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Nevertheless, how these two pathological phenomena are linked with one another remains unclear, especially in neurons. To address the question, a model of iron overload was established with exposure of rat primary cortical neurons to excessive iron. We first verified that iron overload resulted in a decrease in adenosine triphosphate (ATP) production in neurons. Meanwhile, the release of mitochondrial cytochrome <jats:italic>c<\/jats:italic> was significantly increased after iron overload and consequently triggered an apoptosis signal, as revealed by Caspase 3 cleavage. To explore the potential underlying molecular mechanisms, an unlabeled quantitative proteomics approach was applied to primary neurons. Gene Ontology enrichment analysis revealed that 58 mitochondria\u2010associated proteins were significantly altered, including three subunits of mitochondrial complex I and optic atrophy 1(OPA1). Increased NADH\u2010ubiquinone oxidoreductase 75\u00a0kDa subunit and decreased NADH\u2010ubiquinone oxidoreductase subunit A10 levels were further validated by a western blot, and more importantly, complex I activity markedly declined. Iron\u2010induced down\u2010regulation on the OPA1 level was also validated by a western blot, which was not reversed by the anti\u2010oxidant but was reversed by the iron chelator. Moreover, an OPA1\u2010associated key downstream effect, mitochondrial fragmentation, was found to be aggravated in neurons exposed to excessive iron, which is consistent with the down\u2010regulation of OPA1. Furthermore, the protein level of PTEN\u2010induced putative kinase 1, an important protein closely related to complex I activity and mitochondrial fragmentation, also significantly declined in neurons by iron overload. Thus, our findings may shed new light on the linkage between iron toxicity and mitochondrial impairments, such as energy supply deficiency and mitochondrial fragmentation, and further expand the toxic repertoire of iron in the central nerve system.<\/jats:p><\/jats:sec><jats:sec><jats:label\/><jats:p>\n<jats:boxed-text content-type=\"graphic\" position=\"anchor\"><jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/jnc14621-fig-0009-m.png\"><jats:alt-text>image<\/jats:alt-text><\/jats:graphic><\/jats:boxed-text>\n<\/jats:p><jats:p>Cover Image for this issue: doi: <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"doi\" xlink:href=\"10.1111\/jnc.14205\">10.1111\/jnc.14205<\/jats:ext-link>.<\/jats:p><\/jats:sec>","DOI":"10.1111\/jnc.14621","type":"journal-article","created":{"date-parts":[[2018,10,31]],"date-time":"2018-10-31T18:35:25Z","timestamp":1541010925000},"page":"816-830","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":24,"title":["Iron\u2010induced energy supply deficiency and mitochondrial fragmentation in neurons"],"prefix":"10.1111","volume":"147","author":[{"given":"Xiao Tian","family":"Huang","sequence":"first","affiliation":[{"name":"CAS Key Laboratory of Receptor Research Shanghai Institute of Materia Medica Chinese Academy of Sciences Shanghai People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xing","family":"Liu","sequence":"additional","affiliation":[{"name":"CAS Key Laboratory of Receptor Research Shanghai Institute of Materia Medica Chinese Academy of Sciences Shanghai People's 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