bims-mecosi 2026-11-01 papers

bims-mecosi

Biomed News

on Membrane contact sites

Issue of 2026–11–01
fifteen papers selected by
Verena Kohler, Umeå University

A bacterial endosymbiont with a highly reduced genome forms extensive membrane contact sites with host organelles.
TMEM55B Maintains Lysosomal Homeostasis and Promotes ER-Lysosome Calcium Signaling.
Exposure to airborne PM2.5 suppresses mitochondrial associated membranes and MAM-associated metabolic regulators in mouse liver.
VAP organizes presynaptic Ca2+ signaling and synaptic vesicle mobilization through Kv2 membrane contact sites.
They grow up so fast - the birth and development of membrane contact site research.
Altered metabolism and endoplasmic reticulum-mitochondria contacts in multiple sclerosis neurons.
Protein disulfide Isomerase-A1 as a novel organizer of Endoplasmic reticulum-plasma membrane contacts via reticulon 4.
VAPA-dependent lipid transport at ER-lamellar body contact sites promotes human lung surfactant formation.
HBV Infection Induces Changes in Mitochondrial Architecture and Remodeling of Mitochondria-ER Interactions.
PRDX1 as a Redox Gatekeeper at Mitochondrial-ER Contact Sites: Implications for Kidney Fibrosis Progression and Therapy.
Proximity labeling technologies for multiscale spatial proteomics: from organelle contact sites to intercellular and inter-organ communication.
Notoginsenoside R2 Antagonizes Renal Interstitial Fibrosis by Regulating Fatty Acid Oxidation via the CASP2/ALDH3A1 Axis.
Alkaloid extract of Chuanxiong Rhizoma alleviates liver fibrosis by regulating calcium ion communication between endoplasmic reticulum and mitochondria.
Sphingolipid Dysregulation in Type 2 Diabetes and Its Microvascular Complications.
From Benefit to Harm: Context-Dependent Responses to Dietary Interventions.

bioRxiv. 2026 Oct 07. pii: 2026.10.06.757092. [Epub ahead of print]

A bacterial endosymbiont with a highly reduced genome forms extensive membrane contact sites with host organelles.

Dalton J Leprich, Jesse Aaron, Eleni Hughes, Mark S Ladinsky, Pamela J Bjorkman, John P McCutcheon.

Bacterial endosymbionts that establish long-term associations inside of host cells often lose a huge number of genes and become dependent on their hosts for essential cellular functions 1,2 . One such example is the mealybug endosymbiont Tremblaya princeps : its ~139-kb genome encodes only ~120 protein coding genes and lacks all recognizable genes for lipid and fatty acid synthesis, cell wall components, membrane transport, protein translocation, and transmembrane proteins, raising fundamental questions of how Tremblaya's cellular envelope is formed and maintained 3,4 . Here, using a combination of transmission electron microscopy (TEM) and focused ion beam scanning electron microscopy (FIB-SEM) of an entire endosymbiont-containing insect cell, we identified extensive and specific contacts between host cell mitochondria and Tremblaya . These contacts occurred at close membrane appositions and contained electron-dense bridge-like structures closely resembling classical eukaryotic membrane contact sites. Whole-cell segmentation showed that approximately 53% of host mitochondria were in contact with Tremblaya , with some mitochondria extensively wrapped by Tremblaya -associated membranes. Mitochondria in contact with Tremblaya were larger and contained proportionally greater cristae volume and surface density compared to non-contact mitochondria, exhibiting differences in both external and internal mitochondrial architecture. As membrane contact sites are well known to mediate lipid and metabolite exchange between membranes 5-10 , these findings suggest that direct interactions with host organelles may be a source of vital membrane and cellular components for endosymbionts that have lost the autonomous ability to produce and transport these molecules.

DOI: https://doi.org/10.64898/2026.10.06.757092
Traffic. 2026 Dec;pii: e70057. [Epub ahead of print]27(4):

TMEM55B Maintains Lysosomal Homeostasis and Promotes ER-Lysosome Calcium Signaling.

Nagi Mukae, Honoka Maki, Michiko Shirane.

