The different axes of the mammalian mitochondrial unfolded protein response

Abstract

Mitochondria are sensitive to numerous environmental stresses, which can lead to activation of mitochondrial stress responses (MSRs). Of particular recent interest has been the mitochondrial unfolded protein response (UPR^mt), activated to restore protein homeostasis (proteostasis) upon mitochondrial protein misfolding. Several axes of the UPR^mt have been described, creating some confusion as to the nature of the different responses. While distinct molecularly, these different axes are likely mutually beneficial and activated in parallel. This review aims at describing and distinguishing the different mammalian MSR/UPR^mt axes to define key processes and members and to examine the involvement of protein misfolding.

Fig. 1

Folding stress responses. Protein misfolding activates transient, pro-survival stress responses that increase the folding capacity (i.e., modulation of chaperone and protease levels) and decrease the folding load (i.e., decrease in translation) to restore proteostasis. Responses typically last several hours. Prolonged stress activation that cannot alleviate the stress causes alternative outcomes, including cell death. Pharmacological induction of protein misfolding allows the study of the acute response to protein misfolding. Chronic activation of the stress, as observed upon genomic modulation or in disease, leads to the activation of alternative pathways and potentially cell death

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

Fig. 3

Integration of mitochondrial misfolding stress and different UPR^mt axes. Cells contain numerous mitochondria with a certain, low percentage stressed upon basal conditions, due to aging and metabolic damage. Dealing with these refined incidents of mitochondrial proteostasis defects, which are not due to significant environmental perturbation, requires spatially defined responses. The UPR^mt translational response acts via local, posttranslational regulation of MRPP3 levels and can decrease translation, and thus folding load, in an individual mitochondrion. Thus, it acts locally as a first response to mitochondrial protein misfolding in few damaged mitochondria without causing global effects. The transcriptional UPR^mt effects occur cell-wide and likely require passing a certain threshold of mitochondrial proteostasis defects. This suggests a model in which mitochondrion-specific UPR^mt effects (i.e., the UPR^mt translation axis) are activated upon cellular conditions with a certain low percentage of mitochondria suffering from protein misfolding and activation of the cell-wide UPR^mt axes upon proteostasis defects in a large percentage of mitochondria

Fig. 4

Mitochondrial stress responses. Various mitochondrial stresses, not directly linked to mitochondrial protein misfolding, elicit stress responses that are similar to the UPR^mt retrograde signaling and involve the integrated stress response (ISR). These stresses affect important aspects of mitochondria, such as respiration, translation, and mtDNA replication and are distinct from the UPR^mt transcriptional responses. Recent findings suggest a specific mitochondrial ISR that shares common factors with the ISR but driven by different signaling pathways and eliciting alternative outputs