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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\n                    <jats:italic>Ndufs3<\/jats:italic>\n                    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\n                    <jats:italic>Ndufs3<\/jats:italic>\n                    conditional KO mouse model. We showed that deletion of\n                    <jats:italic>Ndufs3<\/jats:italic>\n                    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.\n                  <\/jats:p>","DOI":"10.1172\/jci.insight.141183","type":"journal-article","created":{"date-parts":[[2020,11,4]],"date-time":"2020-11-04T11:01:18Z","timestamp":1604487678000},"source":"Crossref","is-referenced-by-count":21,"title":["Metformin delays neurological symptom onset in a mouse model of neuronal complex I deficiency"],"prefix":"10.1172","volume":"5","author":[{"given":"Susana","family":"Peralta","sequence":"first","affiliation":[{"name":"Department of Neurology and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9202-1527","authenticated-orcid":true,"given":"Milena","family":"Pinto","sequence":"additional","affiliation":[{"name":"Department of Neurology 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