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International Journal of Biological... 2023Diabetic kidney disease (DKD) is a global health issue that presents a complex pathogenesis and limited treatment options. To provide guidance for precise therapies, it... (Review)
Review
Diabetic kidney disease (DKD) is a global health issue that presents a complex pathogenesis and limited treatment options. To provide guidance for precise therapies, it is crucial to accurately identify the pathogenesis of DKD. Several studies have recognized that mitochondrial and endoplasmic reticulum (ER) dysfunction are key drivers of the pathogenesis of DKD. The mitochondria-associated ER membrane (MAM) is a dynamic membrane contact site (MSC) that connects the ER and mitochondria and is essential in maintaining the normal function of the two organelles. MAM is involved in various cellular processes, including lipid synthesis and transport, calcium homeostasis, mitochondrial fusion and fission, and ER stress. Meanwhile, recent studies confirm that MAM plays a significant role in the pathogenesis of DKD by regulating glucose metabolism, lipid metabolism, inflammation, ER stress, mitochondrial fission and fusion, and autophagy. Herein, this review aims to provide a comprehensive summary of the physiological function of MAMs and their impact on the progression of DKD. Subsequently, we discuss the trend of pharmaceutical studies that target MAM resident proteins for treating DKD. Furthermore, we also explore the future development prospects of MAM in DKD research, thereby providing a new perspective for basic studies and clinical treatment of DKD.
Topics: Humans; Diabetic Nephropathies; Mitochondrial Membranes; Endoplasmic Reticulum; Mitochondria; Inflammation; Endoplasmic Reticulum Stress; Diabetes Mellitus
PubMed: 37781026
DOI: 10.7150/ijbs.86608 -
Experimental & Molecular Medicine Feb 2024Dynamic interactions between organelles are responsible for a variety of intercellular functions, and the endoplasmic reticulum (ER)-mitochondrial axis is recognized as... (Review)
Review
Dynamic interactions between organelles are responsible for a variety of intercellular functions, and the endoplasmic reticulum (ER)-mitochondrial axis is recognized as a representative interorganelle system. Several studies have confirmed that most proteins in the physically tethered sites between the ER and mitochondria, called mitochondria-associated ER membranes (MAMs), are vital for intracellular physiology. MAM proteins are involved in the regulation of calcium homeostasis, lipid metabolism, and mitochondrial dynamics and are associated with processes related to intracellular stress conditions, such as oxidative stress and unfolded protein responses. Accumulating evidence has shown that, owing to their extensive involvement in cellular homeostasis, alterations in the ER-mitochondrial axis are one of the etiological factors of tumors. An in-depth understanding of MAM proteins and their impact on cell physiology, particularly in cancers, may help elucidate their potential as diagnostic and therapeutic targets for cancers. For example, the modulation of MAM proteins is utilized not only to target diverse intracellular signaling pathways within cancer cells but also to increase the sensitivity of cancer cells to anticancer reagents and regulate immune cell activities. Therefore, the current review summarizes and discusses recent advances in research on the functional roles of MAM proteins and their characteristics in cancers from a diagnostic perspective. Additionally, this review provides insights into diverse therapeutic strategies that target MAM proteins in various cancer types.
Topics: Humans; Mitochondrial Membranes; Mitochondria; Endoplasmic Reticulum; Neoplasms; Unfolded Protein Response; Endoplasmic Reticulum Stress
PubMed: 38172597
DOI: 10.1038/s12276-023-01137-3 -
Advanced Science (Weinheim,... Oct 2023The lethality and chemotherapy resistance of pancreatic cancer necessitates the urgent development of innovative strategies to improve patient outcomes. To address this...
Sonodynamic Therapy of NRP2 Monoclonal Antibody-Guided MOFs@COF Targeted Disruption of Mitochondrial and Endoplasmic Reticulum Homeostasis to Induce Autophagy-Dependent Ferroptosis.
