The mitochondrial unfolded protein response, a conserved stress response pathway with implications in health and disease

Abstract

The ability to respond to various intracellular and/or extracellular stresses allows the organism to adapt to changing environmental conditions and drives evolution. It is now well accepted that a progressive decline of the efficiency of stress response pathways occurs with aging. In this context, a correct proteostasis is essential for the functionality of the cell, and its dysfunction has been associated with protein aggregation and age-related degenerative diseases. Complex response mechanisms have evolved to deal with unfolded protein stress in different subcellular compartments and their moderate activation translates into positive effects on health. In this review, we focus on the mitochondrial unfolded protein response (UPR(mt)), a response to proteotoxic stress specifically in mitochondria, an organelle with a wide array of fundamental functions, most notably the harvesting of energy from food and the control of cell death. We compare UPR(mt) with the extensively characterized cytosolic heat shock response (HSR) and the unfolded protein response in endoplasmic reticulum (UPR(ER)), and discuss the current knowledge about UPR(mt) signaling pathways as well as their potential involvement in physiology.

Keywords: Aging; Chaperones; Mitochondria; Proteostasis; Signaling.

Fig. 1.

Overview of the mitochondrial unfolded protein response (UPR^mt) signaling in Caenorhabditis elegans. Chaperones heat shock protein (HSP)-6, HSP-60 and the protease CLPP-1 perform protein quality control in the mitochondria. When unfolded, misfolded or unassembled proteins accumulate in the matrix, CLPP-1 cleaves the proteins into short peptides, which are exported by the transporter HAF-1 into the cytoplasm and thereby inhibit mitochondrial protein import. As a result, the transcription factor ATFS-1 cannot be imported into mitochondria for degradation, and therefore translocates to the nucleus, where, presumably in a complex with small ubiquitin-like protein UBL-5 and homeodomain-containing transcription factor DVE-1, it activates the transcription of stress response genes, which reconstitute mitochondrial homeostasis. In a complementary pathway, reactive oxygen species (ROS), generated by oxidative phosphorylation (OXPHOS) complexes (I–V) under stress, activate GCN-2 kinase, which inhibits cytosolic protein translation by phosphorylation of eukaryotic translation initiation factor 2α (eIF2α), thus reducing the protein-folding load in the mitochondria. TIM, translocase of inner membrane complex; TOM, translocase of outer membrane complex; NLS, nuclear localization/export sequence; MTS, mitochondrial targeting sequence; mt, mitochondria.

Fig. 2.

Overview of the mitochondrial matrix UPR^mt in mammals. Upon mitochondrial stress, c-Jun N-terminal kinase (JNK)2 and dsRNA-activated protein kinase (PKR) contribute to the activation of transcription factor c-Jun, which binds to AP-1 elements and activates transcription of the transcription factors CHOP and C/EBPβ. Dimers of CHOP and C/EBPβ then bind to the CHOP element on the promoter of UPR^mt genes that encode mitochondrial protein quality control proteins, such as HSP60 and ClpP, and mitochondrial import components. Two other conserved elements in promoters of UPR^mt response genes, MURE1 and MURE2, are presumably bound by factors that have not yet been identified. PKR inhibits cytosolic protein translation by mediating phosphorylation of eIF2α.

Fig. 3.

Overview of the response to unfolded proteins in the intermembrane space (IMS) in mammals. ROS, produced by stressed mitochondria, activate protein kinase B (AKT), which consequently phosphorylates estrogen receptor α (ERα). Activated ERα then induces IMS protein quality control by increasing the activity of proteasome 26S and inducing the transcription of IMS protease HTRA2 and mitochondrial regulator NRF1.