Mitochondrial unfolded protein response (UPRmt) (UPRmt)

The mitochondrial unfolded protein response (UPRmt) is a conserved stress response pathway that detects proteotoxic stress within mitochondria and induces transcriptional activation of nuclear-encoded genes, including chaperones like HSP60 and proteases such as CLPP and LONP1, to restore mitochondrial protein homeostasis. In mammals, UPRmt signaling intersects closely with the integrated stress response (ISR), where mitochondrial dysfunction activates eIF2α kinases including HRI, GCN2, and PERK via pathways like OMA1-DELE1, leading to ATF4-mediated expression of proteostasis factors and metabolic adaptations. This response promotes recovery from stressors like impaired respiration or protein misfolding by increasing chaperone capacity and reducing protein synthesis load, while severe or chronic activation can trigger apoptosis. Dysregulation of UPRmt and ISR contributes to mitochondrial diseases and neurodegeneration by failing to adapt to proteostasis imbalances. Although implicated in pathology, no approved drugs directly target UPRmt, and therapeutic modulation remains exploratory, with ISR inhibitors showing potential in preclinical models of mitochondrial disorders.

Other names

Mitochondrial integrated stress response (mtISR)Mitochondrial stress response (MSR)