  At membrane contact sites (MCSs) between the endoplasmic reticulum (ER) and endolysosomal compartments, the Protrudin-PDZD8 complex promotes the maturation of endosomes into lysosomes, a process accompanied by acidification. Endosomal maturation is closely associated with both lysosomal acidification and calcium signaling; however, the molecular mechanisms linking the Protrudin-PDZD8 complex to these processes remain unclear. Here, we identified TMEM55B, a lysosome-localized protein, as a binding partner of the Protrudin-PDZD8 complex. TMEM55B has been reported to interact with the v-ATPase complex, suggesting a role in lysosomal function. Suppression of TMEM55B expression reduced the fluorescence of a lysosomal acidification probe, suggesting impaired lysosomal acidification. In addition, TMEM55B depletion attenuated lysosomal Ca2+ release and reuptake and reduced ATP-induced Ca2+ responses in the ER. These findings suggest impaired calcium-induced calcium release (CICR) at ER-lysosome MCSs. By contrast, mitochondrial Ca2+ dynamics were unaffected. Together, these results identify TMEM55B as a factor involved in maintaining lysosomal homeostasis and regulating calcium dynamics. Our findings suggest that TMEM55B cooperates with the Protrudin-PDZD8 complex to contribute to the regulation of lysosomal function at ER-lysosome MCSs.

Keywords:  PDZD8; TMEM55B; calcium signaling; lysosome; membrane contact site

DOI:  https://doi.org/10.1111/tra.70057
Am J Physiol Cell Physiol. 2026 Nov 01. 331(5): C1542-C1554

Exposure to airborne PM2.5 suppresses mitochondrial associated membranes and MAM-associated metabolic regulators in mouse liver.

Qi Chen, Hyunbae Kim, Lucynda Pham, Qinghua Sun, Ren Zhang, Maik Hüttemann, Siddhesh Aras, Lawrence I Grossman, Kezhong Zhang.

  Airborne fine particulate matter ≤2.5 μm in diameter (PM2.5) poses a significant threat to human health due to its capacity to penetrate deep into the respiratory tract and enter the systemic circulation. Mitochondria-associated membranes (MAMs), specialized contact sites between the endoplasmic reticulum (ER) and mitochondria, are central regulators of calcium signaling, stress responses, and energy metabolism. In this study, we reveal that exposure to environmentally relevant PM2.5 disrupts hepatic MAM integrity through an oxidative stress-dependent mechanism. Upon PM2.5 exposure, macrophages take up PM2.5 particles, which can be prevented by treatment with antioxidants or cellular calcium chelators. Transmission electron microscopy examination of MAM structure indicated that PM2.5 inhalation markedly reduces MAM abundance and the proportion of MAM-forming mitochondria in mouse livers. Direct exposure of hepatocytes to PM2.5 particles suppresses both basal and glucagon-induced MAM formation, as visualized using an MAM-specific bimolecular fluorescence complementation sensor. Mechanistically, PM2.5 exposure represses MAM-associated transcriptional programs controlling the mitochondrial unfolded protein response and fatty acid oxidation by downregulation of the cyclic AMP-responsive element-binding protein hepatic-specific/peroxisome proliferator-activated receptor-α regulatory axis. In summary, our studies identify disruption of ER-mitochondria communication as a pivotal mechanism by which PM2.5 impairs mitochondrial homeostasis and metabolic resilience, providing new insight into the pathogenesis of air pollution-associated metabolic disorders.NEW & NOTEWORTHY This study identifies mitochondria-associated membranes (MAMs) as a previously unrecognized target of airborne particulate matter PM2.5 in the liver. We demonstrate that environmentally relevant PM2.5 exposure disrupts endoplasmic reticulum-mitochondria contact sites through an oxidative stress-dependent mechanism. PM2.5 suppresses hepatic MAM formation and thereby impairs mitochondrial unfolded protein response and fatty acid oxidation programs. These findings establish loss of MAM integrity as a major mechanism linking air pollution exposure to mitochondrial dysfunction and metabolic vulnerability.

Keywords:  airborne particulate matter; fatty acid oxidation; metabolic disorders; mitochondria-associated membrane; mitochondrial UPR

DOI:  https://doi.org/10.1152/ajpcell.00103.2026
Proc Natl Acad Sci U S A. 2026 Nov 03. 123(44): e2602106123

VAP organizes presynaptic Ca2+ signaling and synaptic vesicle mobilization through Kv2 membrane contact sites.

