Mitochondrial Unfolded Protein Response and Integrated Stress Response as Promising Therapeutic Targets for Mitochondrial Diseases

Abstract

The development and application of high-throughput omics technologies have enabled a more in-depth understanding of mitochondrial biosynthesis metabolism and the pathogenesis of mitochondrial diseases. In accordance with this, a host of new treatments for mitochondrial disease are emerging. As an essential pathway in maintaining mitochondrial proteostasis, the mitochondrial unfolded protein response (UPR^mt) is not only of considerable significance for mitochondrial substance metabolism but also plays a fundamental role in the development of mitochondrial diseases. Furthermore, in mammals, the integrated stress response (ISR) and UPR^mt are strongly coupled, functioning together to maintain mitochondrial function. Therefore, ISR and UPR^mt show great application prospects in the treatment of mitochondrial diseases. In this review, we provide an overview of the molecular mechanisms of ISR and UPR^mt and focus on them as potential targets for mitochondrial disease therapy.

Keywords: integrated stress response; mitochondrial diseases; mitochondrial function; mitochondrial unfolded protein response.

Figure 1

Activation of the mitochondrial unfolded protein response in C. elegans. Under normal conditions, ATFS-1 is brought into the mitochondria and undergoes disassembly due to the action of LONP-1. However, when ATFS-1 transport is blocked in cases such as homeostasis disturbance, hypoxia, and ETC dysfunction, it accumulates in the perinuclear region and causes activation of the UPRmt. Unfolded proteins are subsequently broken down into polypeptides by CLPP in the mitochondria and then transported out of the mitochondria by the HAF1 transporter to activate the UBL5 and DEV1 transcriptional complex factors. Under stress situations, UPRmt is activated as a result of UBL5 and DEV1 redistribution and chromatin reorganization, which is the consequence of LIN65 translocation from the cytoplasm to the perinuclear area due to MET2 action. Activation of the UPRmt produces a series of biological changes toward restoring mitochondrial function.

Figure 2

Relationship between UPR^mt and ISR and activation process in mammals. (A) Four kinases, GCN2, PERK, HRI, and PKR, regulate ISR activation, and two other specialized phosphatases antagonize the ISR. The ISR controls protein translation mainly through the TC. (B) Mitochondrial dysfunction induces intracellular stress response mainly through GCN2 and HRI. First, activation of the Oma1 endosomal protein results in conversion of DELEL into DELES. Then, the phosphorylation of eIF-2α serine residues by HRI leads to a series of adaptive metabolic changes that promote the recovery of mitochondrial function and increase the expressions of key UPR^mt regulators such as ATF4, ATF5, and CHOP. Second, mitochondrial dysfunction reduces cytoplasmic aspartate and asparagine, which promotes GCN2-induced phosphorylation and, thus, causes corresponding metabolic changes. The activated UPR^mt plays a role in maintaining protein homeostasis in mitochondria to enhance mitochondrial function. The UPR^mt also causes a mild increase in phosphorylation levels.