bims-mecosi 2025-11-23 papers

bims-mecosi

Biomed News

on Membrane contact sites

Issue of 2025–11–23
nine papers selected by
Verena Kohler, Umeå University

Update on VAP, a ubiquitous signpost for the ER.
Soybean glycinin and β-conglycinin disrupted the interaction bwteen mitochondria and endoplasmic reticulum in porcine intestinal epithelial cells through oxidative stress cascades.
Cell Trafficking Disorders Play an Important Role in the Pathogenesis of Skeletal Dysplasias.
Yiqi Huoxue recipe ameliorates diabetic nephropathy by mediating VAPB-PTPIP51 complex to activate autophagy and regulate MAM contact.
Cholesterol Transport from ER to Outer Mitochondria by ERLIN2 in Steroid Metabolism.
Failure of lysosomal acidification and endomembrane network in neurodegeneration.
Reprogramming of lipid metabolism by ORF3a-induced microlipophagy enhances biogenesis of SARS-CoV-2 replication organelle.
Exploring the interplay between mitochondria and endoplasmic reticulum in pulmonary arterial hypertension.
Hepatocyte-Derived Extracellular Vesicles Deliver miR-328-3p to Trigger PP2A-B56δ-Mediated p-NLRP3S295-Dependent Metaflammation in Macrophages upon Microcystin-LR Exposure.

Biol Chem. 2025 Nov 21.

Update on VAP, a ubiquitous signpost for the ER.

Tim P Levine.

  The small protein family of VAMP-associated proteins (VAPs) have the unique position in cell biology as intracellular signposts for the Endoplasmic Reticulum (ER). VAP is recognised by a wide range of other proteins that use it to target the ER, either simply being recruited from the cytoplasm, or being recruited from separate organelles. The latter process makes VAP a component of many bridges between the ER and other compartments at membrane contact sites. The fundamental observations that identify VAP as the ER signpost have largely remained unchanged for over two decades. This review will describe how increased understanding of the special role of VAP in recent years has led to new discoveries: what constitutes the VAP family, how proteins bind to VAP, and which cellular functions connect to the ER using VAP. It will also describe the pitfalls that have led to difficulties determining how some proteins bind VAP and suggest some possibilities for future research.

Keywords:  FFAT motif; cyclic AMP (cAMP); lipid transfer protein (LTP); non-vesicular transport; nucleolus; short linear motif (SLiM)

DOI:  https://doi.org/10.1515/hsz-2025-0199
Dev Comp Immunol. 2025 Nov 15. pii: S0145-305X(25)00212-5. [Epub ahead of print] 105523

Soybean glycinin and β-conglycinin disrupted the interaction bwteen mitochondria and endoplasmic reticulum in porcine intestinal epithelial cells through oxidative stress cascades.

Lei Wang, Chenlong Wang, Hongyan Ding, Shibin Feng, Xichun Wang, Jinjie Wu, Dong Liu.

  Soybean glycinin (11S) and β-conglycinin (7S) are major contributors to allergic diarrhea and intestinal barrier damage in young animals. This study investigated the molecular mechanisms underlying the 7S- and 11S-induced dysfunction of mitochondrial and endoplasmic reticulum (ER) interactions in porcine intestinal epithelial (IPEC-J2) cells via the oxidative stress pathway. The results showed that 7S- and 11S-induced oxidative stress, as evidenced by reduced manganese superoxide dismutase (Mn-SOD) activity and elevated 8-Hydroxy-2'-deoxyguanosine (8-OHdG) levels, with excessive reactive oxygen species (ROS) accumulation and elevated Ca2+ levels; decreased mitochondrial membrane potential (MMP), damaged mitochondria-associated endoplasmic reticulum membranes (MAM) structure; up-regulated the protein expression of glucose-regulated protein 75 (GRP75) and mitochondrial Rho-GTPase 1 (Miro1), while inositol 1,4,5 -trisphosphate receptor (IP3R), voltage-dependent anion channel 1 (VDAC1), mitofusin2 (MFN2) and phosphofurin acidic cluster sorting protein 2 (PACS2) were down-regulated. N-acetylcysteine (NAC)pre-treatment alleviated ROS accumulation and mitigated Ca2+ overload and MAM dysfunction, thereby ameliorating IPEC-J2 cell injury. In conclusion, 7S- and 11S-induced ROS burst to disrupt mitochondria-ER interaction homeostasis, leading to MAM structural damage and calcium dysregulation in IPEC-J2 cells, NAC effectively mitigated this process by scavenging ROS. These findings elucidate the critical involvement of subcellular organelle interaction disorders in food allergy pathogenesis and provide novel insights for targeted intervention strategies.

