The mitochondrial unfolded protein response in human microglia disrupts neuronal–glial communication and promotes senescence
Abstract Mitochondria have evolved a specialized mitochondrial unfolded protein response (UPR mt ) to maintain proteostasis and promote recovery under stress. Studies in simple organisms have shown that UPR mt 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. UPR mt 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 UPR mt in neurodegenerative disease pathogenesis.
Authors
- Hariam Raji (ORCID: https://orcid.org/0000-0002-2705-8857)
- Indra Heckenbach (ORCID: https://orcid.org/0000-0001-7038-4677)
- Christin Weissleder (ORCID: https://orcid.org/0000-0001-8858-9590)
- Stefanie Kalb
- Ivan Nemazanyy (ORCID: https://orcid.org/0000-0001-8080-839X)
- Michela Deleidi (ORCID: https://orcid.org/0000-0003-0357-0124)
- Morten Scheibye‐Knudsen (ORCID: https://orcid.org/0000-0002-6637-1280)
- Federico Bertoli (ORCID: https://orcid.org/0000-0001-5600-1190)
- Insa Hirschberg
- Dario Brunetti (ORCID: https://orcid.org/0000-0002-2740-9370)
- Mariella Bosch
- Maria Jose Perez J. (ORCID: https://orcid.org/0000-0001-8842-4286)
- Mohammed Kehili
- Alicia Lam
Institutions
- University of Copenhagen (DK)
- Centre National de la Recherche Scientifique (FR)
- Inserm (FR)
- University of Milan (IT)
- Hertie Institute for Clinical Brain Research (DE)
- Research Network (United States) (US)
- Max Planck Institute of Immunobiology and Epigenetics (DE)
- Fondazione IRCCS Istituto Neurologico Carlo Besta (IT)
- Institut des Maladies Génétiques Imagine (FR)
- Structure fédérative de recherche Necker (FR)
- University of Tübingen (DE)
Publication Details
- Journal
- Nature Neuroscience
- Published
- 2026-06-26
- DOI
- https://doi.org/10.1038/s41593-026-02320-1
- Citations
- 1
- Primary Topic
- Endoplasmic Reticulum Stress and Disease
- Type
- article
- Field-Weighted Citation Impact
- 8.34
Funders
- Michael J. Fox Foundation for Parkinson's Research
- Università degli Studi di Milano
- EU Joint Programme – Neurodegenerative Disease Research
- European Commission
- Deutsche Forschungsgemeinschaft
- Agence Nationale de la Recherche
- Fondazione Telethon
- Conseil Régional, Île-de-France
- Agencia Nacional de Investigación y Desarrollo
- HORIZON EUROPE Framework Programme