A mitochondrial UPR-mediated metabolic checkpoint regulates hematopoietic stem cell aging
Open accessAbstract
Deterioration of adult stem cells accounts for much of aging-associated compromised tissue maintenance. How stem cells maintain metabolic homeostasis remains elusive. Here, we identified a regulatory branch of the mitochondrial unfolded protein response (UPR(mt)), which is mediated by the interplay of SIRT7 and NRF1 and is coupled to cellular energy metabolism and proliferation. SIRT7 inactivation caused reduced quiescence, increased mitochondrial protein folding stress (PFS(mt)), and compromised regenerative capacity of hematopoietic stem cells (HSCs). SIRT7 expression was reduced in aged HSCs, and SIRT7 up-regulation improved the regenerative capacity of aged HSCs. These findings define the deregulation of a UPR(mt)-mediated metabolic checkpoint as a reversible contributing factor for HSC aging.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Lowering mitochondrial stress in aged HSCs can restore lost stem cell function.
“reducing mitochondrial stress in aged HSCs can reverse loss of stem functioning.”
From Aging of hematopoietic stem cells (2018) · cites this paper as [62]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
López-Otín, C., Blasco, M. A., Partridge, L., Serrano, M., & Kroemer, G. (2013) · Cell · doi:10.1016/j.cell.2013.05.039 · Cited by 14,982 · see citing works
mTOR Signaling in Growth Control and Disease
Laplante, M., & Sabatini, D. M. (2012) · Cell · doi:10.1016/j.cell.2012.03.017 · Cited by 8,509 · see citing works
TSC2 Mediates Cellular Energy Response to Control Cell Growth and Survival
Inoki, K., Zhu, T., & Guan, K.-L. (2003) · Cell · doi:10.1016/s0092-8674(03)00929-2 · Cited by 3,914 · see citing works
Kenyon, C. J. (2010) · Nature · doi:10.1038/nature08980 · Cited by 2,739 · see citing works
Transcriptional paradigms in mammalian mitochondrial biogenesis and function
Scarpulla, R. C. (2008) · Physiological Reviews · doi:10.1152/physrev.00025.2007 · Cited by 1,666 · see citing works
Calorie restriction reduces oxidative stress by SIRT3-mediated SOD2 activation
Qiu, X., Brown, K., Hirschey, M. D., Verdin, E., & Chen, D. (2010) · Cell Metabolism · doi:10.1016/j.cmet.2010.11.015 · Cited by 1,310 · see citing works
Self-citationStem-cell ageing modified by the cyclin-dependent kinase inhibitor p16INK4a
Janzen, V., Forkert, R., Fleming, H. E., Saito, Y., Waring, M. T., Dombkowski, D. M., Cheng, T., DePinho, R. A., Sharpless, N. E., & Scadden, D. T. (2006) · Nature · doi:10.1038/nature05159 · Cited by 1,106 · see citing works
A mitochondrial specific stress response in mammalian cells
Zhao, Q., Wang, J., Levichkin, I. V., Stasinopoulos, S., Ryan, M. T., & Hoogenraad, N. J. (2002) · The EMBO Journal · doi:10.1093/emboj/cdf445 · Cited by 1,026 · see citing works
Hedgehog signalling is essential for maintenance of cancer stem cells in myeloid leukaemia
Zhao, C., Chen, A., Jamieson, C. H. M., Fereshteh, M., Abrahamsson, A. E., Blum, J. M., Kwon, H. Y., Kim, J., Chute, J. P., Rizzieri, D. A., et al. (2009) · Nature · doi:10.1038/nature07737 · Cited by 868 · see citing works
Foxo3a is essential for maintenance of the hematopoietic stem cell pool
Miyamoto, K., Kazuhito, N., & Atsushi, H. (2009) · Kanazawa University Repository for Academic Resources (DSpace) (Kanazawa University) · Cited by 858 · see citing works
Aging Hematopoietic Stem Cells Decline in Function and Exhibit Epigenetic Dysregulation
Chambers, S. M., Shaw, C. A., Gatza, C. E., Fisk, C. J., Donehower, L. A., & Goodell, M. A. (2007) · PLoS Biology · doi:10.1371/journal.pbio.0050201 · Cited by 799 · see citing works
Stem cell aging: mechanisms, regulators and therapeutic opportunities
