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Energy deficits underlie many neurodevelopmental, neuropsychiatric and neurodegenerative diseases implicating mitochondria as a potential therapeutic target. Iron is necessary for neuronal energy output through its direct role in mitochondrial oxidative phosphorylation. Iron deficiency (ID) reduces mitochondrial respiratory and energy capacity in developing hippocampal neurons, causing permanently simplified dendritic arbors and impaired learning and memory. However, the effect of ID on early axonogenesis has not been explored. We used an embryonic mixed-sex primary mouse hippocampal neuron culture model of developmental ID to evaluate mitochondrial respiration and dynamics and effects on axonal morphology. At 7 days in vitro (DIV), ID impaired mitochondrial oxidative phosphorylation capacity and stunted growth of both the primary axon and branches, without affecting branch number. Mitochondrial motility was not altered by ID, suggesting that mitochondrial energy production --- not trafficking --- underlie the axon morphological deficits. These findings provide the first link between iron-dependent neuronal energy production and early axon structural development and emphasize the importance of maintaining sufficient iron during gestation to prevent the negative consequences of ID on brain health across the lifespan.<\/jats:p>\n                <jats:sec>\n                  <jats:title>Significance Statement<\/jats:title>\n                  <jats:p>This study used a primary mouse hippocampal neuron culture model of iron deficiency to address how disruption of iron-regulated mitochondrial activities affects axonal development. After axon initiation but prior to rapid dendrite outgrowth, iron chelation reduced mitochondrial oxidative phosphorylation capacity and stunted the growth of the primary axon and branches but without affecting branch number. Mitochondrial motility was not altered in iron-deficient axons, indicating that reduced neuronal energetic capacity and not impaired axonal mitochondrial trafficking may underlie these morphological deficits. Many neurodevelopmental, neuropsychiatric, and neurodegenerative disorders are characterized by iron and\/or mitochondrial dysregulation, highlighting the importance of advancing knowledge on the effects of mitochondrial deficits in early life as it pertains to optimizing brain health throughout the lifespan.<\/jats:p>\n                <\/jats:sec>","DOI":"10.1101\/2025.10.15.682603","type":"posted-content","created":{"date-parts":[[2025,10,15]],"date-time":"2025-10-15T23:30:13Z","timestamp":1760571013000},"source":"Crossref","is-referenced-by-count":0,"title":["Iron Deficiency Impairs Mitochondrial Energetics and Early Axonal Growth and Branching in Developing Hippocampal Neurons"],"prefix":"10.64898","author":[{"given":"Daniel C.","family":"Mendez","sequence":"first","affiliation":[{"name":"Department of Pediatrics, School of Medicine, University of Minnesota, Minneapolis, MN, 55455"},{"name":"Graduate Program in Neuroscience, University of Minnesota, Minneapolis, MN, 55455"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Karishma","family":"Devgun","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, School of Medicine, University of Minnesota, Minneapolis, MN, 55455"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Timothy R.","family":"Monko","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, School of Medicine, University of Minnesota, Minneapolis, MN, 55455"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Luke H.","family":"Carlson","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, School of Medicine, University of Minnesota, Minneapolis, MN, 55455"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daniel J.","family":"Mickelson","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, School of Medicine, University of Minnesota, Minneapolis, MN, 55455"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lorene M.","family":"Lanier","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, University of Minnesota, Minneapolis, MN, 55455"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael K.","family":"Georgieff","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, School of Medicine, University of Minnesota, Minneapolis, MN, 55455"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Thomas W.","family":"Bastian","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, School of Medicine, University of Minnesota, Minneapolis, MN, 55455"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2026020608015801000_2025.10.15.682603v2.1","doi-asserted-by":"publisher","DOI":"10.1016\/j.conb.2014.02.008"},{"key":"2026020608015801000_2025.10.15.682603v2.2","doi-asserted-by":"publisher","DOI":"10.1002\/advs.202306469"},{"key":"2026020608015801000_2025.10.15.682603v2.3","doi-asserted-by":"publisher","DOI":"10.37745\/ejsp.2013"},{"key":"2026020608015801000_2025.10.15.682603v2.4","doi-asserted-by":"publisher","DOI":"10.1093\/jn\/nxy125"},{"key":"2026020608015801000_2025.10.15.682603v2.5","doi-asserted-by":"publisher","DOI":"10.1177\/1179069519858351"},{"key":"2026020608015801000_2025.10.15.682603v2.6","doi-asserted-by":"publisher","DOI":"10.1177\/2633105520935104"},{"key":"2026020608015801000_2025.10.15.682603v2.7","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.1504-18.2018"},{"key":"2026020608015801000_2025.10.15.682603v2.8","doi-asserted-by":"publisher","DOI":"10.1093\/jn\/nxab429"},{"key":"2026020608015801000_2025.10.15.682603v2.9","doi-asserted-by":"publisher","DOI":"10.1159\/000448514"},{"key":"2026020608015801000_2025.10.15.682603v2.10","doi-asserted-by":"publisher","DOI":"10.1038\/nrn3820"},{"key":"2026020608015801000_2025.10.15.682603v2.11","doi-asserted-by":"publisher","DOI":"10.1159\/000314341"},{"key":"2026020608015801000_2025.10.15.682603v2.12","doi-asserted-by":"publisher","DOI":"10.1126\/science.adu6445"},{"key":"2026020608015801000_2025.10.15.682603v2.13","doi-asserted-by":"publisher","DOI":"10.1007\/s11689-010-9049-0"},{"key":"2026020608015801000_2025.10.15.682603v2.14","doi-asserted-by":"publisher","DOI":"10.1002\/hipo.20307"},{"key":"2026020608015801000_2025.10.15.682603v2.15","doi-asserted-by":"publisher","DOI":"10.3945\/jn.108.096354"},{"key":"2026020608015801000_2025.10.15.682603v2.16","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2022.03.015"},{"key":"2026020608015801000_2025.10.15.682603v2.17","doi-asserted-by":"publisher","DOI":"10.1002\/dneu.22748"},{"key":"2026020608015801000_2025.10.15.682603v2.18","doi-asserted-by":"publisher","DOI":"10.1203\/00006450-200008000-00009"},{"key":"2026020608015801000_2025.10.15.682603v2.19","doi-asserted-by":"crossref","unstructured":"Dotti, C. 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