a, Rapamycin (1nM) extends worm lifespan in a ubl-5-dependent manner, and b,
ubl-5-dependently induced UPRmt (hsp-6::GFP) but not UPRER (hsp-4::GFP) (n=4). c–e, Rapamycin increased respiration (c, n=10) and ATP content but not citrate synthase activity (d, n=3) and induced mitonuclear protein imbalance (e). f–h, In mouse hepatocytes, rapamycin induces mitonuclear protein imbalance (f–g) and induces UPRmt as shown at the protein (f–g, n=3), and transcriptional (h, n=8) level. i, Resveratrol (25 μM) induced mitonuclear protein imbalance in mouse hepatocytes (n=4). j, Hypothetical scheme of the mechanism by which reduced Mrp expression (during aging or genetic inactivation), specific antibiotics, ethidium bromide and rapamycin and resveratrol extend lifespan by inducing UPRmt. Bar graphs are expressed as mean±SEM, * p≤0.05; *** p≤0.001. See also Supplementary Table 2.