Keywords:  IPEC-J2 cell; Soybean glycinin; mitochondria-associated endoplasmic reticulum membranes; reactive oxygen species; β-conglycinin

DOI:  https://doi.org/10.1016/j.dci.2025.105523
Turk Arch Pediatr. 2025 11 03. 60(6): 577-589

Cell Trafficking Disorders Play an Important Role in the Pathogenesis of Skeletal Dysplasias.

Beyhan Tüysüz.

  Cell trafficking is the transfer of signals and metabolic products between cell compartments to maintain crucial biological functions. In recent years, more than 370 genes have been shown to be associated with defects in cellular transport. The aim of this review is to draw attention to the importance of cell trafficking in the pathogenesis of skeletal dysplasia and to attempt to establish a relationship between clinical findings and the functions of the disrupted proteins. Cell trafficking disorders are divided into four main categories: defects in proteins involved in the transport of molecules (cargo) from the cell to the outside (exocytic pathway) or from the outside to the inside (endocytic pathway) and related to the cytoskeleton, membrane contact sites, and autophagy. A number of skeletal dysplasias result from deficiencies in proteins across different categories of cell trafficking, including glycosylation and lysosomal disorders, which are skeletal involvement. It is noteworthy that genes affected in skeletal dysplasias related to cell trafficking are impaired in signaling pathways involved in the embryonic development of bone, membranous and endochondral ossification, and skeletal morphogenesis. Studies investigating the role of cell trafficking in the development of skeletal dysplasias will shed light on the disease's pathogenesis and increase the potential for developing new therapeutic agents.

Keywords:  Autophagy; cell trafficking disorders; cytoskeleton; membrane contact sites; motorproteins; organelles; vesicular trafficking

DOI:  https://doi.org/10.5152/TurkArchPediatr.2025.25159
Front Nutr. 2025 ;12 1634555

Yiqi Huoxue recipe ameliorates diabetic nephropathy by mediating VAPB-PTPIP51 complex to activate autophagy and regulate MAM contact.

Linghao Dai, Mengyi Wang, Bo Wang, Haowei Liang, Yang Guan, Zhongyan Du, Hui Wang.

   Background: Diabetic nephropathy (DN), a major complication of diabetes mellitus (DM), poses a high mortality and a global health burden. Mitochondria-associated endoplasmic reticulum membranes (MAMs) and mediated autophagy are regarded as the crucial factors in the development of DN. The Yiqi Huoxue recipe (YHR), a traditional Chinese medicine formula, has been reported to treat DN and regulate autophagy, while its underlying mechanism remains unclear.
Methods: Firstly, UPLC-MS/MS analysis was performed to identify the chemical components of YHR. Then, C57BL/6 J mice were injected with streptozotocin and fed with high-fat diet to induce DN. YHR (7.8, 15.6 g/kg/d) was administered via intragastric gavage for 8 weeks. Biochemical parameters and oxidative stress indicators were measured; H&E, PAS, and immunohistochemistry staining of nephrin were performed. Mitochondrial Ca2+ levels were assessed by flow cytometry, while autophagosomes and MAMs were examined using transmission electron microscopy (TEM). The expression levels of VAPB, PTPIP51, LC3 II/I, P62 were detected by Western blot. Podocytes overexpressing PTPIP51 or VAPB were analyzed for cell activity using the CCK-8 assay, autophagy flux by TEM, and the expression of LC3 II/I and P62 by Western blot. In si-PTPIP51-transfected and high-glucose (HG)-stimulated podocytes, CCK-8 assay, PCR, TEM, and immunofluorescence staining were performed to detect the YHR-containing serum on cell activity, mtDNA, MAMs, autophagosomes and LC3 expression.
Results: The chemical fingerprint of YHR was constructed and composed chemicals were identified. In DN mice, YHR treatment reduced the elevated fasting blood glucose (FBG), total cholesterol (TC), triglycerides (TG), blood urea nitrogen (BUN), serum creatinine (Scr), urinary albuminuria (ALB), and microscale albuminuria (MAU) levels. It also alleviated kidney and glomerulus damage, mitochondrial Ca2+, oxidative stress, MAM abnormal contact, and activated autophagy. The enhanced expression of MAM complex, VAPB-PTPIP51, were also inhibited in YHR-treated groups. The cell activity and autophagosome formation were significantly inhibited in podocytes overexpressing PTPIP51 (oe-PTPIP51) and VAPB (oe-VAPB). In contrast, in HG-podocytes, si-PTPIP51 promoted the cell activity, mtDNA copy number, MAM contact, autophagosomes formation and LC3 expression. More importantly, the addition of YHR-containing serum enhanced this effect.
Conclusion: YHR may protect kidneys in DN by regulating the MAM complex VAPB-PTPIP51 to trigger autophagy, providing insights into TCM's clinical application and DN drug development.

