{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T11:02:00Z","timestamp":1786964520424,"version":"build-2736575974"},"posted":{"date-parts":[[2025,5,12]]},"group-title":"Developmental Biology","reference-count":70,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,5,12]],"date-time":"2025-05-12T00:00:00Z","timestamp":1747008000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.biorxiv.org\/about\/FAQ#license"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,5,9]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:p>\n                  A key feature of Down syndrome (DS) is reduced neurogenesis. Here, we provide evidence that increased mitochondrial metabolism in DS stem cells reduces their ability to commit to neuroectoderm (NE), one of the earliest steps in the development of the nervous system. We show that mitochondria in induced pluripotent stem cells derived from individuals with DS (3S-iPSCs) have a higher membrane potential and increased capacity for calcium uptake via the mitochondrial calcium uniporter (MCU) compared to isogenic, euploid controls. Consequently, 3S-iPSCs proliferate faster and spend less time in G\n                  <jats:sub>1<\/jats:sub>\n                  of the cell cycle. This reduces the opportunity for growth of a primary cilium, an important developmental signaling hub. Inhibiting MCU or slowing proliferation of 3S-iPSCs is sufficient to increase ciliation and improve commitment to NE. In summary, we provide evidence that a mitochondria-to-cilia signaling axis important during the earliest steps of neurogenesis is dysregulated in DS, yet remains amenable to small molecule intervention.\n                <\/jats:p>","DOI":"10.1101\/2025.05.09.653211","type":"posted-content","created":{"date-parts":[[2025,5,12]],"date-time":"2025-05-12T10:10:15Z","timestamp":1747044615000},"source":"Crossref","is-referenced-by-count":2,"title":["Elevated mitochondrial metabolism in Down syndrome iPSCs reduces commitment to neuroectoderm"],"prefix":"10.64898","author":[{"given":"Malay","family":"Chaklader","sequence":"first","affiliation":[{"name":"Department of Internal Medicine, Division of Cardiology, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75390, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guilherme Henrique","family":"Souza Bomfim","sequence":"additional","affiliation":[{"name":"Department of Molecular Pathobiology, New York University College of Dentistry, 345 East 24 St., New York, NY, 10010, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-7154-7173","authenticated-orcid":false,"given":"Neil","family":"Jeju","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Division of Cardiology, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75390, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yingli","family":"Duan","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Division of Cardiology, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75390, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brian F","family":"Niemeyer","sequence":"additional","affiliation":[{"name":"Linda Crnic Institute for Down Syndrome, University of Colorado Anschutz Medical Campus, 12700 East 19 Avenue, Aurora, CO 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