Fig. 2

The different mammalian UPR^mt axes. Depiction of the different UPR^mt axes that are activated upon mitochondrial protein misfolding/aggregation: (1) The canonical UPR^mt leads to altered localization and levels of CHOP, ATF4, and ATF5. These, together with other unknown transcription factors, lead to the induction of the chaperonins, chaperones, and proteases to increase the folding capacity inside mitochondria. (2) SIRT3 becomes activated as part of the UPR^mt sirtuin axis leading to the deacetylation and relocalization of FOXO3A to the nucleus, where it induces SOD2 and catalase as part of an antioxidant response. (3) Protein misfolding in the intermembrane space activates the UPR^IMS–ERα axis, which acts via AKT and ROS-dependent phosphorylation of ERα, causing induction of NRF1. This in turn leads to increased protease levels, modulation of respiration levels, and enhanced proteasome activity to increase the protein quality control capacity. (4) The UPR^mt translation axis is a local response, largely independent of transcriptional effects in the nucleus. Protein unfolding in the matrix causes the rapid degradation of components of the pre-RNA processing machinery and a shutdown of mitochondrial translation to decrease the mitochondrial folding load