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Molecular Cell Aug 2022Protein import into mitochondria is a highly regulated process, yet how cells clear mitochondria undergoing dysfunctional protein import remains poorly characterized....
Protein import into mitochondria is a highly regulated process, yet how cells clear mitochondria undergoing dysfunctional protein import remains poorly characterized. Here we showed that mitochondrial protein import stress (MPIS) triggers localized LC3 lipidation. This arm of the mitophagy pathway occurs through the Nod-like receptor (NLR) protein NLRX1 while, surprisingly, without the engagement of the canonical mitophagy protein PINK1. Mitochondrial depolarization, which itself induces MPIS, also required NLRX1 for LC3 lipidation. While normally targeted to the mitochondrial matrix, cytosol-retained NLRX1 recruited RRBP1, a ribosome-binding transmembrane protein of the endoplasmic reticulum, which relocated to the mitochondrial vicinity during MPIS, and the NLRX1/RRBP1 complex in turn controlled the recruitment and lipidation of LC3. Furthermore, NLRX1 controlled skeletal muscle mitophagy in vivo and regulated endurance capacity during exercise. Thus, localization and lipidation of LC3 at the site of mitophagosome formation is a regulated step of mitophagy controlled by NLRX1/RRBP1 in response to MPIS.
Topics: Endoplasmic Reticulum; Mitochondria; Mitochondrial Proteins; Mitophagy; Protein Transport
PubMed: 35752171
DOI: 10.1016/j.molcel.2022.06.004 -
Circulation Research May 2023
Topics: Mitochondria; Endoplasmic Reticulum; Heart; Endoplasmic Reticulum Stress; Apoptosis
PubMed: 37228240
DOI: 10.1161/CIRCRESAHA.123.322911 -
The FEBS Journal Jan 2020The endoplasmic reticulum (ER) is a multifunctional organelle that constitutes the entry into the secretory pathway. The ER contributes to the maintenance of cellular... (Review)
Review
The endoplasmic reticulum (ER) is a multifunctional organelle that constitutes the entry into the secretory pathway. The ER contributes to the maintenance of cellular calcium homeostasis, lipid synthesis and productive secretory, and transmembrane protein folding. Physiological, chemical, and pathological factors that compromise ER homeostasis lead to endoplasmic reticulum stress (ER stress). To cope with this situation, cells activate an adaptive signaling pathway termed the unfolded protein response (UPR) that aims at restoring ER homeostasis. The UPR is transduced through post-translational, translational, post-transcriptional, and transcriptional mechanisms initiated by three ER-resident sensors, inositol-requiring protein 1α, activating transcription factor 6α, and PRKR-like endoplasmic reticulum kinase. Determining the in and out of ER homeostasis control and UPR activation still represents a challenge for the community. Hence, standardized criteria and methodologies need to be proposed for monitoring ER homeostasis and ER stress in different model systems. Here, we summarize the pathways that are activated during ER stress and provide approaches aimed at assess ER homeostasis and stress in vitro and in vivo mammalian systems that can be used by researchers to plan and interpret experiments. We recommend the use of multiple assays to verify ER stress because no individual assay is guaranteed to be the most appropriate one.
Topics: Animals; Endoplasmic Reticulum; Endoplasmic Reticulum Stress; Homeostasis; Humans; Signal Transduction; Unfolded Protein Response
PubMed: 31647176
DOI: 10.1111/febs.15107 -
IUBMB Life May 2014Endoplasmic reticulum (ER) is an essential sub-cellular compartment of the eukaryotic cell performing many diverse functions essential for the cell and the whole... (Review)
Review
Endoplasmic reticulum (ER) is an essential sub-cellular compartment of the eukaryotic cell performing many diverse functions essential for the cell and the whole organism. ER molecular chaperones and folding enzymes are multidomain proteins that are designed to support nascent proteins entering ER lumen to achieve their native conformation, mediate post-translational modification, prevent misfolded protein aggregation, and facilitate exit from the ER. Typically the role of ER chaperones expands beyond protein folding. Here, we illustrate the multifunctional nature of many ER associated molecular chaperones and folding enzymes and unique functional overlap of these proteins all designed to support the many functions of the ER membrane.
