bims-mecosi 2025-11-30 papers

bims-mecosi

Biomed News

on Membrane contact sites

Issue of 2025–11–30
fifteen papers selected by
Verena Kohler, Umeå University

Cadherin Regulation of Endoplasmic Reticulum-Plasma Membrane Contact Sites.
Toxoplasma effector TgROP1 establishes membrane contact sites with the endoplasmic reticulum during infection.
TMEM170 proteins are lipid scramblases associated with bridge-type lipid transporters BLTP1/Csf1.
SUPPRESSOR OF LAZY QUADRUPLE 1 acts at ER-plasma membrane contact sites to control a gravitropism pathway in the Arabidopsis stem.
Calcium Tunneling: A Pervasive Signaling Module Mediated by Coupling Store-Operated Ca2+ Entry and Endoplasmic Reticulum Ca2+ Release.
Cardiac SR-Mitochondria Contacts-Impact on Cardiac Physiology and Mitochondrial Fitness.
Insights into the regulation of VPS13 family bridge-like lipid transfer proteins from the structure of VPS13C.
Propofol exerted the neuroprotective effects by regulating renin-angiotensin system and mitochondria-associated endoplasmic reticulum membrane in the postoperative cognitive dysfunction.
Regulatory role of sirtuin-1 by targeting MDM2 to mitochondria-associated membranes formation in the treatment of NAFLD.
MAM-Mediated Mitochondrial Ca2+ Overload and Endoplasmic Reticulum Stress Aggravates Synaptic Plasticity Impairment in Diabetic Mice.
CISD2 ensures adequate ER-mitochondrial coupling, critically supporting mitochondrial function in neurons.
Multiple entanglements of different cell death pathways, in which caspase-8 and BID interact with cardiolipin*, have been identified.
ATG2 is a triglyceride transfer protein.
Disruption of the PIKfyve complex unveils an adaptive mechanism to promote lysosomal repair and mitochondrial homeostasis.
Angelica sinensis polysaccharides prevents marrow cell apoptosis during stress via regulating endoplasmic reticulum-mitochondrion and adaptive metabolism.

bioRxiv. 2025 Oct 15. pii: 2025.10.15.682666. [Epub ahead of print]

Cadherin Regulation of Endoplasmic Reticulum-Plasma Membrane Contact Sites.

Sonam Lhamo, Navaneetha Krishnan Bharathan, William Giang, Kandice R Levental, Cory L Simpson, Stephanie Zimmer, Andrew P Kowalczyk.

The spatial organization and dynamics of the endoplasmic reticulum (ER) govern when and where ER tubules engage with other organelles and the plasma membrane. We previously found that ER tubules are closely associated with desmosomes, but the mechanisms of ER recruitment to these adhesive intercellular junctions were unclear. Here, we demonstrate that adherens junctions recruit ER tubules to intercellular junctions in a manner dependent upon E-cadherin association with α-catenin and vinculin. During cell-cell junction assembly, adherens junctions and ER appear nearly simultaneously at nascent cell-cell contacts, followed by desmosome formation. ER recruitment to cell-cell contacts allows the formation of ER-plasma membrane contact sites (ER-PMCS) and the assembly of a complex comprising adherens junctions, ER-PMCS, and desmosomes. Ablating adherens junctions disrupts this tripartite complex and perturbs global cellular lipid levels. Collectively, our findings identify cadherins as key organizers of ER-PMCS positioning and suggest that this complex integrates cellular mechanical elements with plasma membrane homeostasis.

DOI: https://doi.org/10.1101/2025.10.15.682666
Nat Microbiol. 2025 Nov 25.

Toxoplasma effector TgROP1 establishes membrane contact sites with the endoplasmic reticulum during infection.

Chahat Mehra, Jesús Alvarado Valverde, Ana Margarida Nogueira Matias, Francesca Torelli, Tânia Catarina Medeiros, Julian Straub, James D Asaki, Peter J Bradley, Katja Luck, Steffen Lawo, Moritz Treeck, Lena Pernas.

