The mitochondrial unfolded protein response promotes senescence in human microglia by increasing S-adenosylmethionine availability for polyamine synthesis.

Mitochondria have developed a specialized mitochondrial unfolded protein response (UPRmt) to maintain proteostasis and promote recovery under stress conditions. Research in simple organisms has demonstrated that UPRmt activation in glial cells promotes 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 knowledge gap, we profiled the cell type-specific roles of the UPRmt using human induced pluripotent stem cell-derived neuronal and glial cultures and brain organoids. We found that UPRmt activation induces metabolic rewiring in human microglia, resulting in a senescence phenotype mediated by S-adenosylmethionine availability for polyamine synthesis. Additionally, UPRmt disrupted microglial intercellular communication, leading to microglia-mediated dysfunction of phagocytic pathways and increased inflammatory signaling. Using microglia-brain-assembloids, we observed distinct contributions by microglia to brain senescence and neurodegenerative disease processes driven by mitochondrial stress responses. These findings underscore the profound impact of defects in mitochondrial proteostasis on intercellular networks during brain aging and disease.