The mitochondrial unfolded protein response (UPR) is a cellular stress response related to the mitochondria. The UPR results from unfolded or misfolded proteins in mitochondria beyond the capacity of chaperone proteins to handle them. The UPR can occur either in the mitochondrial matrix or in the mitochondrial inner membrane. In the UPR, the mitochondrion will either upregulate chaperone proteins or invoke proteases to degrade proteins that fail to fold properly. UPR causes the sirtuin SIRT3 to activate antioxidant enzymes and mitophagy.
Mitochondrial electron transport chain mutations that extend the life span of Caenorhabditis elegans (nematode worms) also activate the UPR. Activation of the UPR in nematode worms by increasing NAD+ by supplementation with nicotinamide or nicotinamide riboside has been shown to extend lifespan. Glial and germline mitochondria has been found to play a significant role in the signalling and regulation of UPR have been shown to play a central role Nicotinamide riboside supplementation in mice has also been shown to activate the UPR.