Membrane contact sites (MCS) are essential for organelle communication in eukaryotic cells. Pathogens also establish MCS with host organelles, but the mechanisms underlying these interactions and their role in infection remain poorly understood. Here, using a fluorescence sensor and CRISPR-based loss-of-function screening, together with imaging and proteomics, we identify the parasite effector mediating MCS between host endoplasmic reticulum (ER) and the vacuole containing the intracellular parasite Toxoplasma gondii. TgROP1 acts as a tether and mimics a canonical FFAT motif to bind the host ER proteins VAPA and VAPB. The loss of VAPA/B abolished host ER-Toxoplasma MCS and decreased pathogen growth. These findings indicate that targeting of host MCS tethers is a strategy exploited by pathogens during infection, which could inform future treatment design.

DOI: https://doi.org/10.1038/s41564-025-02193-3
Nat Struct Mol Biol. 2025 Nov 26.

TMEM170 proteins are lipid scramblases associated with bridge-type lipid transporters BLTP1/Csf1.

Cristian Rocha-Roa, Paige Chandran Blair, Gurpreet Sidhu, Daniel Álvarez, Michael Davey, Elizabeth Conibear, Stefano Vanni.

Bulk lipid transport between organelles has been proposed to involve the partnership between bridge-like lipid transfer proteins (BLTPs) and membrane-embedded lipid scramblases. However, for almost all BLTPs, such physical association has not been fully described and, in most cases, the identity of the scramblases is unknown. Here we identify TMEM170-family proteins as endoplasmic reticulum lipid scramblases that physically interact with BLTP1/Csf1 proteins and we provide a revised model detailing the structure of this protein complex in Caenorhabditis elegans. This finding opens avenues to understand the mechanistic basis of lipid transport at membrane contact sites.

DOI: https://doi.org/10.1038/s41594-025-01716-0
Proc Natl Acad Sci U S A. 2025 Dec 02. 122(48): e2510934122

SUPPRESSOR OF LAZY QUADRUPLE 1 acts at ER-plasma membrane contact sites to control a gravitropism pathway in the Arabidopsis stem.

Takeshi Yoshihara, Edgar P Spalding.

  LAZY proteins function early in the process of orienting growth of land plants with respect to the gravity vector (gravitropism). In Arabidopsis, an oppositely oriented and LAZY-independent form of gravitropism causes the inflorescence stems of a lazy quadruple mutant (atlazy1;2;3;4) to grow down and along the surface of the soil. Here, we report on a suppressor mutation that restores an upright inflorescence to a plant lacking LAZY functions. The suppressor of lazy quadruple 1 (slq1) mutation alters one amino acid in a protein belonging to the NPH3/RPT2-like (NRL) family. The wild-type SLQ1 protein restores prostrate growth to the atlazy1;2;3;4 mutant when expressed specifically in the gravity-sensing endodermal cells of the stem. The SLQ1 protein interacts head-to-tail with itself and, regardless of direction, with a homologous protein called SETH6. Distinct subcellular bodies apparently containing concentrated head-to-tail SLQ1 oligomers coated with SETH6 occurred primarily at sites of contact between the ER and the plasma membrane (PM), including plasmodesmata. The suppressing slq1 mutation (S149F) prevented these bodies from forming and reinverted the auxin gradient in the atlazy1;2;3;4 inflorescence, switching its gravitropism from downward to upward. Thus, SLQ1 and at least one homolog (SETH6) function at ER-PM contact sites to counter the LAZY-dependent mechanism, not by inhibiting it but by regulating an apparently LAZY-independent gravity-directed process for creating an auxin gradient. Variation in the relative strengths of a LAZY-dependent and a SLQ1-mediated, LAZY-independent process of opposite effect may produce the great variety of stem organ postures observed in nature.

Keywords:  ER-PM contact sites; NRL10; atlazy1; gravitropism; suppressor screen

DOI:  https://doi.org/10.1073/pnas.2510934122
Cold Spring Harb Perspect Biol. 2025 Nov 24. pii: a041759. [Epub ahead of print]

Calcium Tunneling: A Pervasive Signaling Module Mediated by Coupling Store-Operated Ca2+ Entry and Endoplasmic Reticulum Ca2+ Release.