Cameron D Paton, In Ha Cho, Michael B Hoppa.

  In neurons, the endoplasmic reticulum (ER) forms an extensive network that establishes membrane contact sites (MCSs) with various organelles including the plasma membrane (PM). While MCSs are known to regulate lipid exchange and Ca2+ signaling, their specific roles in synaptic transmission remain poorly understood. Here, we demonstrate that the ER-resident proteins VAPA and VAPB are essential for organizing presynaptic Ca2+ exchange and mobilizing synaptic vesicles. We show that the loss of VAP impairs Ca2+ loading into both the ER and mitochondria during electrical activity. This regulation occurs primarily through VAP interactions with voltage-gated potassium (Kv2) channels at the PM. Our data suggest that the Kv2-VAP complex organizes presynaptic Ca2+ signaling outside the active zone. Without this scaffold, vesicle mobilization for exocytosis is strongly impaired and a larger fraction remains trapped in the reserve pool. These findings reveal a role for Kv2-VAP MCSs in coordinating organelle Ca2+ signaling and the synaptic vesicle cycle.

Keywords:  calcium; endoplasmic reticulum; presynaptic; synaptic transmission; vesicles

DOI:  https://doi.org/10.1073/pnas.2602106123
J Cell Sci. 2026 Oct 15. pii: jcs264796. [Epub ahead of print]139(20):

They grow up so fast - the birth and development of membrane contact site research.

Tim P Levine, Christopher J R Loewen, William A Prinz.

  Over the past 15 years, the field of 'membrane contact sites' and research into direct communication between organelles has taken off. In this Perspective, we look back at how the field has developed. Rather than cover every forward step, we focus on conceptual advances in the study of interorganelle communication - particularly advances that were not obvious at the start of this journey. Among these advances is the demonstration that different functions located at the same membrane contact site interact with each other. Another is that a wide range of molecules are transferred between organelles at contact sites, well beyond the two best-known cargos, Ca2+ and lipids. By looking at the history of the field, we explain how our understanding of Ca2+ flux and lipid transfer have grown at different rates. Finally, we suggest that the field has been liable to several types of error, from concrete thinking about the significance of contact to misusing terms such as 'tether'. Nevertheless, the application of new cutting-edge techniques to the future of contact site research presents many exciting opportunities.

Keywords:  Ca2+ flux; Cyclic AMP; Lipid transfer protein; Membrane contact site; Reification; Signalling hub

DOI:  https://doi.org/10.1242/jcs.264796
Front Neurol. 2026 ;17 1915238

Altered metabolism and endoplasmic reticulum-mitochondria contacts in multiple sclerosis neurons.

Celina Böse, Adriana Rehm, Zhixiao Wu, Anna-Sophia Karl, Sanja Augustyniak, Pia Renk, Anke Salmen, Ralf Gold, Konstanze F Winklhofer, Barbara Gisevius, Verian Bader, Jeremias Motte.

   Background: Genetic factors are estimated to account for approximately 30-50% of the risk for developing Multiple sclerosis (MS). Distinct mitochondrial variants, impairments in the respiratory chain, and mitochondrial dysfunction have been reported in individuals affected by MS. Mitochondria and the endoplasmic reticulum (ER) form membrane contact sites (ERMCs) that control important biological functions. Dysregulated ERMCs have been associated with a number of severe consequences for homeostasis, including altered mitochondrial calcium levels, impaired ATP production and abnormal lipid transfer. All of these mechanisms are thought to play an important role in the pathogenesis and disease progression of MS. Here, we investigated the hypothesis that the mitochondrial predisposition plays a crucial role in contributing to MS development.
Methods: Mitochondrial functionality was analyzed in a model of human induced primary neurons (iPNs), and neuronal precursor cells (NPCs), differentiated from induced pluripotent stem cells (iPSCs) from people with MS and healthy controls (HCs). Seahorse analysis was performed for investigation of the bioenergetic profile of the cells. ERMC and mitochondrial morphological analysis were carried out to investigate the potential impact of mitochondrial dysfunction in MS-derived neurons.
Results: Seahorse analysis revealed significant differences in the respiratory complexes (spare capacity: p = 0.0002; non-mitochondrial oxygen consumption: p = 0.0207) and glycolysis (p = 0.0001; glycolytic reserve p = 0.0018) from MS-derived iPNs compared to HCs. We further investigated mitochondrial dysfunction in NPCs (maximal respiration p = 0.0491; non-mitochondrial oxygen consumption: p = 0.0226) and a significant difference in glycolytic reserve (p = 0.0359) from MS-derived NPC compared to HCs. Furthermore, we identified a significantly higher amount of ERMCs (p < 0.0001) and altered mitochondrial morphology in MS-derived iPNs compared to HC.
Discussion: Our data are highlighting the importance of genetic mitochondrial contribution to MS pathology, by showing that MS-derived NPCs and iPNs exhibit altered mitochondrial behavior and morphology compared to healthy control (HC)-derived cells.

