The mitochondrial unfolded protein response in human microglia disrupts neuronal-glial communication and promotes senescence.
Overview
- Mechanisms and Therapy of Genetic Brain Diseases, Institut Imagine,Paris, France
- Aligning Science Across Parkinson’s (ASAP) Collaborative Research Network,Chevy Chase, MD USA
- Present Address: Max Planck Institute of Immunobiology and Epigenetics,Freiburg, Germany
- Hertie Institute for Clinical Brain Research, University of Tübingen,Tübingen, Germany
- Platform for Metabolic Analyses, Structure Fédérative de Recherche Necker, INSERM US24/CNRS UAR 3633,Paris, France
- Department of Clinical Sciences and Community Health, Excellence Department 2023–2027, University of Milan,Milan, Italy
- Unit of Medical Genetics and Neurogenetics, Fondazione IRCCS Istituto Neurologico ‘Carlo Besta’,Milan, Italy
- Department of Cellular and Molecular Medicine, Center for Healthy Aging, University of Copenhagen,Copenhagen, Denmark
Abstract
Mitochondria have evolved a specialized mitochondrial unfolded protein response (UPRmt) to maintain proteostasis and promote recovery under stress. Studies in simple organisms have shown that UPRmt activation in glial cells supports proteostasis through beneficial non-cell-autonomous communication with neurons. However, the role of mitochondrial stress responses in the human brain remains unclear. To address this gap, we investigated the cell-type-specific effects of mitochondrial proteotoxic stress using human induced pluripotent stem cell-derived neuronal and glial cultures, as well as brain organoids. Here we show that mitochondrial proteotoxic stress induces metabolic rewiring in human microglia, marked by depletion of S-adenosylmethionine and lipid remodeling, ultimately leading to a senescent phenotype. Using human neuronal–glial tricultures and microglia-containing brain organoids, we identified the specific contributions of microglia to brain senescence and mitochondrial stress-driven neurodegenerative processes. UPRmt activation disrupts microglial communication with neighboring cells, triggering inflammatory signaling and impairing proteostasis. Together, these findings reveal how impaired mitochondrial proteostasis alters intercellular networks and identify a critical role for the UPRmt in neurodegenerative disease pathogenesis.
Reproduced under the paper's license (CC BY), from the paper cited above.
Code
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Zenodo 20507096
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Data
Datasets cited
- geo:GSE274283, at NCBI GEO; found in “Data availability”
Data availability
All data supporting the findings of this study are available within the article and its supplementary information files. Bulk and scRNA-seq datasets generated in this study have been deposited in the Gene Expression Omnibus (GEO) under accession numbers GSE274283 (http://
Reproduced under the paper's license (CC BY), from the paper cited above.
Versions
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Version 2, 28 September 2026
- Publisher: n/a → Nature Portfolio
Version 1, 27 September 2026: the first record
Recorded: type, language, journal, volume, issue, pages, dates, 14 authors, 4 keywords, 10 MeSH terms, 8 funders, 86 references, 23 RRIDs.
Cite
This paper
Perez J, M. J., Lam, A., Weissleder, C., Bertoli, F., Raji, H., Bosch, M., Nemazanyy, I., Kalb, S., Kehili, M., Hirschberg, I., Brunetti, D., Heckenbach, I., Scheibye-Knudsen, M., & Deleidi, M. (2026). The mitochondrial unfolded protein response in human microglia disrupts neuronal-glial communication and promotes senescence. Nature neuroscience, 29(8), 1858-1872. https://
BibTeX
@article{perezj2026mitoc
author = {Perez J, Maria Jose and Lam, Alicia and Weissleder, Christin and Bertoli, Federico and Raji, Hariam and Bosch, Mariella and Nemazanyy, Ivan and Kalb, Stefanie and Kehili, Mohammed and Hirschberg, Insa and Brunetti, Dario and Heckenbach, Indra and Scheibye-Knudsen, Morten and Deleidi, Michela},
title = {{The mitochondrial unfolded protein response in human microglia disrupts neuronal-glial communication and promotes senescence}},
journal = {Nature neuroscience},
year = {2026},
month = jun,
volume = {29},
number = {8},
pages = {1858--1872},
publisher = {Nature Portfolio},
issn = {1097-6256},
doi = {10.1038/
url = {https://
pmid = {42362883},
pmcid = {PMC13433254}
}
RIS
TY - JOUR
AU - Perez J, Maria Jose
AU - Lam, Alicia
AU - Weissleder, Christin
AU - Bertoli, Federico
AU - Raji, Hariam
AU - Bosch, Mariella
AU - Nemazanyy, Ivan
AU - Kalb, Stefanie
AU - Kehili, Mohammed
AU - Hirschberg, Insa
AU - Brunetti, Dario
AU - Heckenbach, Indra
AU - Scheibye-Knudsen, Morten
AU - Deleidi, Michela
TI - The mitochondrial unfolded protein response in human microglia disrupts neuronal-glial communication and promotes senescence
T2 - Nature neuroscience
J2 - Nat Neurosci
PY - 2026
DA - 2026/
VL - 29
IS - 8
SP - 1858
EP - 1872
SN - 1097-6256
PB - Nature Portfolio
DO - 10.1038/
UR - https://
LA - en
ER -
CSL-JSON
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