Oh, J., Lee, Y. D., & Wagers, A. J. (2014) · Nature Medicine · doi:10.1038/nm.3651 · Cited by 796 · see citing works
Metabolic Plasticity in Stem Cell Homeostasis and Differentiation
Folmes, C. D. L., Dzeja, P. P., Nelson, T. J., & Terzic, A. (2012) · Cell stem cell · doi:10.1016/j.stem.2012.10.002 · Cited by 664 · see citing works
SIRT7 links H3K18 deacetylation to maintenance of oncogenic transformation
Barber, M. F., Michishita-Kioi, E., Xi, Y., Tasselli, L., Kioi, M., Moqtaderi, Z., Tennen, R. I., Paredes, S., Young, N. L., Chen, K., et al. (2012) · Nature · doi:10.1038/nature11043 · Cited by 621 · see citing works
Self-citationChromatin modifications as determinants of muscle stem cell quiescence and chronological aging
Liu, L., Cheung, T. H., Charville, G. W., Hurgo, B. M. C., Leavitt, T., Shih, J., Brunet, A., & Rando, T. A. (2013) · Cell Reports · doi:10.1016/j.celrep.2013.05.043 · Cited by 544 · see citing works
The mitochondrial UPR – protecting organelle protein homeostasis
Haynes, C. M., & Ron, D. (2010) · Journal of Cell Science · doi:10.1242/jcs.075119 · Cited by 490 · see citing works
Self-citationSIRT3 Reverses Aging-Associated Degeneration
Brown, K., Xie, S., Qiu, X., Mohrin, M., Shin, J., Liu, Y., Zhang, D., Scadden, D. T., & Chen, D. (2013) · Cell Reports · doi:10.1016/j.celrep.2013.01.005 · Cited by 436 · see citing works
Self-citationPuzzles, promises and a cure for ageing
Vijg, J., & Campisi, J. (2008) · Nature · doi:10.1038/nature07216 · Cited by 407 · see citing works
Lai, L., Leone, T. C., Zechner, C., Schaeffer, P. J., Kelly, S. M., Flanagan, D. P., Medeiros, D. M., Kovacs, A., & Kelly, D. P. (2008) · Genes & Development · doi:10.1101/gad.1661708 · Cited by 326 · see citing works
Mechanisms that Regulate Stem Cell Aging and Life Span
Signer, R. A. J., & Morrison, S. J. (2013) · Cell Stem Cell · doi:10.1016/j.stem.2013.01.001 · Cited by 320 · see citing works
SIRT7 represses Myc activity to suppress ER stress and prevent fatty liver disease
Shin, J., He, M., Liu, Y., Paredes, S., Villanova, L., Brown, K., Qiu, X., Nabavi, N., Mohrin, M., Wojnoonski, K., et al. (2013) · Cell Reports · doi:10.1016/j.celrep.2013.10.007 · Cited by 287 · see citing works
Sirtuins: guardians of mammalian healthspan
Giblin, W., Skinner, M. E., & Lombard, D. B. (2014) · Trends in Genetics · doi:10.1016/j.tig.2014.04.007 · Cited by 280 · see citing works
A SIRT7-Dependent Acetylation Switch of GABPβ1 Controls Mitochondrial Function
Ryu, D., Jo, Y. S., Sasso, G. L., Stein, S., Zhang, H., Perino, A., Lee, J. U., Zeviani, M., Romand, R., Hottiger, M. O., et al. (2014) · Cell Metabolism · doi:10.1016/j.cmet.2014.08.001 · Cited by 258 · see citing works
Haynes, C. M., Fiorese, C. J., & Lin, Y. (2013) · Trends in Cell Biology · doi:10.1016/j.tcb.2013.02.002 · Cited by 209 · see citing works
Self-citationFOXO3 shares common targets with ASCL1 genome-wide and inhibits ASCL1-dependent neurogenesis
Webb, A. E., Pollina, E. A., Vierbuchen, T., Urbán, N., Ucar, D., Leeman, D. S., Martynoga, B., Sewak, M., Rando, T. A., Guillemot, F., et al. (2013) · Cell Reports · doi:10.1016/j.celrep.2013.06.035 · Cited by 164 · see citing works
Real‐Time Quantitative PCR Analysis of Mitochondrial DNA Content
Venegas, V., Wang, J., Dimmock, D., & Wong, L. (2011) · Current Protocols in Human Genetics · doi:10.1002/0471142905.hg1907s68 · Cited by 133 · see citing works
Vakhrusheva, O., Braeuer, D., Liu, Z., Braun, T. W., & Bober, E. (2008) · PubMed · Cited by 85 · see citing works
A quick and quantitative chromatin immunoprecipitation assay for small cell samples
Dahl, J. A. (2007) · Frontiers in bioscience · doi:10.2741/2438 · Cited by 44 · see citing works
Foxo3a is essential for maintenance of the hematopoietic stem cell pool.