Raphael Courjaret, Khaled Machaca.

The ability of the cell to generate precise and sustained intracellular Ca2+ signals is governed by multiple spatial and temporal restrictions. Ca2+ flowing into the cell through plasma membrane channels activates multiple effectors but is limited to targets in the vicinity of the channel. To reach distant effectors, cells developed a mechanism termed "Ca2+ tunneling" where extracellular Ca2+ entering the cell through "store-operated Ca2+ entry" is shuttled through the lumen of the cortical endoplasmic reticulum to be released by inositol 1,4,5-trisphosphate receptors toward distal targets. Here, we review the mechanisms and functions of Ca2+ tunneling in light of recent findings linking the structure of the cortical endoplasmic reticulum at membrane contact sites and the organization of the tunneling machinery.

DOI: https://doi.org/10.1101/cshperspect.a041759
Cells. 2025 Nov 11. pii: 1762. [Epub ahead of print]14(22):

Cardiac SR-Mitochondria Contacts-Impact on Cardiac Physiology and Mitochondrial Fitness.

Celia Fernandez-Sanz, Shey-Shing Sheu, Sergio De la Fuente.

  In adult cardiomyocytes, within the Mitochondrial Associated Membranes (MAMs), the sarcoplasmic reticulum (SR) and mitochondria juxtapose each other, forming a unique and highly repetitive functional structure throughout the cells. These SR-mitochondria contact sites have emerged as critical structures that regulate various physiological processes, including lipid exchange, calcium (Ca2+) communication, control of excitation-contraction bioenergetics coupling, and reactive oxygen species (ROS) production. Over the years, several scientific studies have reported the accumulation of diverse proteins within these SR-mitochondria close contacts. Some proteins strategically accumulate in these areas to enhance their function, such as the mitochondrial Ca2+ uniporter, while others perform non-canonical roles, such as DRP1 acting as a bioenergetics regulator. The purpose of this review is to provide a comprehensive compilation of the proteins that have been reported to be enriched in cardiac MAMs. We aim to show how their positioning is crucial for proper cardiac physiology and fitness, as well as how mispositioning may contribute to cardiac diseases. Additionally, we will discuss the gaps in our understanding and identify the necessary components to fully comprehend physiological communication between the sarcoplasmic SR and mitochondria in cardiac tissue.

Keywords:  MAMs; SR; bioenergetics; heart; microdomains; mitochondria

DOI:  https://doi.org/10.3390/cells14221762
bioRxiv. 2025 Nov 11. pii: 2025.11.10.687702. [Epub ahead of print]

Insights into the regulation of VPS13 family bridge-like lipid transfer proteins from the structure of VPS13C.

Dazhi Li, Xinbo Wang, Bodan Hu, Hongyan Hao, Stephanie Hamill, Yuting Li, Guochao Chen, Pietro De Camilli, Karin M Reinisch.

Bridge-like lipid transfer proteins (BLTPs) play central roles in redistributing lipids from their primary site of synthesis in the endoplasmic reticulum to other organelles. They comprise bridge-domains spanning between organelles at contact sites that allow lipids to transit the cytosol between adjacent membranes. The assembly of BLTPs into complexes with adaptor proteins enables their lipid transfer ability. To address the mechanisms underlying assembly and regulation of BLTP complexes, we used cryo-EM to resolve the structure of one such BLTP, the Parkinson's protein VPS13C, at near-atomic resolution. The structure identifies a lipid-transfer-nonpermissive conformation, where the built-in C-terminal VAB adaptor module blocks the end of the lipid transfer bridge, interfering with lipid delivery. We also identify calmodulin, central to calcium signaling, as a VPS13 partner, suggesting calcium regulation of VPS13 function. Altogether, this structure of intact VPS13C serves as starting point to understand its regulation and, more broadly, that of other BLTPs.