Keywords:  Huoxue; VAPB–PTPIP51; Yiqi; autophagy; diabetic; mitochondria-associated endoplasmic reticulum membranes; nephropathy; recipe

DOI:  https://doi.org/10.3389/fnut.2025.1634555
Mol Cell Biol. 2025 Nov 18. 1-16

Cholesterol Transport from ER to Outer Mitochondria by ERLIN2 in Steroid Metabolism.

Himangshu S Bose, William E Burak, Randy M Whittal.

  Cholesterol trafficking from the endoplasmic reticulum (ER) through the mitochondria-associated ER membrane (MAM) and finally to mitochondria is essential for mammalian survival. ER lipid raft-associated protein 2 (ERLIN2) scaffolds raft-like microdomains in the trans-Golgi network, endosomes, and plasma membrane. We found that ERLIN2 assists in rolling cholesterol trafficking-associated lipid vesicles by facilitating the intermediate folding of cholesterol trafficker steroidogenic acute regulatory protein (StAR) from the ER to MAM prior to delivery to the outer mitochondrial membrane. Each ERLIN2-StAR interaction is short. The absence of ERLIN2 ablates mitochondrial cholesterol transport. Over time, StAR association with ERLIN2 increases from the ER to MAM, thereby enhancing mitochondrial cholesterol transport. Thus, ERLIN2 is central for regulating mitochondrial cholesterol trafficking required for mitochondrial steroid metabolism.

Keywords:  Steroids; cholesterol; endoplasmic reticulum; mitochondria associated-ER membrane (MAM); pregnenolone; steroidogenic acute regulatory protein (StAR)

DOI:  https://doi.org/10.1080/10985549.2025.2583172
Exp Mol Med. 2025 Nov 18.

Failure of lysosomal acidification and endomembrane network in neurodegeneration.

Seo-Hyun Kim, Young-Sin Cho, Yong-Keun Jung.

Lysosomes have emerged as central hubs in the regulation of the endomembrane system, extending beyond degradation to coordinate organelle communication. Central to this regulatory role is vacuolar-type H+-ATPase (V-ATPase), a proton pump that acidifies the lysosomal lumen to enable hydrolase activity and support proteostasis. In addition to its lysosomal functions, V-ATPase influences the physiology of other organelles, including the endoplasmic reticulum (ER), Golgi apparatus and mitochondria, through both direct and indirect mechanisms involving acidification-dependent processes, such as protein folding, vesicular trafficking and stress responses. V-ATPase dysfunction compromises interorganelle communication through multiple mechanisms, including impaired calcium and lipid exchange at contact sites, disrupted organelle positioning and defective autophagic and stress signaling. In neurodegenerative diseases, such as Alzheimer's and Parkinson's diseases, V-ATPase impairment contributes to lysosomal storage pathology, ER stress, Golgi fragmentation and mitochondrial dysfunction. ER-endolysosome tethering proteins and mitochondria-lysosome contacts are particularly sensitive to pH and trafficking defects. These disruptions result in a cascade of organelle dysfunction and contribute to disease progression. Here, in this Review, we highlight how V-ATPase governs both local lysosomal function and broader organelle network integrity, positioning it as a critical regulator of endomembrane homeostasis and a potential therapeutic target in neurodegenerative conditions.

DOI: https://doi.org/10.1038/s12276-025-01579-x
PLoS Pathog. 2025 Nov 21. 21(11): e1013676

Reprogramming of lipid metabolism by ORF3a-induced microlipophagy enhances biogenesis of SARS-CoV-2 replication organelle.

Zhifei Li, Xianfeng Hui, Miaomiao Zheng, Zhicheng He, Wenjing Huai, Binbin Ding, Meilin Jin, Yali Qin, Mingzhou Chen.