Miyamoto, K., Araki, K. Y., Naka, K., Arai, F., Takubo, K., Yamazaki, S., Matsuoka, S., Miyamoto, T., Ito, K., Ohmura, M., et al. (2007) · Cell stem cell · doi:10.1016/j.stem.2007.02.001 · Cited by 41 · see citing works
[Inhibitory role of SirT7 in the growth of P19 cell line].
Lu, J.-Y., Zhang, Y., & Shen, Y. (2009) · PubMed · doi:10.3881/j.issn.1000-503x.2009.06.014 · Cited by 1 · see citing works
Flagged first, then by citations
Research works printed but not linked: 2
- [2]López-Otín C Blasco MA Partridge L Serrano M Kroemer G Cell 2013 153 1194 1217 23746838 PMC3836174
- [11]Vakhrusheva O Braeuer D Liu Z Braun T Bober E J. Physiol. Pharmacol 2008 59 suppl. 9 201 212 19261981
Cited by
Sorted by citations
Hallmarks of aging: An expanding universe
López-Otín, C., Blasco, M. A., Partridge, L., Serrano, M., & Kroemer, G. (2023) · Cell · doi:10.1016/j.cell.2022.11.001 · Cited by 6,549 · see citing works
The mitochondrial basis of aging
Sun, N., Youle, R. J., & Finkel, T. (2016) · Molecular Cell · doi:10.1016/j.molcel.2016.01.028 · Cited by 1,441 · see citing works
Autophagy maintains the metabolism and function of young and old stem cells
Ho, T. T., Warr, M. R., Adelman, E. R., Lansinger, O. M., Flach, J., Verovskaya, E. V., Figueroa, M. E., & Passegué, E. (2017) · Nature · doi:10.1038/nature21388 · Cited by 896 · see citing works
Mitonuclear communication in homeostasis and stress
Quirós, P. M., Mottis, A., & Auwerx, J. (2016) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm.2016.23 · Cited by 787 · see citing works
Metabolic Control of Longevity
López-Otín, C., Galluzzi, L., Freije, J. M. P., Madeo, F., & Kroemer, G. (2016) · Cell · doi:10.1016/j.cell.2016.07.031 · Cited by 753 · see citing works
Aging of hematopoietic stem cells
de Haan, G., & Lazare, S. S. (2018) · Blood · doi:10.1182/blood-2017-06-746412 · Cited by 432 · see citing works
He, M., Chiang, H.-H., Luo, H., Zheng, Z., Qiao, Q., Wang, L., Tan, M., Ohkubo, R., Mu, W.-C., Zhao, S., et al. (2020) · Cell Metabolism · doi:10.1016/j.cmet.2020.01.009 · Cited by 425 · see citing works
Self-citationNuclear DNA damage signalling to mitochondria in ageing
Fang, E. F., Scheibye-Knudsen, M., Chua, K. F., Mattson, M. P., Croteau, D. L., & Bohr, V. A. (2016) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm.2016.14 · Cited by 387 · see citing works
Repairing mitochondrial dysfunction in disease
Sorrentino, V., Menzies, K. J., & Auwerx, J. (2018) · Annual Review of Pharmacology and Toxicology · doi:10.1146/annurev-pharmtox-010716-104908 · Cited by 337 · see citing works
Protein acetylation in metabolism – metabolites and cofactors
Menzies, K. J., Zhang, H., Katsyuba, E., & Auwerx, J. (2016) · Nature Reviews Endocrinology · doi:10.1038/nrendo.2015.181 · Cited by 331 · see citing works
Metabolic regulation of stem cell function in tissue homeostasis and organismal ageing
Chandel, N. S., Jasper, H., Ho, T. T., & Passegué, E. (2016) · Nature Cell Biology · doi:10.1038/ncb3385 · Cited by 326 · see citing works
Ho, Y.-H., del Toro, R., Rivera-Torres, J., Rak, J., Korn, C., García-García, A., Macías, D., González-Gómez, C., del Monte, A., Wittner, M., et al. (2019) · Cell Stem Cell · doi:10.1016/j.stem.2019.06.007 · Cited by 315 · see citing works