Keywords:  endoplasmic reticulum; endoplasmic reticulum-mitochondria contacts; metabolism; mitochondria; multiple sclerosis

DOI:  https://doi.org/10.3389/fneur.2026.1915238
Redox Biol. 2026 Oct 24. pii: S2213-2317(26)00455-6. [Epub ahead of print]98 104456

Protein disulfide Isomerase-A1 as a novel organizer of Endoplasmic reticulum-plasma membrane contacts via reticulon 4.

Tiphany C De Bessa, Percillia Vs Oliveira, Sara Ventura, Gabriele Vm Gabriel, Marina S De Bessa, Stefanne Cp da Silva, Victor Debbas, Celio X Santos, Ajay Shah, Francisco Rm Laurindo.

  Endoplasmic reticulum (ER)-plasma membrane (PM) contact sites (ER-PMc) are nanodomains essential for ER functions such as Ca2+ signaling, lipid metabolism, cell signaling and ER stress responses. However, how ER-PMc dynamics relate to protein folding-related ER oxidoreductases is unclear. We hypothesized that ER-PMc are signaling hubs regulated by ER redox chaperones from the Protein Disulfide Isomerase (PDI) family such as PDIA1. We show that PDIA1 co-localizes with ER-PMc and co-immunoprecipitates with the scaffold protein extended synaptotagmin-3 (E-Syt3). E-Syt3 overexpression increases levels of the ER-shaping protein Reticulon-4 (RTN4), which promotes tubular ER formation, and switches RTN4B1 to B2 isoform. These effects occur in parallel with the increased number of ER-PMc, while PDIA1 secretion is mildly impaired, rather than increased. Importantly, PDIA1 silencing increases number and decreases size of ER-PMc, while affecting ER morphology and tubulation and down-regulating RTN4-B expression. Conversely, RTN4 silencing impairs PDIA1 association with ER-PMc. This indicates that PDIA1 sustains RTN4-B-driven ER tubulation and ER-PMc stability, while RTN4 supports PDIA1 targeting to ER-PMc. Functionally, PDIA1 silencing markedly reduces cytosolic calcium influx, and IP3 receptor activation. Together, our findings position PDIA1 as an integral component and new functional organizer of ER-PMc sites. We propose a model in which ER proteostasis, via PDIA1, converges with ER morpho-structure, via RTN4, to integrate redox and Ca2+ signaling at ER-PM interfaces.

Keywords:  E-Syt3; Endoplasmic reticulum; PDIA1; Plasma membrane contact; RTN4

DOI:  https://doi.org/10.1016/j.redox.2026.104456
Dev Cell. 2026 Oct 30. pii: S1534-5807(26)00366-7. [Epub ahead of print]

VAPA-dependent lipid transport at ER-lamellar body contact sites promotes human lung surfactant formation.

Zoé Grimanelli, Shashank Dadsena, Franziska Meichsner, Lena Hipp, Janathan Altuzar, Jinsuo Bo, Keerti Singh, Sophie Abélanet, Felix Marbach, Sacha Ferdinandusse, Frédéric M Vaz, Özge Altug-Teber, Oliver Brandau, Ana Rita Dias Araújo, Anne-Sophie Gay, Jessica Tacco, Clara Pradelli, Romain Gautier, Simone Reu-Hofer, Christian Mühlfeld, Morten Kampelmann, Marcus Höring, Gerhard Liebisch, Susanne Hämmerling, Xiaohua Yang, Julian Warfsmann, Maja Hempel, Dorothea Haas, Matthias Griese, Bruno Mesmin, Matias Simons.

