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Biological Chemistry May 2020Contact sites, areas where two organelles are held in close proximity through the action of molecular tethers, enable non-vesicular communication between compartments.... (Review)
Review
Contact sites, areas where two organelles are held in close proximity through the action of molecular tethers, enable non-vesicular communication between compartments. Mitochondria have been center stage in the contact site field since the discovery of the first contact between mitochondria and the endoplasmic reticulum (ER) over 60 years ago. However, only now, in the last decade, has there been a burst of discoveries regarding contact site biology in general and mitochondrial contacts specifically. The number and types of characterized contacts increased dramatically, new molecular mechanisms enabling contact formation were discovered, additional unexpected functions for contacts were shown, and their roles in cellular and organismal physiology were emphasized. Here, we focus on mitochondria as we highlight the most recent developments, future goals and unresolved questions in the field.
Topics: Animals; Endoplasmic Reticulum; Humans; Mitochondria; Saccharomyces cerevisiae
PubMed: 32324151
DOI: 10.1515/hsz-2020-0133 -
Nature Communications Mar 2024Vertebrates transport hydrophobic triglycerides through the circulatory system by packaging them within amphipathic particles called Triglyceride-Rich Lipoproteins. Yet,...
Vertebrates transport hydrophobic triglycerides through the circulatory system by packaging them within amphipathic particles called Triglyceride-Rich Lipoproteins. Yet, it remains largely unknown how triglycerides are loaded onto these particles. Mutations in Phospholipase A2 group 12B (PLA2G12B) are known to disrupt lipoprotein homeostasis, but its mechanistic role in this process remains unclear. Here we report that PLA2G12B channels lipids within the lumen of the endoplasmic reticulum into nascent lipoproteins. This activity promotes efficient lipid secretion while preventing excess accumulation of intracellular lipids. We characterize the functional domains, subcellular localization, and interacting partners of PLA2G12B, demonstrating that PLA2G12B is calcium-dependent and tightly associated with the membrane of the endoplasmic reticulum. We also detect profound resistance to atherosclerosis in PLA2G12B mutant mice, suggesting an evolutionary tradeoff between triglyceride transport and cardiovascular disease risk. Here we identify PLA2G12B as a key driver of triglyceride incorporation into vertebrate lipoproteins.
Topics: Animals; Mice; Biological Transport; Endoplasmic Reticulum; Lipoproteins; Triglycerides
PubMed: 38453914
DOI: 10.1038/s41467-024-46102-4 -
Circulation Research May 2023
Topics: Mitochondria; Endoplasmic Reticulum; Heart; Endoplasmic Reticulum Stress; Apoptosis
PubMed: 37228240
DOI: 10.1161/CIRCRESAHA.123.322911 -
Cells Mar 2021The maintenance of cellular homeostasis involves the participation of multiple organelles. These organelles are associated in space and time, and either cooperate or... (Review)
Review
The maintenance of cellular homeostasis involves the participation of multiple organelles. These organelles are associated in space and time, and either cooperate or antagonize each other with regards to cell function. Crosstalk between organelles has become a significant topic in research over recent decades. We believe that signal transduction between organelles, especially the endoplasmic reticulum (ER) and mitochondria, is a factor that can influence the cell fate. As the cellular center for protein folding and modification, the endoplasmic reticulum can influence a range of physiological processes by regulating the quantity and quality of proteins. Mitochondria, as the cellular "energy factory," are also involved in cell death processes. Some researchers regard the ER as the sensor of cellular stress and the mitochondria as an important actuator of the stress response. The scientific community now believe that bidirectional communication between the ER and the mitochondria can influence cell death. Recent studies revealed that the death signals can shuttle between the two organelles. Mitochondria-associated membranes (MAMs) play a vital role in the complex crosstalk between the ER and mitochondria. MAMs are known to play an important role in lipid synthesis, the regulation of Ca homeostasis, the coordination of ER-mitochondrial function, and the transduction of death signals between the ER and the mitochondria. Clarifying the structure and function of MAMs will provide new concepts for studying the pathological mechanisms associated with neurodegenerative diseases, aging, and cancers. Here, we review the recent studies of the structure and function of MAMs and its roles involved in cell death, especially in apoptosis.