A human circulating immune cell landscape in aging and COVID-19
Zheng, Y., Liu, X., Le, W., Xie, L., Li, H., Wen, W., Wang, S., Ma, S., Huang, Z., Ye, J., et al. (2020) · Protein & Cell · doi:10.1007/s13238-020-00762-2 · Cited by 270 · see citing works
Cellular and epigenetic drivers of stem cell ageing
Ermolaeva, M., Neri, F., Ori, A., & Rudolph, K. L. (2018) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-018-0020-3 · Cited by 272 · see citing works
Chaperone-mediated autophagy sustains haematopoietic stem-cell function
Dong, S., Wang, Q., Kao, Y.-R., Diaz, A., Tasset, I., Kaushik, S., Thiruthuvanathan, V., Zintiridou, A., Nieves, E., Dzieciatkowska, M., et al. (2021) · Nature · doi:10.1038/s41586-020-03129-z · Cited by 275 · see citing works
Vannini, N., Campos, V., Girotra, M., Trachsel, V., Rojas-Sutterlin, S., Tratwal, J., Ragusa, S., Stefanidis, E., Ryu, D., Rainer, P. Y., et al. (2019) · Cell Stem Cell · doi:10.1016/j.stem.2019.02.012 · Cited by 218 · see citing works
The Metabolic Impact on Histone Acetylation and Transcription in Ageing
Peleg, S., Feller, C., Ladurner, A. G., & Imhof, A. (2016) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2016.05.008 · Cited by 178 · see citing works
Hematopoietic Stem Cells and Their Roles in Tissue Regeneration
Lee, J. Y., & Hong, S.-H. (2020) · International Journal of Stem Cells · doi:10.15283/ijsc19127 · Cited by 165 · see citing works
Signaling networks determining life span
Riera, C. E., Merkwirth, C., De Magalhaes Filho, C. D., & Dillin, A. (2016) · Annual Review of Biochemistry · doi:10.1146/annurev-biochem-060815-014451 · Cited by 161 · see citing works
Luo, H., Mu, W.-C., Karki, R., Chiang, H.-H., Mohrin, M., Shin, J. J., Ohkubo, R., Ito, K., Kanneganti, T.-D., & Chen, D. (2019) · Cell Reports · doi:10.1016/j.celrep.2018.12.101 · Cited by 161 · see citing works
Self-citationNAD <sup>+</sup> supplementation rejuvenates aged gut adult stem cells
Igarashi, M., Miura, M., Williams, E., Jaksch, F., Kadowaki, T., Yamauchi, T., & Guarente, L. (2019) · Aging Cell · doi:10.1111/acel.12935 · Cited by 138 · see citing works
Blank, M. F., & Grummt, I. (2017) · Transcription · doi:10.1080/21541264.2016.1276658 · Cited by 111 · see citing works
Aged hematopoietic stem cells are refractory to bloodborne systemic rejuvenation interventions
Ho, T. T., Dellorusso, P. V., Verovskaya, E. V., Bakker, S. T., Flach, J., Smith, L. K., Ventura, P. B., Lansinger, O. M., Hérault, A., Zhang, S. Y., et al. (2021) · Journal of Experimental Medicine · doi:10.1084/jem.20210223 · Cited by 101 · see citing works
Kruta, M., Sunshine, M. J., Chua, B. A., Fu, Y., Chawla, A., Dillingham, C. H., Hidalgo San Jose, L., De Jong, B., Zhou, F. J., & Signer, R. A. J. (2021) · Cell Stem Cell · doi:10.1016/j.stem.2021.07.009 · Cited by 100 · see citing works
Aging-induced IL27Ra signaling impairs hematopoietic stem cells
He, H., Xu, P., Zhang, X., Liao, M., Dong, Q., Cong, T., Tang, B., Yang, X., Ye, M., Chang, Y., et al. (2020) · Blood · doi:10.1182/blood.2019003910 · Cited by 94 · see citing works
HDAC8 cooperates with SMAD3/4 complex to suppress SIRT7 and promote cell survival and migration
Tang, X., Li, G., Su, F., Cai, Y., Shi, L., Meng, Y., Liu, Z., Sun, J., Wang, M., Qian, M., et al. (2020) · Nucleic Acids Research · doi:10.1093/nar/gkaa039 · Cited by 91 · see citing works
