Mitochondrial aging defects emerge in directly reprogrammed human neurons due to their metabolic profile
Open accessAbstract
Mitochondria are a major target for aging and are instrumental in the age-dependent deterioration of the human brain, but studying mitochondria in aging human neurons has been challenging. Direct fibroblast-to-induced neuron (iN) conversion yields functional neurons that retain important signs of aging, in contrast to iPSC differentiation. Here, we analyzed mitochondrial features in iNs from individuals of different ages. iNs from old donors display decreased oxidative phosphorylation (OXPHOS)-related gene expression, impaired axonal mitochondrial morphologies, lower mitochondrial membrane potentials, reduced energy production, and increased oxidized proteins levels. In contrast, the fibroblasts from which iNs were generated show only mild age-dependent changes, consistent with a metabolic shift from glycolysis-dependent fibroblasts to OXPHOS-dependent iNs. Indeed, OXPHOS-induced old fibroblasts show increased mitochondrial aging features similar to iNs. Our data indicate that iNs are a valuable tool for studying mitochondrial aging and support a bioenergetic explanation for the high susceptibility of the brain to aging.
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Fibroblast-derived iNs preserve substantial signatures of human aging, including transcriptomic, nuclear pore, mitochondrial, epigenetic, and other aspects of aging.
“Fibroblast-derived iNs preserve substantial signatures of human aging, including transcriptomic, nuclear pore, mitochondrial, epigenetic, and other aspects of aging (Herdy et al., 2019; Huh et al., 2016; Kim et al., 2018; Mertens et al., 2015a; Traxler et al., 2019).”
From Age-dependent instability of mature neuronal fate in induced neurons from Alzheimer’s patients (2021) · cites this paper as Kim et al., 2018
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- Authors
- Kim, Y., Zheng, X., Ansari, Z., Bunnell, M. C., Herdy, J. R., Traxler, L., Lee, H., Paquola, A. C. M., Blithikioti, C., Ku, M., Schlachetzki, J. C. M., Winkler, J., Edenhofer, F., Glass, C. K., Paucar, A. A., Jaeger, B. N., Pham, S., Boyer, L., Campbell, B. C., Hunter, T., Mertens, J., & Gage, F. H.
- Affiliations
- Salk Institute for Biological Studies (US)
- Friedrich-Alexander-Universität Erlangen-Nürnberg (DE)
- Universität Innsbruck (AT)
- University of California San Diego (US)
- Corresponding author
- Gage, Fred H.
- ORCID
- Venue
- Cell Reports
- Publisher
- Elsevier BV
- Published
- 2018-05
- Volume
- 23
- Issue
- 9
- Pages
- 2550-2558
- ISSN
- 2211-1247 (ISSN-L)
- PMC
- PMC6478017
- OpenAlex
- W2805679083
- Cited by
- 117
- References
- 38
- Citations by year
- 2026: 11 · 2025: 9 · 2024: 15 · 2023: 13 · 2022: 14 · 2021: 18 · 2020: 15 · 2019: 12 · 2018: 10
- FWCI
- 4.89
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Cell Reports (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Institute on Aging (R01-AG056306-01, K99-AG056679-01)
- University of California, San Diego
- JPB Foundation
- Leona M. and Harry B. Helmsley Charitable Trust
- American Federation for Aging Research
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pluripotent Stem Cells Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Keywords
- mitochondrial aging, induced neurons, fibroblast-to-neuron conversion, oxidative phosphorylation, mitochondrial membrane potential, axonal mitochondria, brain aging, cellular metabolism, glycolysis, oxidized proteins, energy production, donor age
- MeSH terms
- Adolescent, Adult, Aged, Aged, 80 and over, Aging, Cell Differentiation, Cells, Cultured, Child, Child, Preschool, Fibroblasts, Gene Expression Regulation, Humans, Infant, Infant, Newborn, Middle Aged, Mitochondria, Neurons, Oxidative Phosphorylation, Phenotype, Tissue Donors, Genes, Mitochondrial, Metabolomics, Young Adult, Cellular Reprogramming
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