The lethality and chemotherapy resistance of pancreatic cancer necessitates the urgent development of innovative strategies to improve patient outcomes. To address this issue, we designed a novel drug delivery system named GDMCN2,which uses iron-based metal organic framework (Fe-MOF) nanocages encased in a covalent organic framework (COF) and modified with the pancreatic cancer-specific antibody, NRP2. After being targeted into tumor cells, GDMCN2 gradually release the sonosensitizer sinoporphyrin sodium (DVDMS) and chemotherapeutic gemcitabine (GEM) and simultaneously generated reactive oxygen species (ROS) under ultrasound (US) irradiation. This system can overcome gemcitabine resistance in pancreatic cancer and reduce its toxicity to non-targeted cells and tissues. In a mechanistic cascade, the release of ROS activates the mitochondrial transition pore (MPTP), leading to the release of Ca and induction of endoplasmic reticulum (ER) stress. Therefore, microtubule-associated protein 1A/1B-light chain 3 (LC3) is activated, promoting lysosomal autophagy. This process also induces autophagy-dependent ferroptosis, aided by the upregulation of Nuclear Receptor Coactivator 4 (NCOA4). This mechanism increases the sensitivity of pancreatic cancer cells to chemotherapeutic drugs and increases mitochondrial and DNA damage. The findings demonstrate the potential of GDMCN2 nanocages as a new avenue for the development of cancer therapeutics.
Topics: Humans; Metal-Organic Frameworks; Cell Line, Tumor; Reactive Oxygen Species; Ferroptosis; Apoptosis; Antibodies, Monoclonal; Autophagy; Gemcitabine; Pancreatic Neoplasms; Endoplasmic Reticulum
PubMed: 37661565
DOI: 10.1002/advs.202303872 -
Cell Stress & Chaperones Sep 2023Conditions that cause proteotoxicity like high temperature trigger the activation of unfolded protein response (UPR). The cytosolic (CPR) and endoplasmic reticulum (ER)...
Conditions that cause proteotoxicity like high temperature trigger the activation of unfolded protein response (UPR). The cytosolic (CPR) and endoplasmic reticulum (ER) UPR rely on heat stress transcription factor (HSF) and two members of the basic leucine zipper (bZIP) gene family, respectively. In tomato, HsfA1a is the master regulator of CPR. Here, we identified the core players of tomato ER-UPR including the two central transcriptional regulators, namely bZIP28 and bZIP60. Interestingly, the induction of ER-UPR genes and the activation of bZIP60 are altered in transgenic plants where HsfA1a is either overexpressed (A1aOE) or suppressed (A1CS), indicating an interplay between CPR and ER-UPR systems. Several ER-UPR genes are differentially expressed in the HsfA1a transgenic lines either exposed to heat stress or to the ER stress elicitor tunicamycin (TUN). The ectopic expression of HsfA1a is associated with higher tolerance against TUN. On the example of the ER-resident Hsp70 chaperone BIP3, we show that the presence of cis-elements required for HSF and bZIP regulation serves as a putative platform for the co-regulation of these genes by both CPR and ER-UPR mechanisms, in the case of BIP3 in a stimulatory manner under high temperatures. In addition, we show that the accumulation of HsfA1a results in higher levels of three ATG genes and a more sensitized induction of autophagy in response to ER stress which also supports the increased tolerance to ER stress of the A1aOE line. These findings provide a basis for the coordination of protein homeostasis in different cellular compartments under stress conditions.
Topics: Solanum lycopersicum; Arabidopsis; Arabidopsis Proteins; Unfolded Protein Response; Endoplasmic Reticulum
PubMed: 36449150
DOI: 10.1007/s12192-022-01316-7 -
Journal of the American Chemical Society Nov 2023Autophagy is responsible for the degradation of large intracellular contents, such as unwanted protein aggregates and organelles. Impaired autophagy can therefore lead...
Autophagy is responsible for the degradation of large intracellular contents, such as unwanted protein aggregates and organelles. Impaired autophagy can therefore lead to the accumulation of pathological aggregates, correlating with aging and neurodegenerative diseases. However, a broadly applicable methodology is not available for the targeted degradation of protein aggregates or organelles in mammalian cells. Herein, we developed a series of autophagy receptor-inspired targeting chimeras (AceTACs) that can induce the targeted degradation of aggregation-prone proteins and protein aggregates (e.g., huntingtin, TDP-43, and FUS mutants), as well as organelles (e.g., mitochondria, peroxisomes, and endoplasmic reticulum). These antibody-fusion-based AceTAC degraders were designed to mimic the function of autophagy receptors, simultaneously binding with the cellular targets and the LC3 proteins on the autophagosomal membrane, eventually transporting the target to the autophagy-lysosomal process for degradation. The AceTAC degradation system provides design principles for antibody-based degradation through autophagy, largely expanding the scope of intracellular targeted degradation technologies.
