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<p>Mitochondria have evolved a specialized mitochondrial unfolded protein response (UPR<sup>mt</sup>) to maintain proteostasis and promote recovery under stress. Studies in simple organisms have shown that UPR<sup>mt</sup> 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<sup>mt</sup> 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<sup>mt</sup> in neurodegenerative disease pathogenesis.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年6月26日

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  • Maria Jose Perez J,
  • Alicia Lam,
  • Christin Weissleder,
  • Federico Bertoli,
  • Hariam Raji,
  • Mariella Bosch,
  • Ivan Nemazanyy,
  • Stefanie Kalb,
  • Mohammed Kehili,
  • Insa Hirschberg,
  • Dario Brunetti,
  • Indra Heckenbach,
  • Morten Scheibye-Knudsen,
  • Michela Deleidi

摘要

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.