DOI: https://doi.org/10.1101/2025.11.10.687702
BMC Anesthesiol. 2025 Nov 22.

Propofol exerted the neuroprotective effects by regulating renin-angiotensin system and mitochondria-associated endoplasmic reticulum membrane in the postoperative cognitive dysfunction.

Wen Ding, Yijun Zheng, XueYan Li, Hu Lv, Jun Zhang, Wei Chen.



Keywords:  Mitochondria-associated endoplasmic reticulum membrane; Neuroprotection; Postoperative cognitive dysfunction; Propofol; Renin-angiotensin system

DOI:  https://doi.org/10.1186/s12871-025-03503-2
Cell Commun Signal. 2025 Nov 28. 23(1): 514

Regulatory role of sirtuin-1 by targeting MDM2 to mitochondria-associated membranes formation in the treatment of NAFLD.

Rui Zhang, Quanwei Zhang, ZiYi Cui, BenZeng Huang, Manman Li, Haitian Ma.

  Non-alcoholic fatty liver disease (NAFLD) is a common liver disorder characterized by excessive fat accumulation in the liver. Aberrant enrichment of mitochondria-associated membranes (MAMs) plays a significant role in promoting the overproduction of reactive oxygen species (ROS). However, the precise role of MAMs in NAFLD and the potential targets regulating MAMs formation remain unclear.This study demonstrated that SIRT1 inhibits abnormal MAM enrichment in the livers of NAFLD mice and PA-incubated hepatocytes. Moreover, the protective effects of SIRT1 against NAFLD caused by excessive caloric intake are closely associated with its ability to block MAMs-induced mitochondrial Ca2⁺ overload. This regulation alleviates Ca2⁺ dysregulation and subsequently inhibits ROS overproduction-mediated mitochondrial dysfunction. Transcriptomic analysis confirmed that mouse double minute 2 homolog (MDM2) may acts as a downstream target of activated SIRT1 in regulating MAMs formation and thereby protecting against the development of NAFLD. Taken together, this reseach revealed that SIRT1 activation inhibits the aberrant formation of MAMs caused by excessive calorie intake. This effect is linked to the suppression of MDM2 expression and disruption of its interaction of MDM2 with resident MAMs Ca2 + channels by SIRT1, ultimately alleviating mitochondrial Ca2⁺ overload induced mitochondria oxidative stress.

Keywords:  Mitochondria-associated membranes; Mouse double minute 2 homolog; Nonalcoholic fatty liver disease; SIRT1 signal

DOI:  https://doi.org/10.1186/s12964-025-02251-7
Brain Sci. 2025 Oct 28. pii: 1157. [Epub ahead of print]15(11):

MAM-Mediated Mitochondrial Ca2+ Overload and Endoplasmic Reticulum Stress Aggravates Synaptic Plasticity Impairment in Diabetic Mice.

Jie Zhang, Jie Jiang, Haocong Li, Junliang Deng, Wei Dong, Huidan Deng.

  Background: As a chronic threat to human and animal health, diabetes impairs cognition and synaptic plasticity through mechanisms that remain unresolved. This study aims to explore whether mitochondria-associated endoplasmic reticulum membrane (MAM)-mediated mitochondrial Ca2+ overload and endoplasmic reticulum stress plays an important role in high-glucose-induced synaptic plasticity damage in hippocampal neurons. Methods and Results: In diabetic mice, cognitive dysfunction was tightly linked to the synaptic plasticity impairment, manifesting as significant reductions in both mRNA and protein levels of PSD-95, GAP-43, and SYP. Concomitantly, aberrant increases in MAM number and structural alterations, along with pronounced up-regulation of Mfn2, were observed in hippocampal tissue from diabetic mice and cultured hippocampal neurons exposed to high glucose. High glucose also elevated MAM-located Ca2+ transporters (IP3R, GRP75, MCU, and VDAC1), provoking mitochondrial Ca2+ overload and activating ERS, particularly via the IRE1α pathway. Knockdown of Mfn2 ameliorated these high-glucose-induced MAM abnormalities, suppressed mitochondrial Ca2+ overload and ERS, and exerted a protective effect against high-glucose-induced synaptic plasticity damage. Application of the inhibitor MCU-i4 to block Ca2+ transport within MAM reduced high-glucose-induced mitochondrial Ca2+ overload, relieved ERS, and improved high-glucose-induced synaptic plasticity impairment. Application of the inhibitor 4μ8C to suppress the IRE1α pathway of ERS alleviated mitochondrial Ca2+ overload and improved high-glucose-induced synaptic plasticity impairment. Conclusions: High glucose elicits MAM dysregulation, which precipitates reciprocal mitochondrial Ca2+ overload and ER stress, jointly driving hippocampal synaptic plasticity impairment.