Topics: Animals; Protein Aggregates; Autophagy; Endoplasmic Reticulum; Lysosomes; Peroxisomes; Mammals
PubMed: 37748140
DOI: 10.1021/jacs.3c05199 -
International Journal of Molecular... May 2024Pain is a complex and multifaceted experience. Recent research has increasingly focused on the role of endoplasmic reticulum (ER) stress in the induction and modulation... (Review)
Review
Pain is a complex and multifaceted experience. Recent research has increasingly focused on the role of endoplasmic reticulum (ER) stress in the induction and modulation of pain. The ER is an essential organelle for cells and plays a key role in protein folding and calcium dynamics. Various pathological conditions, such as ischemia, hypoxia, toxic substances, and increased protein production, may disturb protein folding, causing an increase in misfolding proteins in the ER. Such an overload of the folding process leads to ER stress and causes the unfolded protein response (UPR), which increases folding capacity in the ER. Uncompensated ER stress impairs intracellular signaling and cell function, resulting in various diseases, such as diabetes and degenerative neurological diseases. ER stress may be a critical universal mechanism underlying human diseases. Pain sensations involve the central as well as peripheral nervous systems. Several preclinical studies indicate that ER stress in the nervous system is enhanced in various painful states, especially in neuropathic pain conditions. The purpose of this narrative review is to uncover the intricate relationship between ER stress and pain, exploring molecular pathways, implications for various pain conditions, and potential therapeutic strategies.
Topics: Humans; Endoplasmic Reticulum Stress; Animals; Unfolded Protein Response; Pain; Endoplasmic Reticulum; Signal Transduction; Neuralgia; Protein Folding
PubMed: 38732214
DOI: 10.3390/ijms25094995 -
Journal of Cellular Physiology Apr 2024Mitochondria and endoplasmic reticulum (ER) contact sites (MERCs) are protein- and lipid-enriched hubs that mediate interorganellar communication by contributing to the...
Mitochondria and endoplasmic reticulum (ER) contact sites (MERCs) are protein- and lipid-enriched hubs that mediate interorganellar communication by contributing to the dynamic transfer of Ca, lipid, and other metabolites between these organelles. Defective MERCs are associated with cellular oxidative stress, neurodegenerative disease, and cardiac and skeletal muscle pathology via mechanisms that are poorly understood. We previously demonstrated that skeletal muscle-specific knockdown (KD) of the mitochondrial fusion mediator optic atrophy 1 (OPA1) induced ER stress and correlated with an induction of Mitofusin-2, a known MERC protein. In the present study, we tested the hypothesis that Opa1 downregulation in skeletal muscle cells alters MERC formation by evaluating multiple myocyte systems, including from mice and Drosophila, and in primary myotubes. Our results revealed that OPA1 deficiency induced tighter and more frequent MERCs in concert with a greater abundance of MERC proteins involved in calcium exchange. Additionally, loss of OPA1 increased the expression of activating transcription factor 4 (ATF4), an integrated stress response (ISR) pathway effector. Reducing Atf4 expression prevented the OPA1-loss-induced tightening of MERC structures. OPA1 reduction was associated with decreased mitochondrial and sarcoplasmic reticulum, a specialized form of ER, calcium, which was reversed following ATF4 repression. These data suggest that mitochondrial stress, induced by OPA1 deficiency, regulates skeletal muscle MERC formation in an ATF4-dependent manner.
Topics: Animals; Mice; Activating Transcription Factor 4; Calcium; Endoplasmic Reticulum; Endoplasmic Reticulum Stress; Lipids; Mitochondria; Muscle, Skeletal; Neurodegenerative Diseases; Male; Mice, Inbred C57BL; Cells, Cultured; GTP Phosphohydrolases
PubMed: 38419397
DOI: 10.1002/jcp.31204 -
Cell Reports Jan 2024Lysosomes and the endoplasmic reticulum (ER) are Ca stores mobilized by the second messengers NAADP and IP, respectively. Here, we establish Ca signals between the two...
