Mitochondrial UPR (mtUPR)

The mitochondrial unfolded protein response (mtUPR) is a stress-signalling pathway activated when the capacity of mitochondrial chaperones — including HSP60, HSP70 and the AAA+ protease ClpP — is overwhelmed by misfolded or aggregated proteins within the mitochondrial matrix. In Caenorhabditis elegans, mtUPR is mediated by the transcription factor ATFS-1, which under stress traffics to the nucleus rather than being imported into mitochondria; in mammals, the homologous pathway involves ATF5 along with other transcription factors including ATF4 and CHOP. Activation of the mtUPR upregulates mitochondrial chaperones, proteases and metabolic genes to restore organelle homeostasis, and its induction by interventions such as NAD+ precursors and mild mitochondrial stress has been linked to lifespan extension in model organisms, though the translation to mammals is not fully established.