regions (third and fourth rows) of Ndufs3 nKO mice showing less nuclei staining in the CA3 pyramidal layer (framed by a white rectangle). Original magnification, ×10. (D) Immunohistochemical images of NeuN staining on cortex (first row) and hippocampus (second row) of 4-month-old animals showing fewer neurons in hippocampi of Ndufs3 nKO mice in the CA1 pyramidal layer (framed by a black rectangle). Original magnification, ×10. (E) Immunohistochemical images of GFAP staining on different brain regions of 4-month-old animals showing increased inflammation in the cortex and hippocampus regions of Ndufs3 nKO mice (arrows). (F) Western blots and (G) relative quantification of protein homogenates from motor cortices, piriform cortices, and hippocampi of control and Ndufs3 nKO animals at 3 and 4 months of age, probing for neuronal marker TUJ1, astrocyte activation (GFAP), and NDUFS3. β-Actin and vinculin antibodies were used as loading controls. GFAP levels were increased in all regions of nKO mice at 4 months of age. TUJ1 levels were decreased at 4 months of age in hippocampi of nKO mice. Data are represented as mean ± SEM (n = 4–5/group). P values were determined by Student’s t test. **P < 0.01, ***P < 0.001

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