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Updated: Jun 28, 2026

Mitochondrial Preparation from Microglia for Glycan Analysis
06:40

Mitochondrial Preparation from Microglia for Glycan Analysis

Published on: May 30, 2025

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

Maria Jose Perez J1,2,3, Alicia Lam4, Christin Weissleder4,5

  • 1Mechanisms and Therapy of Genetic Brain Diseases, Institut Imagine, Paris, France. perezm@ie-freiburg.mpg.de.

Nature Neuroscience
|June 26, 2026
PubMed

Insights

Mitochondrial stress in human microglia causes senescence and inflammation, disrupting communication with neurons. This mitochondrial unfolded protein response (UPRmt) plays a key role in neurodegenerative disease pathogenesis.

Area of Science:

  • Neuroscience
  • Cell Biology
  • Mitochondrial Biology

Background:

  • Mitochondria possess a specialized mitochondrial unfolded protein response (UPRmt) crucial for maintaining cellular proteostasis under stress.
  • In simpler organisms, UPRmt in glial cells aids neuronal proteostasis via non-cell-autonomous communication.
  • The function of mitochondrial stress responses in the human brain is not well understood.

Purpose of the Study:

  • To investigate the cell-type-specific impacts of mitochondrial proteotoxic stress in the human brain.
  • To elucidate the role of microglia in human brain senescence and neurodegeneration driven by mitochondrial stress.

Main Methods:

  • Utilized human induced pluripotent stem cell-derived neuronal and glial cultures.
  • Employed human brain organoids, including those containing microglia.
  • Established human neuronal-glial tricultures to model intercellular interactions.

Main Results:

  • Mitochondrial proteotoxic stress induced metabolic rewiring in human microglia, characterized by S-adenosylmethionine depletion and lipid remodeling, leading to senescence.
  • Microglia were identified as key contributors to brain senescence and mitochondrial stress-induced neurodegenerative processes.
  • UPRmt activation disrupted microglial intercellular communication, initiating inflammatory signaling and impairing proteostasis.

Conclusions:

  • Impaired mitochondrial proteostasis alters intercellular communication networks within the brain.
  • The UPRmt plays a critical role in the pathogenesis of neurodegenerative diseases.
  • Microglial dysfunction driven by mitochondrial stress contributes to brain aging and neurodegeneration.

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