  Vesicle-associated membrane protein-associated proteins (VAPs) establish membrane contact sites (MCS) between the endoplasmic reticulum (ER) and other organelles through interactions with FFAT-containing proteins, coordinating lipid synthesis, transfer, and metabolism. Their tissue-specific functions remain poorly understood. We report a patient with a homozygous nonsense variant in VAPA (p.(Glu12∗)), presenting with profound global developmental delay and progressive surfactant dysfunction leading to cholesterol pneumonitis and pulmonary fibrosis. Alternative translation initiation partially bypasses the premature stop codon, producing an N-terminally truncated VAPA protein with impaired FFAT binding capacity and disrupted lamellar body (LB) formation in human alveolar type 2 cells. We identify the pulmonary disease-associated ATP-binding cassette transporter A3 (ABCA3), a regulator of surfactant lipid accumulation, as a VAPA interactor. VAPA-ABCA3 interaction facilitates lipid exchange at previously uncharacterized ER-LB MCSs, a function lost upon VAPA truncation. Our findings establish VAPA-dependent MCS dysfunction as a mechanism of syndromic lung disease and define a pathway for surfactant lipid trafficking.

Keywords:  alveolar epithelial cells; cholesterol; endoplasmic reticulum; lamellar bodies; lipid transfer; lipidomics; membrane contact sites; phospholipids; surfactant

DOI:  https://doi.org/10.1016/j.devcel.2026.10.004
Pathogens. 2026 Sep 24. pii: 1009. [Epub ahead of print]15(10):

HBV Infection Induces Changes in Mitochondrial Architecture and Remodeling of Mitochondria-ER Interactions.

Leonardo Duca, Carlotta Castelli, Anna Rosa Garbuglia, Laura Falasca.

  Mitochondria are central hubs of cellular metabolism, playing essential roles in energy production, lipid metabolism, calcium homeostasis, and redox signaling. Findings show that many of these activities are regulated by contact sites between mitochondria and the endoplasmic reticulum (ER) (mitochondria-ER contacts, MERCs). Several studies suggest that Hepatitis B Virus (HBV) can affect mitochondrial functions, inducing metabolic alterations and oxidative stress. This work aimed to investigate, at an ultrastructural level, whether HBV infection causes changes in mitochondrial architecture and MERC modulation. Using HepG2-NTCP cells as an in vitro model system, we analyzed mitochondrial modifications after HBV infection at 2, 5, and 10 days. Electron and confocal microscopy analyses highlighted changes in mitochondrial morphology with a progressive enlargement of mitochondrial size and a remodeling of the mitochondrial network, together with an increase in MERC establishment. Moreover, functional assays showed decreased ATP production, despite increased mitochondrial membrane potential and tight regulation of mitochondrial reactive oxygen species (mtROS) levels. These findings suggest that HBV does not cause irreversible mitochondrial damage but drives a dynamic and coordinated adaptation involving metabolism, ultrastructure, ER interaction, and network organization.

Keywords:  HBV; HepG2-NTCP cells; MERCs; confocal microscopy; electron microscopy; endoplasmic reticulum; mitochondria; mitochondria–ER contacts

DOI:  https://doi.org/10.3390/pathogens15101009
Antioxidants (Basel). 2026 Oct 01. pii: 1263. [Epub ahead of print]15(10):

PRDX1 as a Redox Gatekeeper at Mitochondrial-ER Contact Sites: Implications for Kidney Fibrosis Progression and Therapy.

Yang Zhang, Jaeyeon Lee, Nan-Nan Yu, Mei-Hua Jin, Ying-Hao Han, Hyo-Jin Park, Deog-Bon Koo, Hu-Nan Sun, Dong-Seok Lee.

