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Previous studies suggest inhibitory interneuron susceptibility to mitochondrial impairment, especially of parvalbumin-expressing interneurons (PV<jats:sup>+<\/jats:sup>). We have developed a mouse model of mitochondrial dysfunction specifically in PV<jats:sup>+<\/jats:sup> cells via conditional <jats:italic>Tfam<\/jats:italic> knockout, that exhibited a juvenile-onset progressive phenotype characterised by cognitive deficits, anxiety-like behaviour, head-nodding, stargazing, ataxia, and reduced lifespan. A brain region-dependent decrease of OXPHOS complexes I and IV in PV<jats:sup>+<\/jats:sup> neurons was detected, with Purkinje neurons being most affected. We validated these findings in a neuropathological study of patients with pathogenic mtDNA and <jats:italic>POLG<\/jats:italic> variants showing PV<jats:sup>+<\/jats:sup> interneuron loss and deficiencies in complexes I and IV. This mouse model offers a drug screening platform to propel the discovery of therapeutics to treat severe neurological impairment due to mitochondrial dysfunction.<\/jats:p>","DOI":"10.1038\/s42003-023-05238-7","type":"journal-article","created":{"date-parts":[[2023,10,23]],"date-time":"2023-10-23T15:02:33Z","timestamp":1698073353000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["A novel mouse model of mitochondrial disease exhibits juvenile-onset severe neurological impairment due to parvalbumin cell mitochondrial dysfunction"],"prefix":"10.1038","volume":"6","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6641-9483","authenticated-orcid":false,"given":"Elizaveta A.","family":"Olkhova","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carla","family":"Bradshaw","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alasdair","family":"Blain","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Debora","family":"Alvim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Doug M.","family":"Turnbull","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1453-4022","authenticated-orcid":false,"given":"Fiona E. 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The research is locally relevant. The roles and responsibilities were agreed among collaborators ahead of the research and capacity-building plans for local researchers were discussed. The study has been approved by a local ethics review committee. The research does not result in stigmatisation, incrimination, discrimination, or otherwise personal risk to participants. The research was conducted in line with health and safety regulations at Newcastle University, where all appropriate guidelines on chemical and biological safety, as well as relevant risk assessments for all procedures, were followed. We have taken local and regional research relevant to your study into account in citations, which was conducted at Newcastle University.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval"}}],"article-number":"1078"}}