Lysosomes and the endoplasmic reticulum (ER) are Ca stores mobilized by the second messengers NAADP and IP, respectively. Here, we establish Ca signals between the two sources as fundamental building blocks that couple local release to global changes in Ca. Cell-wide Ca signals evoked by activation of endogenous NAADP-sensitive channels on lysosomes comprise both local and global components and exhibit a major dependence on ER Ca despite their lysosomal origin. Knockout of ER IP receptor channels delays these signals, whereas expression of lysosomal TPC2 channels accelerates them. High-resolution Ca imaging reveals elementary events upon TPC2 opening and signals coupled to IP receptors. Biasing TPC2 activation to a Ca-permeable state sensitizes local Ca signals to IP. This increases the potency of a physiological agonist to evoke global Ca signals and activate a downstream target. Our data provide a conceptual framework to understand how Ca release from physically separated stores is coordinated.
Topics: Two-Pore Channels; Calcium Signaling; Inositol; Endoplasmic Reticulum; Lysosomes; Calcium; NADP; Inositol 1,4,5-Trisphosphate Receptors; Inositol 1,4,5-Trisphosphate
PubMed: 38160394
DOI: 10.1016/j.celrep.2023.113628 -
Developmental Cell Oct 2023Newly synthesized proteins in the endoplasmic reticulum (ER) are sorted by coat protein complex II (COPII) at the ER exit site en route to the Golgi. Under cellular...
Newly synthesized proteins in the endoplasmic reticulum (ER) are sorted by coat protein complex II (COPII) at the ER exit site en route to the Golgi. Under cellular stresses, COPII proteins become targets of regulation to control the transport. Here, we show that the COPII outer coat proteins Sec31 and Sec13 are selectively sequestered into the biomolecular condensate of SCOTIN/SHISA-5, which interferes with COPII vesicle formation and inhibits ER-to-Golgi transport. SCOTIN is an ER transmembrane protein with a cytosolic intrinsically disordered region (IDR), which is required and essential for the formation of condensates. Upon IFN-γ stimulation, which is a cellular condition that induces SCOTIN expression and condensation, ER-to-Golgi transport was inhibited in a SCOTIN-dependent manner. Furthermore, cancer-associated mutations of SCOTIN perturb its ability to form condensates and control transport. Together, we propose that SCOTIN impedes the ER-to-Golgi transport through its ability to form biomolecular condensates at the ER membrane.
Topics: Vesicular Transport Proteins; Biological Transport; Protein Transport; Endoplasmic Reticulum; Golgi Apparatus
PubMed: 37816329
DOI: 10.1016/j.devcel.2023.08.030 -
ELife Jul 2023Loss of endoplasmic reticular (ER) Ca activates store-operated Ca entry (SOCE) by causing the ER localized Ca sensor STIM to unfurl domains that activate Orai channels...
Loss of endoplasmic reticular (ER) Ca activates store-operated Ca entry (SOCE) by causing the ER localized Ca sensor STIM to unfurl domains that activate Orai channels in the plasma membrane at membrane contact sites (MCS). Here, we demonstrate a novel mechanism by which the inositol 1,4,5 trisphosphate receptor (IPR), an ER-localized IP-gated Ca channel, regulates neuronal SOCE. In human neurons, SOCE evoked by pharmacological depletion of ER-Ca is attenuated by loss of IPRs, and restored by expression of IPRs even when they cannot release Ca, but only if the IPRs can bind IP. Imaging studies demonstrate that IPRs enhance association of STIM1 with Orai1 in neuronal cells with empty stores; this requires an IP-binding site, but not a pore. Convergent regulation by IPRs, may tune neuronal SOCE to respond selectively to receptors that generate IP.
Topics: Humans; Calcium Signaling; Stromal Interaction Molecule 1; Cell Membrane; Endoplasmic Reticulum; Neurons; Calcium
PubMed: 37466241
DOI: 10.7554/eLife.80447