  Peroxiredoxins (PRDXs) constitute a class of thiol-dependent oxidoreductive regulatory factors whose functions extend beyond peroxide detoxification to include the regulation of oxidoreductive signaling, organelle homeostasis, and cell fate determination. The emerging role of PRDX1-6 in fibrotic diseases-particularly PRDX1's function as an oxidoreductive signaling modulator dependent on specific pathological contexts during renal injury and fibrosis-calls for further investigation. We propose a dual-regulatory model in which PRDX1 simultaneously governs both the mitochondrial reactive oxygen species (ROS)-JNK/Smad signaling pathway and the endoplasmic reticulum (ER) stress-protein kinase R-like endoplasmic reticulum kinase (PERK)/eukaryotic initiation factor 2α (eIF2α)/activating transcription factor 4 (ATF4)/C/EBP homologous protein (CHOP)-gasdermin E (GSDME) signaling pathway, thereby linking organelle oxidoreductive imbalance to epithelial cell injury, inflammatory cell death, and fibrotic remodeling. Notably, we hypothesize that the mitochondria-associated membranes (MAMs) serve as a critical spatial interface for the convergence of these signaling pathways. At the MAMs, PRDX1 may function as an "oxidoreductive gatekeeper," buffering local peroxide signaling while coordinating the oxidoreductive balance, Ca2+ transport, and mitochondrial homeostasis between the ER and mitochondria. This theoretical framework provides a potential basis for elucidating the context-dependent role of PRDX1 in both acute and chronic renal injury, and identifies the PRDX1-MAMs oxidoreductive gating axis as a promising therapeutic target for renal fibrosis.

Keywords:  kidney fibrosis; oxidative stress; peroxiredoxins; reactive oxygen species

DOI:  https://doi.org/10.3390/antiox15101263
Biochem Biophys Res Commun. 2026 Oct 17. pii: S0006-291X(26)01527-5. [Epub ahead of print]841 154761

Proximity labeling technologies for multiscale spatial proteomics: from organelle contact sites to intercellular and inter-organ communication.

Danhua Chen, Hailong Zhao, Hongmei Zhao, Jing Wang.

  Proximity labeling (PL) converts molecular proximity into covalent tags that can be enriched and identified by mass spectrometry. Faster ligases and engineered peroxidases have broadened the applications of PL. Genetically encoded split systems add spatial control, helping extend bait-centered mapping to organelle interfaces, intercellular interactions and extracellular communication. This Review discusses how these approaches address two related questions: which proteins occupy a defined interface, and how proteins move from their site of origin to a recipient compartment, cell or tissue. We examine how interface-associated proteins are identified and how source-destination labeling follows protein movement. We then consider the further evidence needed to explain their mechanisms and biological functions. By relating experimental design to the biological boundary under study, this Review offers practical guidance for selecting PL strategies across multiple scales.

Keywords:  Intercellular communication; Organelle contact sites; Protein trafficking; Proximity labeling; Secretome; Spatial proteomics

DOI:  https://doi.org/10.1016/j.bbrc.2026.154761
Phytother Res. 2026 Oct 28.

Notoginsenoside R2 Antagonizes Renal Interstitial Fibrosis by Regulating Fatty Acid Oxidation via the CASP2/ALDH3A1 Axis.

Guanting Chen, Tao Li, Zhenzhen Wang, Hao Zhao, Xiaoxia Xun, Yijiao Wang, Shiyuan Jiang, Qing Zhang, Weiwei Sun, Kang Yang, Yaoxian Wang.