Keywords:  diabetes-associated cognitive dysfunction; endoplasmic reticulum stress; mitochondria-associated endoplasmic reticulum membranes; mitochondrial Ca2+ overload

DOI:  https://doi.org/10.3390/brainsci15111157
Acta Neuropathol Commun. 2025 Nov 26. 13(1): 242

CISD2 ensures adequate ER-mitochondrial coupling, critically supporting mitochondrial function in neurons.

Jens Loncke, Ian de Ridder, Rita La Rovere, Annika Vaarmann, Guizhen Fan, Karan Ahuja, Irina Serysheva, Catherine Verfaillie, Martijn Kerkhofs, Jan B Parys, Allen Kaasik, Geert Bultynck, Tim Vervliet.

  Loss of Cisd2, an iron-sulfur cluster transfer protein, results in type 2 Wolfram syndrome (WS2), a disorder associated with severe impacts on pancreatic β cell and neuronal functions. Cisd2 has been implicated in regulating intracellular Ca2+ signaling. However, the molecular basis and cellular consequences remain poorly understood. In this work, we demonstrate that Cisd2 intersects with intracellular Ca2+ dynamics at different levels, by interacting with the inositol-1,4,5-trisphosphate receptors and as a regulator of ER-mitochondria tethering. As such, loss of Cisd2 in HeLa cells results in reduced ER-mitochondrial Ca2+ transfer while only modestly impacting cytosolic Ca2+ signaling. In HeLa cells, Cisd2 deficiency promotes autophagic flux, yet has minimal impact on mitochondrial function. However, studying the impact of Cisd2 deficiency in human induced pluripotent stem cell -derived cortical neurons revealed a severe loss of glutamate-evoked Ca2+ responses in cytosol and associated uptake in mitochondria due to loss of ER-mitochondria contact sites. Correlating with the profound changes in cellular Ca2+ handling, mitochondrial function (oxygen consumption rate, ATP production, mitochondrial potential maintenance) declined severely, while autophagic flux was increased. Overall, these deficiencies further impact the resilience of Cisd2-deficient cortical neurons to cell stress as Cisd2-KO neurons were highly sensitive to staurosporine, an inducer of apoptosis. Overall, this work is one of the first to decipher the impact of Cisd2 on ER-mitochondria Ca2+ handling in a WS2 disease-relevant cell models, thereby revealing a unique dependence of neurons on Cisd2 for their mitochondrial health and cell stress resilience.

Keywords:  Apoptosis; Ca2+ signaling; Cisd2; ER-mitochondria contact sites; Neurodegeneration; Wolfram syndrome

DOI:  https://doi.org/10.1186/s40478-025-02132-7
Front Cell Dev Biol. 2025 ;13 1667611

Multiple entanglements of different cell death pathways, in which caspase-8 and BID interact with cardiolipin*, have been identified.

Patrice X Petit.