Topics: Animals; Apoptosis; Apoptosis Regulatory Proteins; Calcium Signaling; Endoplasmic Reticulum; Energy Metabolism; Humans; Lipogenesis; Mitochondria; Mitochondrial Membranes; Mitochondrial Proteins
PubMed: 33809551
DOI: 10.3390/cells10030657 -
Cells Jul 2020Contact sites between mitochondria and endoplasmic reticulum (ER) are points in which the two organelles are in close proximity. Due to their structural and functional... (Review)
Review
Contact sites between mitochondria and endoplasmic reticulum (ER) are points in which the two organelles are in close proximity. Due to their structural and functional complexity, their exploitation as pharmacological targets has never been considered so far. Notwithstanding, the number of compounds described to target proteins residing at these interfaces either directly or indirectly is rising. Here we provide original insight into mitochondria-ER contact sites (MERCs), with a comprehensive overview of the current MERCs pharmacology. Importantly, we discuss the considerable potential of MERCs to become a druggable target for the development of novel therapeutic strategies.
Topics: Animals; Endoplasmic Reticulum; Humans; Mitochondria; Mitochondrial Membranes
PubMed: 32646031
DOI: 10.3390/cells9071637 -
Science Advances Mar 2023Proteins destined for the secretory compartment of the cell are cotranslationally translocated into the endoplasmic reticulum. The majority of these proteins are...
Proteins destined for the secretory compartment of the cell are cotranslationally translocated into the endoplasmic reticulum. The majority of these proteins are N-glycosylated, a co- and posttranslational modification that ensures proper protein folding, stability, solubility, and cellular localization. Here, we show that the [Formula: see text] subunit of the signal recognition particle receptor (SR) is required for assembly of the N-glycosylation-competent translocon. We report that guanine analog chemical probes identified by high-throughput screening or mutation of the SR-[Formula: see text] guanosine triphosphate binding site cause an N-glycosylation-deficient phenotype. Neither method alters the association of SR-[Formula: see text] with SR-[Formula: see text], but both approaches reduce the association of SR-[Formula: see text] with the oligosaccharyltransferase complex. These experiments demonstrate that SR-[Formula: see text] has a previously unrecognized function coordinating endoplasmic reticulum translation with N-glycosylation.
Topics: Glycosylation; Receptors, Cytoplasmic and Nuclear; Endoplasmic Reticulum; Receptors, Peptide
PubMed: 36921042
DOI: 10.1126/sciadv.ade8079 -
Oxidative Medicine and Cellular... 2021The mitochondrial-associated endoplasmic reticulum membrane (MAM) is located between the outer mitochondrial membrane and the endoplasmic reticulum membrane. The MAM is... (Review)
Review
The mitochondrial-associated endoplasmic reticulum membrane (MAM) is located between the outer mitochondrial membrane and the endoplasmic reticulum membrane. The MAM is involved in a wide range of cellular functions, including calcium signaling, the division and fusion of mitochondria, endoplasmic reticulum stress, and the synthesis and transport of lipids. Recent studies have discovered that the MAM is involved in the pathogenesis of diabetic nephropathy (DN). In this article, we summarize the structure, function and role of the MAM in DN. We hope this study will provide clues and a theoretical basis for mechanistic and targeted drug research on DN.
Topics: Animals; Cell Membrane; Diabetic Nephropathies; Endoplasmic Reticulum; Humans; Mitochondria
PubMed: 34777695
DOI: 10.1155/2021/8054817 -
Nephron 2023Endoplasmic reticulum (ER) stress response is a conservative mechanism involving a complex network of different molecular branches to determine cell fate through... (Review)
Review
BACKGROUND
Endoplasmic reticulum (ER) stress response is a conservative mechanism involving a complex network of different molecular branches to determine cell fate through specific transcription factors and downstream executors. Emerging evidence shows that ER stress is implicated in the occurrence and progression of acute kidney injury (AKI) in different animal models and human patients. However, there is still a lack of therapeutics targeting the ER in AKI.