Infection by positive-strand RNA viruses necessitates membrane expansion and elevated phospholipid biosynthesis, whereby fatty acids stored as triacylglycerols in lipid droplets (LDs) are mobilized to promote metabolic processes and membrane biogenesis. The replication organelles (ROs) of coronavirus associate with modified host endomembrane; however, the molecular mechanisms underlying the expansion and modification of these membranes remain poorly understood. Here, we show that viral protein orf3a collaborates with nsp3, nsp4, nsp6 to facilitate the formation of ROs in SARS-CoV-2. Importantly, orf3a targets LDs to ROs, establishing novel membrane contact sites and induces host cell microlipophagy, which supplies essential lipids for RO biogenesis. Subsequently, Following the formation of ROs, nsp3, with assistance from nsp12, indirectly recruits phosphatidylinositol 4-kinase beta (PI4KB) to ROs, to produce phosphatidylinositol 4-phosphate (PI4P). This action creates a PI4P-enriched microenvironment that enhances SARS-CoV-2 replication. Our findings elucidate the mechanism governing RO generation during SARS-CoV-2 infection and suggest that targeting microlipophagy pharmacologically may represent a promising strategy for the development of anti-coronaviruses therapies.

DOI: https://doi.org/10.1371/journal.ppat.1013676
Front Cardiovasc Med. 2025 ;12 1623775

Exploring the interplay between mitochondria and endoplasmic reticulum in pulmonary arterial hypertension.

Zhipeng Liao, Yuanzhou He.

  Pulmonary arterial hypertension (PAH) is a subtype of pulmonary hypertension (PH), characterized by pulmonary arterial remodeling. This disease frequently progresses to right heart failure and can result in patient mortality. Research at the cellular and molecular level is gradually revealing the mechanism underlying the development of pulmonary arterial hypertension, providing new avenues for treatment by identifying potential therapeutic targets. Contact between the endoplasmic reticulum and mitochondria has been recognized for several decades. And an increasing number of laboratory and clinical studies are beginning to elucidate the relationship between PAH and the interplay involving mitochondria and the endoplasmic reticulum. In this review, we first introduce the basic normal biological functions and processes of MAM-based mitochondrial-endoplasmic reticulum interactions. We then discuss how the dysfunction contributes to pulmonary arterial hypertension (PAH), focusing on three key aspects, mitochondrial dynamics, calcium homeostasis, and endoplasmic reticulum stress. Clarifying these issues may provide important insights for therapeutic interventions in PAH.

Keywords:  ER stress; calcium; mitochondria-associated endoplasmic reticulum membranes; mitochondrial dynamics; pulmonary arterial hypertension

DOI:  https://doi.org/10.3389/fcvm.2025.1623775
Adv Sci (Weinh). 2025 Nov 19. e07039

Hepatocyte-Derived Extracellular Vesicles Deliver miR-328-3p to Trigger PP2A-B56δ-Mediated p-NLRP3S295-Dependent Metaflammation in Macrophages upon Microcystin-LR Exposure.

Jia-Shen Wu, Xin-Yu Zhang, Xin-Yu Ma, Yue-Yue Wei, Lei-Lei Wang, Ze-Bang Du, Xiao-Gang Xia, Lin Che, Dong-Bei Guo, Han-Ying Zheng, You-Liang Yao, Wen-Gang Li, Yu-Chun Lin, Zhong-Ning Lin.

  Microcystin-LR (MC-LR) exacerbates metabolic dysfunction-associated steatotic liver disease (MASLD) by inducing histopathological damage and lipid metabolism disorders. Inducible hepatocyte-derived extracellular vesicles (iHD-EVs) released after xenobiotic exposure activate the macrophage NOD-like receptor protein 3 (NLRP3) inflammasome. Suppression of NLRP3 phosphorylation at serine 295 (p-NLRP3S295) is previously shown to alleviate MASLD progression. Here, it is demonstrated that microcystin-LR (MC-LR)-induced iHD-EVs reduced deliver of miR-328-3p to macrophages, thereby upregulating protein phosphatase 2A (PP2A)-B56δ. Consequent PP2A-B56δ activation disrupts inositol 1,4,5-triphosphate receptor and voltage-dependent anion channel 1 coupling, evokes mitochondria-associated endoplasmic reticulum membrane (MAM) calcium (Ca2+) overload, and recruits p-NLRP3S295 into the inflammasome. Neutralization of p-NLRP3S295 with a site-specific monoclonal antibody (anti-p-NLRP3S295 mAb) markedly attenuates liver inflammation and injury in MC-LR-exposed mice. Collectively, the miR-328-3p/PP2A-B56δ/p-NLRP3S295 axis is identified as a crucial driver of metaflammation and establishes circulating EV-miR-328-3p as a novel biomarker and anti-p-NLRP3S295 mAbs as translational tools for MC-LR-associated MASLD.

Keywords:  Extracellular vesicle miR‐328‐3p; MC‐LR‐associated MASLD; PP2A‐B56δ; Site‐specific monoclonal antibody; p‐NLRP3S295‐dependent metaflammation

DOI:  https://doi.org/10.1002/advs.202507039