  Mitochondria play a central role in cellular bioenergetics, being major counterparts in ATP production and thus in the maintenance of cells, but they are also key mediators of different types of cell death (apoptosis, necroptosis, ferroptosis, etc.) and are among the main players in autophagy. With respect to death receptor-mediated apoptosis, activation of the mitochondrial pathway is required for the induction of apoptosis in cells (extrinsic pathway), referred to as "type II" cells. In type I cells, activation of the extrinsic pathway through a large amount of caspase-8 allows direct activation of caspase-3 and is sufficient to induce apoptosis. This small review is dedicated to the often forgoten molecule of the BCL-2 family, BID. Special emphasis will be placed on the importance of the cardiolipin/caspase-8/BID platform located at the outer mitochondrial membrane surface that generates tBID, which is the actor of BAX/BAK delocalization and oligomerization at the mitochondrial surface and then transmits death signals in the apoptotic pathway. New insights into the regulation of caspase-8 and BID have emerged, and their originality in the context of their activation and function will be highlighted. We will focus on results from biophysical studies of artificial membranes, i.e., lipid-supported monolayers or giant unilamellar vesicles containing cardiolipin. The destabilization of mitochondrial bioenergetics by tBID insertion at the mitochondrial contact site is presented. Since it inhibits the electron transfer chain, superoxide anion generation is essential for BAX oligomerization. We will take you on a journey through these new developments that reveal a surprisingly high degree of redundancy and crosstalk between the apoptotic, necroptotic, and pyroptotic cell death pathways. Taken together, the mitochondrial contact site and cristae organization system (MICOS) is a critical determinant of mitochondrial membrane architecture and physiology. Its close crosstalk with many other mitochondrial protein machineries identifies the MICOS as a central hub in an interwoven network that ensures mitochondrial functionality and integration into the cellular context. It is becoming increasingly clear that the activation platform built around caspase-8/cardiolipin and BID is involved in multiple types of cell death, including apoptosis, ferroptosis (oxytosis), necroptosis and autophagic death.

Keywords:  BID; cardiolipin; cardiolipin peroxidation; cell death; giant unilamellar vesicles; mitochondria; outer mitochondrial membrane; tBID

DOI:  https://doi.org/10.3389/fcell.2025.1667611
Proc Natl Acad Sci U S A. 2025 Dec 02. 122(48): e2517469122

ATG2 is a triglyceride transfer protein.

Justin L Korfhage, Helin Elhan, Neng Wan, Yingying Lu, Lisa Kauffmann, Govindaiah Pilli, Devin M Fuller, Anna M Rios, Karin M Reinisch, Krishna Rao Maddipati, Abdou Rachid Thiam, Thomas J Melia.

  Bridge-like lipid transfer proteins (BLTPs) are established to function in phospholipid transport between bilayers at organelle-organelle contact sites. However, the BLTP ATG2A also associates with lipid droplets in cells, which present a unique phospholipid monolayer topology and which are composed of many additional types of lipids. Whether BLTPs are active in this environment and which lipid species are substrates for transport has been unknown. Here, we use synthetic organelles with bilayers (liposomes), monolayers (artificial lipid droplets), or a mixture of the two membrane structures to demonstrate the tight binding of ATG2 specifically to monolayers via its collection of COOH-terminal amphipathic helices. This stable binding enables ATG2 to transfer phospholipids much more effectively. Unexpectedly, the neutral lipid triacylglycerol is also rapidly transported, with kinetics similar to those of phospholipid transport. Lipidomics of purified ATG2A suggests that a similar transfer of both phospholipids and triacylglycerol occurs in cells. Our work implies that BLTPs likely collect on LDs as part of a broad lipid homeostasis program, which will include the movement of both phospholipids and neutral lipids.

Keywords:  ATG2A; bridge-like lipid transfer; lipid droplet

DOI:  https://doi.org/10.1073/pnas.2517469122
Nat Commun. 2025 Nov 28. 16(1): 10761

Disruption of the PIKfyve complex unveils an adaptive mechanism to promote lysosomal repair and mitochondrial homeostasis.

Candice Kutchukian, Maria Casas, Rose E Dixon, Eamonn J Dickson.

