2. Academic Validation
  3. The mitochondrial unfolded protein response in human microglia disrupts neuronal-glial communication and promotes senescence

The mitochondrial unfolded protein response in human microglia disrupts neuronal-glial communication and promotes senescence

  • Nat Neurosci. 2026 Jun 26. doi: 10.1038/s41593-026-02320-1.
Maria Jose Perez J 1 2 3,  Alicia Lam 4,  Christin Weissleder 4 5,  Federico Bertoli 4 5,  Hariam Raji 4 5,  Mariella Bosch 6,  Ivan Nemazanyy 7,  Stefanie Kalb 6,  Mohammed Kehili 4,  Insa Hirschberg 6,  Dario Brunetti 8 9,  Indra Heckenbach 10,  Morten Scheibye-Knudsen 10,  Michela Deleidi 11 12
Affiliations

Affiliations

  • 1 Mechanisms and Therapy of Genetic Brain Diseases, Institut Imagine, Paris, France. [email protected].
  • 2 Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, Chevy Chase, MD, USA. [email protected].
  • 3 Max Planck Institute of Immunobiology and Epigenetics, Freiburg, Germany. [email protected].
  • 4 Mechanisms and Therapy of Genetic Brain Diseases, Institut Imagine, Paris, France.
  • 5 Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, Chevy Chase, MD, USA.
  • 6 Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.
  • 7 Platform for Metabolic Analyses, Structure Fédérative de Recherche Necker, INSERM US24/CNRS UAR 3633, Paris, France.
  • 8 Department of Clinical Sciences and Community Health, Excellence Department 2023-2027, University of Milan, Milan, Italy.
  • 9 Unit of Medical Genetics and Neurogenetics, Fondazione IRCCS Istituto Neurologico 'Carlo Besta', Milan, Italy.
  • 10 Department of Cellular and Molecular Medicine, Center for Healthy Aging, University of Copenhagen, Copenhagen, Denmark.
  • 11 Mechanisms and Therapy of Genetic Brain Diseases, Institut Imagine, Paris, France. [email protected].
  • 12 Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, Chevy Chase, MD, USA. [email protected].
PMID: 42362883 DOI: 10.1038/s41593-026-02320-1
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.

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