  Renal interstitial fibrosis (RIF) is a major driver of chronic kidney disease (CKD) progression, yet effective therapies remain limited. The Shen-Yan-Fang-Shuai formula (SYFSF) exhibits clinical renoprotective effects; however, its active components and mechanisms remain unclear. This study identifies notoginsenoside R2 (NGR2) as a core active compound of SYFSF that directly binds to caspase-2 (CASP2). Integrative multi-omics analyses in unilateral ureteral obstruction (UUO) rats and transforming growth factor-β1 (TGF-β1)-induced NRK-52E cells demonstrate that NGR2 upregulates CASP2, enhances the CASP2-aldehyde dehydrogenase 3 family member A1 (ALDH3A1) interaction, and promotes ALDH3A1 deubiquitination, thereby stabilizing ALDH3A1. This stabilization restores the integrity of mitochondria-associated endoplasmic reticulum membranes (MAMs) and improves fatty acid oxidation (FAO) by upregulating carnitine palmitoyltransferase 1A (CPT1A), acyl-CoA dehydrogenase long chain (ACADL), and peroxisome proliferator-activated receptor α (PPARα). It also reduces lipid accumulation, oxidative stress, epithelial-mesenchymal transition (EMT), inflammation, and collagen deposition. In vivo, NGR2 ameliorates renal dysfunction and fibrosis. Mechanistically, NGR2 binds the caspase activation and recruitment domain (CARD) of CASP2 without occluding the ubiquitin-interacting motif-like (UIML) region required for its deubiquitinase function, thereby increasing CASP2 abundance and stability rather than activating its apoptotic protease activity, and facilitating ubiquitin chain removal from ALDH3A1. These findings demonstrate that SYFSF and NGR2 antagonize RIF by targeting the CASP2/ALDH3A1 axis to restore MAM function and FAO, providing a molecular basis for traditional Chinese medicine in CKD therapy.

Keywords:  ALDH3A1; CASP2; Shen‐Yan‐Fang‐Shuai formula; fatty acid oxidation; mitochondria‐associated endoplasmic reticulum membranes; renal interstitial fibrosis

DOI:  https://doi.org/10.1002/ptr.70481
Chin Herb Med. 2026 Oct;18(4): 1022-1033

Alkaloid extract of Chuanxiong Rhizoma alleviates liver fibrosis by regulating calcium ion communication between endoplasmic reticulum and mitochondria.

Jiaorong Qu, Kaihong Xie, Zixuan Huo, Jianan Li, Le Wang, Xiaojiaoyang Li.

   Objective: To decipher the anti-fibrosis effects and mechanisms of alkaloid extract of Chuanxiong Rhizoma (CXAL) by modulating endoplasmic reticulum (ER) and mitochondrial disorders through combination of network pharmacological methods with molecular biology.
Methods: After identifying the components of CXAL through UHPLC-HRMS, a bile duct ligation (BDL)-induced liver fibrosis mouse model was established and CXAL was administered in a dose gradient as 5, 10 and 20 mg/kg. Then, liver serum level, expression analysis of liver fibrosis-related genes, pathological staining and immunofluorescence (IF) staining were performed to detect the efficacy of CXAL. Based on target sets from open online databases, network pharmacology and cell type enrichment analysis were performed to locate the pathways and the cell type targeted by CXAL. Furthermore, qPCR, immunofluorescence, ROS-related assays, Mito-SOX, mitochondrial-associated ER membrane (MAM) identification, and calcium ion (Ca2+) flux detection techniques were applied in vitro to evaluate the efficacy of CXAL on the ER, mitochondria, and MAMs in AML12 cells following DCA treatment.
Results: Serological and hepatic histopathological findings indicated the administration of CXAL significantly reduced BDL-increased plasma hyaluronic acid (HA), laminin (LN), total bile acids (TBA) and alkaline phosphatase (ALP) levels, pro-fibrotic markers and liver histopathological changes during liver fibrosis. A total of 57 common targets between the 206 targets of represented CXAL components from TCMSP Database/DrugBank Database and 500 targets associated wtih liver fibrosis from the Gene Cards database were enriched in ER/mitochondrial-related pathways and were specifically localized to hepatocytes in liver. Further in vivo and in vitro investigations revealed that CXAL ameliorated ER stress, mitochondrial dysfunction, MAMs structural damage and aberrant Ca2+ flux. Mechanistically, as MAMs serve as a bridge for Ca2+ communication between the ER and the mitochondria, it found that CXAL might inhibit Ca2+ flux from the ER to the mitochondria through the MAM-associated component, inositol 1,4,5-trisphosphate receptor type 1 (ITPR1). Meanwhile, CXAL upregulated mitofusin 2 (MFN2) to promote the retrieval of Ca2+ from the mitochondria into the ER, thus reducing the accumulation of Ca2+ in the mitochondria.
Conclusion: The administration of CXAL exhibits notable anti-fibrotic properties in the BDL-induced mouse model. The protective effects of CXAL on the ER stress and mitochondrial dysfunction can be attributed to the restoration of Ca2+ influx between the ER and the mitochondrial, mediated by MAM proteins ITPR1 and MFN2.