Lysosomes are essential organelles that regulate cellular homeostasis through complex membrane interactions. Phosphoinositide lipids play critical roles in orchestrating these functions by recruiting specific proteins to organelle membranes. The PIKfyve/Fig4/Vac14 complex regulates PI(3,5)P₂ metabolism, and intriguingly, while loss-of-function mutations cause neurodegeneration, acute PIKfyve inhibition shows therapeutic potential in neurodegenerative disorders. We demonstrate that PIKfyve/Fig4/Vac14 dysfunction triggers a compensatory response where reduced mTORC1 activity leads to ULK1-dependent trafficking of ATG9A and PI4KIIα from the TGN to lysosomes. This increases lysosomal PI(4)P, facilitating cholesterol and phosphatidylserine transport at ER-lysosome contacts to promote membrane repair. Concurrently, elevated lysosomal PI(4)P recruits ORP1L to ER-lysosome-mitochondria three-way contacts, enabling PI(4)P transfer to mitochondria that drives ULK1-dependent fragmentation and increased respiration. These findings reveal a role for PIKfyve/Fig4/Vac14 in coordinating lysosomal repair and mitochondrial homeostasis, offering insights into cellular stress responses.

DOI: https://doi.org/10.1038/s41467-025-65798-6
J Ethnopharmacol. 2025 Nov 26. pii: S0378-8741(25)01660-5. [Epub ahead of print] 120968

Angelica sinensis polysaccharides prevents marrow cell apoptosis during stress via regulating endoplasmic reticulum-mitochondrion and adaptive metabolism.

Honghui Jiang, Chen Min, Biyao Wang, Ziling Wang, Nianci Sun, Kunhang Du, Cheng Wang, Caihong Huang, Yaping Wang, Lu Wang.

   ETHNOPHARMACOLOGICAL RELEVANCE: Traditional Chinese medicine has garnered increasing attention for its efficacy in alleviating stress-induced myelosuppression. Angelica sinensis (Oliv.) Diels root, a crucial traditional medicinal material, was widely utilized for its blood-invigorating effects in conditions such as menstrual disorder, stress-induced anemia, and myelosuppression. Angelica sinensis polysaccharides (ASP), a key natural active ingredient of Angelica sinensis, exhibited a significant potential in antagonizing 5-fluorouracil (5-FU)-induced stress-related oxidative damage to bone marrow cells; however, the underlying mechanism remains to be fully elucidated.
AIM OF THE STUDY: To explore the protective effect and underlying mechanism of ASP on the regulatory axis involving endoplasmic reticulum (ER) stress, mitochondrial dysfunction, apoptosis, and adaptive metabolism, under hematopoietic stress conditions.
MATERIALS AND METHODS: Comprehensive approaches combining network pharmacology, RNA-sequencing, in vivo experimental validation including electron microscopy, Western Blot, qRT-PCR techniques, and mitochondrial function assays were performed on marrow cells in C57BL/6J mice.
RESULTS: ASP significantly preserved the morphology and function of ER and mitochondria under 5-FU stress, alleviating 5-FU-induced apoptosis. Mechanistically, ASP ameliorated ER stress via downregulating signals of unfolded protein response including GRP78, IRE1, ATF6, CHOP and inflammatory factor NF-ĸB, reducing ER-released Ca2+ and Ca2+/ROS positive feedback cascade reaction. ASP maintained IP3R-GRP75-VDAC1 calcium channel of mitochondria-associated-membranes (MAMs), invigorating mitochondrial functional proteins, and inhibiting Cytochrome C release. Strikingly, ASP enhanced glycolytic-related genetic and protein expression via PI3K/AKT /HIF pathway.
CONCLUSIONS: These findings elucidate a novel protective mechanism of ASP against hematopoietic stress caused by chemotherapeutic drug, and identify its multi-target regulation of ER-MAMs-mitochondria and an coincident adaptive metabolism of glycolysis for marrow cell to survive, outlining the prospects for its clinical application in hematopoietic stress.

Keywords:  5-Fluorouracil; Angelica sinensis polysaccharides; ER stress; Mitochondria-associated-membranes; Mitochondrion; Oxidative stress

DOI:  https://doi.org/10.1016/j.jep.2025.120968