Mitochondrial stress response drives microglial senescence

Nature Neuroscience, Published online: 26 June 2026; doi:10.1038/s41593-026-02264-6

The mitochondrial unfolded protein response (UPRmt) drives microglial senescence and disrupts essential glia–neuron communication. By triggering lipid droplet accumulation and dysregulating the S-adenosylmethionine–polyamine axis, UPRmt fuels the senescence-associated secretory pathway, impairs synaptic pruning and accelerates misfolded protein pathology. In this issue of Nature Neuroscience, Perez et al. identify UPRmt as a primary driver of metabolic vulnerability in human microglia.