Keywords:  Chuanxiong Rhizoma; calcium ion; endoplasmic reticulum stress; hepatocyte; liver fibrosis; mitochondrial

DOI:  https://doi.org/10.1016/j.chmed.2025.09.002
Int J Mol Sci. 2026 Oct 12. pii: 9043. [Epub ahead of print]27(20):

Sphingolipid Dysregulation in Type 2 Diabetes and Its Microvascular Complications.

Ya Wen, Yayun Lin, Yi Liu, Li Zhao.

  Sphingolipids arestructural components of cell membranes and bioactive mediators governing cellular metabolism and intercellular communication. Beyond their classical roles in insulin sensitivity and glucose/lipid homeostasis, ceramide, sphingosine-1-phosphate (S1P), sphingomyelin and glycosphingolipids coordinate through lipid rafts, extracellular vesicles, organelle contact sites and circulating carriers to facilitate signaling among pancreas, liver, adipose tissue, vascular endothelium and kidney. This review summarizes literature on how dietary and endogenous sphingolipids contribute to T2DM and its microvascular complications. Preclinical studies, mainly in cultured cells and rodent models, indicate that overnutrition with excess take of saturated and industrial trans fats promotes ceramide accumulation, which impairs AKT/AMPK signaling, enhancing hepatic gluconeogenesis and β-cell dysfunction, whereas S1P exerts protective metabolic and vascular effects. Whether these mechanisms are similarly dominant in humans remains to be established. Chain-length-specific ceramides generated by distinct ceramide synthases (CerS1-6) determine organelle and intercellular responses in experimental models. In human observational studies, ceramide/S1P ratios and selected sphingolipid species have been associated with metabolic risk, but their diagnostic and risk-stratification value requires clinical validation. We further discuss nutritional patterns, antidiabetic and lipid-lowering agents, and emerging nanomedicine or exosome-based strategies that restore sphingolipid balance. Targeting compartment- and chain-length-specific sphingolipid signaling may provide more precise therapeutic opportunities for T2DM and its complications.

Keywords:  T2DM; ceramide; glucolipotoxicity; sphingolipid; sphingosine-1-phosphate

DOI:  https://doi.org/10.3390/ijms27209043
Physiology (Bethesda). 2026 Oct 20.

From Benefit to Harm: Context-Dependent Responses to Dietary Interventions.

Lingyan Zhou, Zihan Guo, Jiahui Xiao, Wei Du, Yingzhe Ding, Feixiang Bao, Xingguo Liu.

  Diet is a major determinant of human health and disease, and dietary interventions have emerged as promising adjunctive strategies to preserve neuronal function, improve metabolic control, suppress tumor growth, and delay aging. However, accumulating evidence indicates that their effects are critically dependent on the underlying metabolic, genetic, and pathological context. Beyond conventional adverse effects of excessive dietary restriction, such as nutrient deficiencies, muscle loss, and impaired immunity, recent studies have revealed novel context-dependent adverse effects with new mechanisms. Our study demonstrated that glucose restriction (GR) selectively induces degeneration of neurons with mitochondrial DNA (mtDNA) depletion by disrupting calcium homeostasis at mitochondria-endoplasmic reticulum contact sites (MERCS), revealing that the vulnerability to GR is critically determined by the pre-existing mitochondrial state. Another study showed that extreme GR promotes lung tumor metastasis by reshaping the pulmonary premetastatic immune microenvironment through tumor-derived exosomal tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), challenging the conventional view that GR is uniformly anti-tumorigenic. Together, these findings highlight that the same dietary intervention can produce divergent or even opposing outcomes depending on biological context. Here, we review major dietary interventions, including calorie restriction (CR), fasting diet, ketogenic diet (KD), and GR,and extend a context-dependent framework in which their effects are shaped by mitochondrial integrity, hormonal milieu, tissue-specific metabolism, oncogenic alterations, and immune status. This review underscores the importance of patient stratification and biomarker-guided optimization for the safe and effective application of dietary interventions.

Keywords:  Aging; Dietary Interventions; Metabolism; Neurodegeneration; Tumors

DOI:  https://doi.org/10.1152/physiol.00026.2026