Topics: Animals; Calcium Signaling; Cystine; Endoplasmic Reticulum; Endoplasmic Reticulum Stress; Humans; Molecular Chaperones; Protein Folding; Unfolded Protein Response
PubMed: 24839203
DOI: 10.1002/iub.1272 -
The Journal of Physiology Jun 2016Endoplasmic reticulum (ER)-plasma membrane (PM) junctions are contact sites between the ER and the PM; the distance between the two organelles in the junctions is below... (Review)
Review
Endoplasmic reticulum (ER)-plasma membrane (PM) junctions are contact sites between the ER and the PM; the distance between the two organelles in the junctions is below 40 nm and the membranes are connected by protein tethers. A number of molecular tools and technical approaches have been recently developed to visualise, modify and characterise properties of ER-PM junctions. The junctions serve as the platforms for lipid exchange between the organelles and for cell signalling, notably Ca(2+) and cAMP signalling. Vice versa, signalling events regulate the development and properties of the junctions. Two Ca(2+) -dependent mechanisms of de novo formation of ER-PM junctions have been recently described and characterised. The junction-forming proteins and lipids are currently the focus of vigorous investigation. Junctions can be relatively short-lived and simple structures, forming and dissolving on the time scale of a few minutes. However, complex, sophisticated and multifunctional ER-PM junctions, capable of attracting numerous protein residents and other cellular organelles, have been described in some cell types. The road from simplicity to complexity, i.e. the transformation from simple 'nascent' ER-PM junctions to advanced stable multiorganellar complexes, is likely to become an attractive research avenue for current and future junctologists. Another area of considerable research interest is the downstream cellular processes that can be activated by specific local signalling events in the ER-PM junctions. Studies of the cell physiology and indeed pathophysiology of ER-PM junctions have already produced some surprising discoveries, likely to expand with advances in our understanding of these remarkable organellar contact sites.
Topics: Animals; Cell Membrane; Endoplasmic Reticulum; Humans; Intercellular Junctions
PubMed: 26939537
DOI: 10.1113/JP271142 -
FEBS Letters Sep 2019The synthesis, quality control, and trafficking of a third of the eukaryotic proteome takes place at the endoplasmic reticulum (ER), which is the largest cellular... (Review)
Review
The synthesis, quality control, and trafficking of a third of the eukaryotic proteome takes place at the endoplasmic reticulum (ER), which is the largest cellular organelle. Thus, biosynthetic trafficking from the ER, although constitutive, has to be tightly controlled. Increasing evidence indicates that the ER acts as a platform that initiates signaling events. In this review, we focus on signaling pathways that target components of the ER export machinery to regulate protein export. In addition, we discuss how signaling generated at the ER regulates various homeostatic cellular processes such as cell growth and proliferation, and how the deregulation thereof is involved in disease.
Topics: Animals; Endoplasmic Reticulum; Humans; Mutation; Signal Transduction
PubMed: 31381144
DOI: 10.1002/1873-3468.13569 -
Experimental Diabetes Research 2012The endoplasmic reticulum (ER) is an organelle entrusted with lipid synthesis, calcium homeostasis, protein folding, and maturation. Perturbation of ER-associated... (Review)
Review
The endoplasmic reticulum (ER) is an organelle entrusted with lipid synthesis, calcium homeostasis, protein folding, and maturation. Perturbation of ER-associated functions results in an evolutionarily conserved cell stress response, the unfolded protein response (UPR) that is also called ER stress. ER stress is aimed initially at compensating for damage but can eventually trigger cell death if ER stress is excessive or prolonged. Now the ER stress has been associated with numerous diseases. For instance, our recent studies have demonstrated the important role of ER stress in diabetes-induced cardiac cell death. It is known that apoptosis has been considered to play a critical role in diabetic cardiomyopathy. Therefore, this paper will summarize the information from the literature and our own studies to focus on the pathological role of ER stress in the development of diabetic cardiomyopathy. Improved understanding of the molecular mechanisms underlying UPR activation and ER-initiated apoptosis in diabetic cardiomyopathy will provide us with new targets for drug discovery and therapeutic intervention.
