Mitochondria have developed a specialized unfolded protein response (UPRmt) to maintain proteostasis and promote recovery under stress conditions. Research in simpler organisms has demonstrated that UPRmt activation in glial cells promotes protein homeostasis through beneficial cell-nonautonomous communication to neurons. To address the role of mitochondrial stress responses in the human brain we profiled the cell-type-specific role of human UPRmt using human induced pluripotent stem cell (iPSC)-derived neurons, astrocytes and microglia. We found that UPRmt activationinduces a cell-type specific response characterized by microglial senescence.