SUMMARY
Several therapeutic chemicals, including a compound that induces activating transcription factor 6 (ATF6) and chemical chaperones, have been developed to target the ER in the treatment of AKI. Meanwhile, ER stress-inducible secreted proteins, mesencephalic astrocyte-derived neurotrophic factor (MANF), and cysteine-rich with EGF-like domains 2 (CRELD2) could serve as potential ER stress biomarkers in the early diagnosis and treatment response monitoring of human patients with AKI.
KEY MESSAGES
Experimental and clinical evidence suggests the critical role of ER in the pathogenesis and progression of AKI, and ER is a novel target in AKI therapy.
Topics: Animals; Humans; Acute Kidney Injury; Endoplasmic Reticulum; Endoplasmic Reticulum Stress
PubMed: 36116429
DOI: 10.1159/000526050 -
Phytotherapy Research : PTR Jan 2022The endoplasmic reticulum (ER) is the place where proteins and lipids are biosynthesized and where transmembrane proteins are folded. Both pathological and physiological... (Review)
Review
The endoplasmic reticulum (ER) is the place where proteins and lipids are biosynthesized and where transmembrane proteins are folded. Both pathological and physiological situations may disturb the function of the ER, resulting in ER stress. Under stress conditions, the cells initiate a defensive procedure known as the unfolded protein response (UPR). Cases of severe stress lead to autophagy and/or the induction of cell apoptosis. Many studies implicate ER stress as a major factor contributing to many diseases. Therefore, the modulation of ER stress pathways has become an attractive therapeutic target. Quercetin is a plant-derived metabolite belonging to the flavonoids class which presents a range of beneficial effects including anti-inflammatory, cardioprotective, anti-oxidant, anti-obesity, anti-carcinogenic, anti-atherosclerotic, anti-diabetic, anti-hypercholesterolemic, and anti-apoptotic activities. Quercetin also has anti-cancer activity, and can be used as an adjuvant to decrease resistance to cancer chemotherapy. Furthermore, the effect of quercetin can be increased with the help of nanotechnology. This review discusses the role of quercetin in the modulation of ER stress (and related diseases) and provides novel evidence for the beneficial use of quercetin in therapy.
Topics: Apoptosis; Endoplasmic Reticulum; Endoplasmic Reticulum Stress; Quercetin; Unfolded Protein Response
PubMed: 34528309
DOI: 10.1002/ptr.7283 -
Proceedings of the National Academy of... Apr 2023Ribosomes that stall while translating cytosolic proteins are incapacitated by incomplete nascent chains, termed "arrest peptides" (APs) that are destroyed by the...
Ribosomes that stall while translating cytosolic proteins are incapacitated by incomplete nascent chains, termed "arrest peptides" (APs) that are destroyed by the ubiquitin proteasome system (UPS) via a process known as the ribosome-associated quality control (RQC) pathway. By contrast, APs on ribosomes that stall while translocating secretory proteins into the endoplasmic reticulum (ER-APs) are shielded from cytosol by the ER membrane and the tightly sealed ribosome-translocon junction (RTJ). How this junction is breached to enable access of cytosolic UPS machinery and 26S proteasomes to translocon- and ribosome-obstructing ER-APs is not known. Here, we show that UPS and RQC-dependent degradation of ER-APs strictly requires conjugation of the ubiquitin-like (Ubl) protein UFM1 to 60S ribosomal subunits at the RTJ. Therefore, UFMylation of translocon-bound 60S subunits modulates the RTJ to promote access of proteasomes and RQC machinery to ER-APs.
Topics: Ribosomes; Endoplasmic Reticulum; Ribosomal Proteins; Quality Control; Ubiquitins
PubMed: 37036982
DOI: 10.1073/pnas.2220340120