Unfolded Protein Response

The mitochondrial unfolded protein response (UPRmt) is essential to safeguard mitochondria from proteotoxic damage by activating a dedicated transcriptional response in the nucleus to restore proteostasis1,2. Yet, it remains unclear how the information on mitochondria misfolding stress (MMS) is signalled to the nucleus as part of the human UPRmt (refs. 3,4). Here, we show that UPRmt signalling is driven by the release of two individual signals in the cytosol-mitochondrial reactive oxygen species (mtROS) and accumulation of mitochondrial protein precursors in the cytosol (c-mtProt). Combining proteomics and genetic approaches, we identified that MMS causes the release of mtROS into the cytosol. In parallel, MMS leads to mitochondrial protein import defects causing c-mtProt accumulation. Both signals integrate to activate the UPRmt; released mtROS oxidize the cytosolic HSP40 protein DNAJA1, which leads to enhanced recruitment of cytosolic HSP70 to c-mtProt. Consequently, HSP70 releases HSF1, which translocates to the nucleus and activates transcription of UPRmt genes. Together, we identify a highly controlled cytosolic surveillance mechanism that integrates independent mitochondrial stress signals to initiate the UPRmt. These observations reveal a link between mitochondrial and cytosolic proteostasis and provide molecular insight into UPRmt signalling in human cells.

Cellular homeostasis is intricately influenced by stimuli from the microenvironment, including signaling molecules, metabolites, and pathogens. Functioning as a signaling hub within the cell, mitochondria integrate information from various intracellular compartments to regulate cellular signaling and metabolism. Multiple studies have shown that mitochondria may respond to various extracellular signaling events. However, it is less clear how changes in the extracellular matrix (ECM) can impact mitochondrial homeostasis to regulate animal physiology. We find that ECM remodeling alters mitochondrial homeostasis in an evolutionarily conserved manner. Mechanistically, ECM remodeling triggers a TGF-β response to induce mitochondrial fission and the unfolded protein response of the mitochondria (UPRMT). At the organismal level, ECM remodeling promotes defense of animals against pathogens through enhanced mitochondrial stress responses. We postulate that this ECM-mitochondria crosstalk represents an ancient immune pathway, which detects infection- or mechanical-stress-induced ECM damage, thereby initiating adaptive mitochondria-based immune and metabolic responses.

Mitochondria and the endoplasmic reticulum (ER) have a synergistic relationship and are key regulatory hubs in maintaining cell homeostasis. Communication between these organelles is mediated by mitochondria ER contact sites (MERCS), allowing the exchange of material and information, modulating calcium homeostasis, redox signalling, lipid transfer and the regulation of mitochondrial dynamics. MERCS are dynamic structures that allow cells to respond to changes in the intracellular environment under normal homeostatic conditions, while their assembly/disassembly are affected by pathophysiological conditions such as ageing and disease. Disruption of protein folding in the ER lumen can activate the Unfolded Protein Response (UPR), promoting the remodelling of ER membranes and MERCS formation. The UPR stress receptor kinases PERK and IRE1, are located at or close to MERCS. UPR signalling can be adaptive or maladaptive, depending on whether the disruption in protein folding or ER stress is transient or sustained. Adaptive UPR signalling via MERCS can increase mitochondrial calcium import, metabolism and dynamics, while maladaptive UPR signalling can result in excessive calcium import and activation of apoptotic pathways. Targeting UPR signalling and the assembly of MERCS is an attractive therapeutic approach for a range of age-related conditions such as neurodegeneration and sarcopenia. This review highlights the emerging evidence related to the role of redox mediated UPR activation in orchestrating inter-organelle communication between the ER and mitochondria, and ultimately the determination of cell function and fate.

The endoplasmic reticulum (ER) unfolded protein response (UPR) is a conserved eukaryotic pathway crucial for restoring cellular homeostasis under ER stress. However, diverse viruses infecting mammalian or plant cells strategically hijack and manipulate the UPR pathways featuring sensor proteins IRE1, PERK, ATF6, and bZIP17/28 to promote viral replication. While UPR is designed to provide cellular adaptive functions in response to stresses, viruses can instead exploit UPR components to instead enhance viral protein folding and remodel ER membranes for viral replication. Exploiting the UPR presents a critical dilemma: while mild UPR activation facilitates virus replication and survival, excessive or prolonged activation triggers host programmed cell death (PCD), prematurely terminating infection. Navigating this UPR tightrope is central to successful infection and replication of the virus. Viruses are not passive triggers of ER stress and the UPR. Viruses have evolved sophisticated "braking mechanisms" to actively modulate UPR signaling intensity. By fine-tuning the UPR, viruses harness the beneficial aspects of the UPR while crucially preventing the activation cascade from reaching the lethal threshold that initiates PCD. By carefully controlling the UPR balance, viruses ensure host cell survival for a sufficient duration to maximize viral progeny production. This review details the intricate interactions between the cellular UPR and infecting viruses, including links to cellular clearance pathways like autophagy and ER-associated degradation (ERAD), across different viral families (flaviviruses, coronaviridae, and potyviruses) and hosts (plants and animals). Understanding the sophisticated viral manipulation of the UPR equilibrium reveals fundamental insights into host-pathogen co-evolution and highlights novel potential targets for antiviral strategies aimed at disrupting this delicate balance.