Elevated mitochondrial metabolism in Down syndrome iPSCs reduces commitment to neuroectoderm
Abstract 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 1 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 iPSCs.
Authors
- Edwin A. Rosado-Olivieri (ORCID: https://orcid.org/0000-0003-4756-0956)
- Théodore Nguyen (ORCID: https://orcid.org/0009-0008-8906-9544)
- Brian F. Niemeyer (ORCID: https://orcid.org/0000-0002-2020-2238)
- Malay Chaklader (ORCID: https://orcid.org/0000-0003-2192-7537)
- Rodrigo S. Lacruz (ORCID: https://orcid.org/0000-0002-0776-6143)
- Joaquin Maximiliano Espinosa (ORCID: https://orcid.org/0000-0001-9048-1941)
- Beverly A. Rothermel (ORCID: https://orcid.org/0000-0001-9037-6703)
- Guilherme Henrique Souza Bomfim (ORCID: https://orcid.org/0000-0001-9454-7266)
- Neil Jeju (ORCID: https://orcid.org/0009-0008-7154-7173)
- Weichun Lin
- Jiankun Zhu
- Yingli Duan
Institutions
- University of Dallas (US)
- University of Colorado Anschutz Medical Campus (US)
- New York University (US)
- The University of Texas Southwestern Medical Center (US)
Publication Details
- Journal
- EMBO Reports
- Published
- 2026-10-30
- DOI
- https://doi.org/10.1038/s44319-026-00944-9
- Primary Topic
- Down syndrome and intellectual disability research
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Global Down Syndrome Foundation
- Harry S. Moss Heart Trust
- National Institutes of Health
- National Institute of Neurological Disorders and Stroke
- National Institute of Dental and Craniofacial Research
- Eunice Kennedy Shriver National Institute of Child Health and Human Development