Topics: Animals; Diabetic Cardiomyopathies; Endoplasmic Reticulum; Endoplasmic Reticulum Stress; Heart; Homeostasis; Humans; Models, Biological; Myocardium; Unfolded Protein Response
PubMed: 22144992
DOI: 10.1155/2012/827971 -
Frontiers in Immunology 2022Neuronal cells are specialists for rapid transfer and translation of information. Their electrical properties relay on a precise regulation of ion levels while their... (Review)
Review
Neuronal cells are specialists for rapid transfer and translation of information. Their electrical properties relay on a precise regulation of ion levels while their communication neurotransmitters and neuropeptides depends on a high protein and lipid turnover. The endoplasmic Reticulum (ER) is fundamental to provide these necessary requirements for optimal neuronal function. Accumulation of misfolded proteins in the ER lumen, reactive oxygen species and exogenous stimulants like infections, chemical irritants and mechanical harm can induce ER stress, often followed by an ER stress response to reinstate cellular homeostasis. Imbedded between glial-, endothelial-, stromal-, and immune cells neurons are constantly in communication and influenced by their local environment. In this review, we discuss concepts of tissue homeostasis and innate immunity in the central and peripheral nervous system with a focus on its influence on ER stress, the unfolded protein response, and implications for health and disease.
Topics: Endoplasmic Reticulum; Endoplasmic Reticulum Stress; Homeostasis; Neurons; Unfolded Protein Response
PubMed: 35572517
DOI: 10.3389/fimmu.2022.859703 -
Antioxidants & Redox Signaling Jun 2014Understanding isoform- and context-specific subcellular Nox reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase compartmentalization allows relevant... (Review)
Review
SIGNIFICANCE
Understanding isoform- and context-specific subcellular Nox reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase compartmentalization allows relevant functional inferences. This review addresses the interplay between Nox NADPH oxidases and the endoplasmic reticulum (ER), an increasingly evident player in redox pathophysiology given its role in redox protein folding and stress responses.
RECENT ADVANCES
Catalytic/regulatory transmembrane subunits are synthesized in the ER and their processing includes folding, N-glycosylation, heme insertion, p22phox heterodimerization, as shown for phagocyte Nox2. Dual oxidase (Duox) maturation also involves the regulation by ER-resident Duoxa2. The ER is the activation site for some isoforms, typically Nox4, but potentially other isoforms. Such location influences redox/Nox-mediated calcium signaling regulation via ER targets, such as sarcoendoplasmic reticulum calcium ATPase (SERCA). Growing evidence suggests that Noxes are integral signaling elements of the unfolded protein response during ER stress, with Nox4 playing a dual prosurvival/proapoptotic role in this setting, whereas Nox2 enhances proapoptotic signaling. ER chaperones such as protein disulfide isomerase (PDI) closely interact with Noxes. PDI supports growth factor-dependent Nox1 activation and mRNA expression, as well as migration in smooth muscle cells, and PDI overexpression induces acute spontaneous Nox activation.
CRITICAL ISSUES
Mechanisms of PDI effects include possible support of complex formation and RhoGTPase activation. In phagocytes, PDI supports phagocytosis, Nox activation, and redox-dependent interactions with p47phox. Together, the results implicate PDI as possible Nox organizer.
FUTURE DIRECTIONS
We propose that convergence between Noxes and ER may have evolutive roots given ER-related functional contexts, which paved Nox evolution, namely calcium signaling and pathogen killing. Overall, the interplay between Noxes and the ER may provide relevant insights in Nox-related (patho)physiology.
Topics: Animals; Endoplasmic Reticulum; Endoplasmic Reticulum Stress; Humans; NADPH Oxidases; Oxidative Stress; Protein Folding; Reactive Oxygen Species; Signal Transduction
PubMed: 24386930
DOI: 10.1089/ars.2013.5605 -
Cold Spring Harbor Perspectives in... Aug 2012In a complex multicellular organism, different cell types engage in specialist functions, and as a result, the secretory output of cells and tissues varies widely.... (Review)
Review
In a complex multicellular organism, different cell types engage in specialist functions, and as a result, the secretory output of cells and tissues varies widely. Whereas some quiescent cell types secrete minor amounts of proteins, tissues like the pancreas, producing insulin and other hormones, and mature B cells, producing antibodies, place a great demand on their endoplasmic reticulum (ER). Our understanding of how protein secretion in general is controlled in the ER is now quite sophisticated. However, there remain gaps in our knowledge, particularly when applying insight gained from model systems to the more complex situations found in vivo. This article describes recent advances in our understanding of the ER and its role in preparing proteins for secretion, with an emphasis on glycoprotein quality control and pathways of disulfide bond formation.
Topics: Calnexin; Calreticulin; Disulfides; Endoplasmic Reticulum; Glycoproteins; Glycosylation; Models, Biological; Protein Binding; Protein Biosynthesis; Protein Transport
PubMed: 22700933
DOI: 10.1101/cshperspect.a012872