{
  "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.",
  "abstract_shown": true,
  "affiliations": [
    "Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, Chevy Chase, MD, USA. perezm@ie-freiburg.mpg.de",
    "Max Planck Institute of Immunobiology and Epigenetics, Freiburg, Germany. perezm@ie-freiburg.mpg.de",
    "Mechanisms and Therapy of Genetic Brain Diseases, Institut Imagine, Paris, France. perezm@ie-freiburg.mpg.de",
    "Mechanisms and Therapy of Genetic Brain Diseases, Institut Imagine, Paris, France",
    "Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, Chevy Chase, MD, USA",
    "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",
    "Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, Chevy Chase, MD, USA. michela.deleidi@institutimagine.org",
    "Mechanisms and Therapy of Genetic Brain Diseases, Institut Imagine, Paris, France. michela.deleidi@institutimagine.org"
  ],
  "article_type": null,
  "arxiv": null,
  "author_total": 14,
  "authors": [
    {
      "affs": [
        0,
        1,
        2
      ],
      "name": "Maria Jose Perez J.",
      "orcid": "0000-0001-8842-4286"
    },
    {
      "affs": [
        3
      ],
      "name": "Alicia Lam"
    },
    {
      "affs": [
        4,
        3
      ],
      "name": "Christin Weissleder",
      "orcid": "0000-0001-8858-9590"
    },
    {
      "affs": [
        4,
        3
      ],
      "name": "Federico Bertoli",
      "orcid": "0000-0001-5600-1190"
    },
    {
      "affs": [
        4,
        3
      ],
      "name": "Hariam Raji",
      "orcid": "0000-0002-2705-8857"
    },
    {
      "affs": [
        5
      ],
      "name": "Mariella Bosch",
      "orcid": "0009-0004-4890-3679"
    },
    {
      "affs": [
        6
      ],
      "name": "Ivan Nemazanyy",
      "orcid": "0000-0001-8080-839X"
    },
    {
      "affs": [
        5
      ],
      "name": "Stefanie Kalb"
    },
    {
      "affs": [
        3
      ],
      "name": "Mohammed Kehili"
    },
    {
      "affs": [
        5
      ],
      "name": "Insa Hirschberg"
    },
    {
      "affs": [
        7,
        8
      ],
      "name": "Dario Brunetti",
      "orcid": "0000-0002-2740-9370"
    },
    {
      "affs": [
        9
      ],
      "name": "Indra Heckenbach",
      "orcid": "0000-0001-7038-4677"
    },
    {
      "affs": [
        9
      ],
      "name": "Morten Scheibye‐Knudsen",
      "orcid": "0000-0002-6637-1280"
    },
    {
      "affs": [
        10,
        11
      ],
      "name": "Michela Deleidi",
      "orcid": "0000-0003-0357-0124"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/92mby1ht9kvjc.bib",
  "cited_by": 14,
  "doi": "10.1038/s41593-026-02320-1",
  "fulltext_url": null,
  "id": "92mby1ht9kvjc",
  "issns": [
    "1097-6256",
    "1546-1726"
  ],
  "landing_url": "https://doi.org/10.1038/s41593-026-02320-1",
  "language": "en",
  "licence": "CC-BY",
  "licence_label": "CC BY",
  "licence_source": "journal",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "openalex",
      "2808|Neuroinflammation and Neurodegeneration Mechanisms"
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  "pdf_url": "https://www.nature.com/articles/s41593-026-02320-1.pdf",
  "pmcid": "PMC13433254",
  "pmid": "42362883",
  "published": "2026-06-26",
  "publisher": "Nature Portfolio",
  "ris": "https://research.draconitic.com/paper/92mby1ht9kvjc.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T13:26:53Z",
      "native_id": "W7166144197",
      "source": "openalex",
      "url": "https://doi.org/10.1038/s41593-026-02320-1"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "openalex:2808|Neuroinflammation and Neurodegeneration Mechanisms",
      "subfield": "neurology"
    }
  ],
  "title": "The mitochondrial unfolded protein response in human microglia disrupts neuronal–glial communication and promotes senescence",
  "title_text": "The mitochondrial unfolded protein response in human microglia disrupts neuronal–glial communication and promotes senescence",
  "type": "peer-reviewed",
  "updated_at": "2026-11-09T13:21:12Z",
  "url": "https://research.draconitic.com/paper/92mby1ht9kvjc",
  "venue": "Nature Neuroscience",
  "versions": []
}