Maillo, C., Martín, J., Sebastián, D., Hernández-Alvarez, M., García-Rocha, M., Reina, O., Zorzano, A., Fernandez, M., & Méndez, R. (2017) · Nature Cell Biology · doi:10.1038/ncb3461 · Cited by 82 · see citing works
Sirtuins at the Service of Healthy Longevity
Watroba, M., & Szukiewicz, D. (2021) · Frontiers in Physiology · doi:10.3389/fphys.2021.724506 · Cited by 64 · see citing works
Novel Insights into the Anti-Aging Role of Mitophagy
(2018) · International Review of Cell and Molecular Biology · doi:10.1016/bs.ircmb.2018.05.005 · Cited by 56 · see citing works
Sera, Y., Nakata, Y., Ueda, T., Yamasaki, N., Koide, S., Kobayashi, H., Ikeda, K.-I., Kobatake, K., Iwasaki, M., Oda, H., et al. (2021) · Blood · doi:10.1182/blood.2019001044 · Cited by 42 · see citing works
SIRT7 activates p53 by enhancing PCAF-mediated MDM2 degradation to arrest the cell cycle
Lu, Y.-F., Xu, X.-P., Lu, X.-P., Zhu, Q., Liu, G., Bao, Y.-T., Wen, H., Li, Y.-L., Gu, W., & Zhu, W.-G. (2020) · Oncogene · doi:10.1038/s41388-020-1305-5 · Cited by 40 · see citing works
Tran, K. A., Gilbert, M., Vazquez, B. N., Ianni, A., Garcia, B. A., Vaquero, A., & Berger, S. L. (2025) · Molecular Cell · doi:10.1016/j.molcel.2025.05.025 · Cited by 15 · see citing works
Maldonado, M., Chen, J., Duan, H., Huang, T., Jiang, G., & Zhong, Y. (2021) · Translational Medicine of Aging · doi:10.1016/j.tma.2021.02.001 · Cited by 11 · see citing works
- Authors
- Mohrin, M., Shin, J., Liu, Y., Brown, K., Luo, H., Xi, Y., Haynes, C. M., & Chen, D.
- Affiliations
- University of California, Berkeley (US)
- Memorial Sloan Kettering Cancer Center (US)
- Corresponding author
- Mohrin, Mary
- Shin, Jiyung
- Liu, Yufei
- Brown, Katharine
- Chen, Danica
- Venue
- Science
- Published
- 2015-03-20
- Volume
- 347
- Issue
- 6228
- Pages
- 1374-1377
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- PMC
- PMC4447312
- OpenAlex
- W2095048801
- Cited by
- 490
- References
- 30
- Citations by year
- 2026: 34 · 2025: 32 · 2024: 30 · 2023: 43 · 2022: 36 · 2021: 58 · 2020: 60 · 2019: 37 · 2018: 48 · 2017: 45 · 2016: 49 · 2015: 17
- FWCI
- 41.59
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Science (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- NIH (R01 AG040990, R01AG040061, T32 AG000266)
- Ellison Medical Foundation
- Glenn Foundation
- NSF Graduate Research Fellowship Program
- Siebel Stem Cell Institute
- Topics
- Health Sciences › Medicine › Hematology › Hematopoietic Stem Cell Transplantation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Health Sciences › Medicine › Geriatrics and Gerontology › Sirtuins and Resveratrol in Medicine
- Keywords
- mitochondrial unfolded protein response, hematopoietic stem cell aging, SIRT7, NRF1, stem cell quiescence, energy metabolism, stem cell proliferation, regenerative capacity, metabolic checkpoint, aging
- MeSH terms
- Animals, Energy Metabolism, Hematopoietic Stem Cells, Humans, Mice, Mutant Strains, Mitochondria, Protein Biosynthesis, Cellular Senescence, Mitochondrial Proteins, Sirtuins, Nuclear Respiratory Factor 1, Mice, Unfolded Protein Response, HEK293 Cells, Cell Cycle Checkpoints
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
