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Here we show that Olduvai domains act in a dosage-dependent manner to suppress mitochondrial metabolism. Transcriptomic, proteomic, and live-cell imaging analyses of cells overexpressing NBPF1 (which encodes seven Olduvai domains) reveal pronounced downregulation of mitochondrial pathways, including electron transport chain components and NADH dehydrogenase activity, as well as reduced mitochondrial abundance. By limiting energy availability, this suppression delays cellular maturation and developmental timing. We propose that the resulting prolongation of neurogenesis increases neuron production, providing a mechanistic link between Olduvai copy number expansion and the evolutionary enlargement of the human brain. This dosage-sensitive mitochondrial regulation may also contribute to broader neotenic features of human development, offering a unifying molecular mechanism for brain expansion and the neotenic traits that distinguish humans from other primates.<\/p>","DOI":"10.21203\/rs.3.rs-10345985\/v1","type":"posted-content","created":{"date-parts":[[2026,7,18]],"date-time":"2026-07-18T11:31:36Z","timestamp":1784374296000},"source":"Crossref","is-referenced-by-count":0,"title":["Olduvai Domains Downregulate Mitochondrial Pathways to Promote Human Brain Evolution and Neoteny"],"prefix":"10.21203","author":[{"given":"Jonathon G.","family":"Keeney","sequence":"first","affiliation":[{"name":"University of Colorado Anschutz Medical Campus"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Astling","sequence":"additional","affiliation":[{"name":"University of Colorado Anschutz Medical Campus"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vanessa","family":"Andries","sequence":"additional","affiliation":[{"name":"Ghent University"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karl","family":"Vandepoele","sequence":"additional","affiliation":[{"name":"Ghent University"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nathan","family":"Anderson","sequence":"additional","affiliation":[{"name":"University of Colorado Anschutz Medical Campus"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan M.","family":"Davis","sequence":"additional","affiliation":[{"name":"University of Colorado Anschutz Medical Campus"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pamela","family":"Lopert","sequence":"additional","affiliation":[{"name":"University of Colorado Anschutz Medical Campus"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manisha","family":"Patel","sequence":"additional","affiliation":[{"name":"University of Colorado Anschutz Medical Campus"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ken","family":"Jones","sequence":"additional","affiliation":[{"name":"University of Coloado Anschutz Medical Campus"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan","family":"Vandenbussche","sequence":"additional","affiliation":[{"name":"Ghent Univeristy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kris","family":"Gevaert","sequence":"additional","affiliation":[{"name":"Ghent University"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"An","family":"Staes","sequence":"additional","affiliation":[{"name":"Ghent University"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Santos","family":"Franco","sequence":"additional","affiliation":[{"name":"University of Colorado Anschutz Medical Campus"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natasia","family":"Paukovich","sequence":"additional","affiliation":[{"name":"University of Colorado Anschutz Medical Campus"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Beat","family":"Vogeli","sequence":"additional","affiliation":[{"name":"University of Colorado Anschutz Medical Campus"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frans van","family":"Roy","sequence":"additional","affiliation":[{"name":"Ghent University"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James M.","family":"Sikela","sequence":"additional","affiliation":[{"name":"University of Colorado Anschutz Medical Campus"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"102182","DOI":"10.1016\/j.gde.2024.102182","article-title":"Linking mitochondria metabolism, developmental timing, and human brain evolution","volume":"86","author":"Casimir P","year":"2024","unstructured":"Casimir P, Iwata R, Vanderhaeghen P (2024) Linking mitochondria metabolism, developmental timing, and human brain evolution. 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