Mitochondria have evolved a specialized mitochondrial unfolded protein response (UPRmt) to maintain protein homeostasis and promote recovery under stress. Studies in simple organisms show that activating UPRmt in glial cells supports protein homeostasis 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 used human induced pluripotent stem cell-derived neurons and glia cultures, as well as brain organoids, to study the cell-type-specific effects of mitochondrial proteotoxic stress. We show that mitochondrial proteotoxic stress triggers metabolic rewiring in human microglia, marked by depletion of S-adenosylmethionine and lipid remodeling, eventually leading to a senescence-like state. Using human neuron-glia co-cultures and microglia-containing brain organoids, we identified the specific contribution of microglia to brain aging and neurodegenerative processes driven by mitochondrial stress. Activating UPRmt disrupts microglial communication with neighboring cells, triggering inflammatory signals and impairing protein balance. Together, these findings reveal how disrupted mitochondrial protein homeostasis reshapes intercellular networks and highlight the critical role of UPRmt in the mechanisms of neurodegenerative diseases.

Reference news:

DOI: 10.1038/s41593-026-02320-1

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