bims-mecosi 2026-09-06 papers

bims-mecosi

Biomed News

on Membrane contact sites

Issue of 2026–09–06
seven papers selected by
Verena Kohler, Umeå University

Role of mitochondria-associated ER membranes in lipid metabolism: implications for renal lipotoxicity.
Tunable Chemical and Optical Modulation of ER-Plasma Membrane Contact-Site Geometry, Dynamics, and Protein Recruitment with High-Fidelity Visualization.
Ceramide transfer protein regulates G-protein-coupled phospholipase signalling in photoreceptors.
Crosstalk between UPR and mitochondria: The triad of ER-mitochondria contacts, Ca²⁺, and ROS.
Spatial-Bioenergetic-Immune Axis in Type 2 Diabetes Mellitus-Associated Sarcopenia: A Review from Pathogenesis to Targeted Reconstruction.
The ER-Golgi Lipid Exchanger PsORP1 Is Essential for Phytophthora sojae Development and Is Blocked by Oxathiapiprolin via Its OSBP-Related Domain (ORD).
Hypertensive mt. tRNAIle4263A>G mutation orchestrates vascular senescence and apoptosis by activation of mitochondria-ER interplay.

Biosci Rep. 2026 Sep 16. pii: BSR20260413. [Epub ahead of print]46(9):

Role of mitochondria-associated ER membranes in lipid metabolism: implications for renal lipotoxicity.

Yile Gao, Minghui Shao, Ya Fang, Jiangping Zeng, Hong Sun.

  Dysregulated lipid metabolism is implicated in renal injury associated with diabetic nephropathy, acute kidney injury, chronic kidney disease, nephrotic syndrome, and renal cell carcinoma. However, its causal role and mechanisms remain ambiguous. Mitochondria-associated ER membranes (MAMs) are contact sites between the endoplasmic reticulum and mitochondria that facilitate the integration of lipid trafficking, mitochondrial metabolism, calcium signaling, and redox homeostasis within cells. Recent evidence from patient biopsies and experimental renal models suggests that altered MAM integrity is linked to ectopic lipid deposition, mitochondrial dysfunction, oxidative stress, and renal injury. The present review examines evidence suggesting that MAM dysregulation may contribute to the abnormal metabolism of phospholipids (PLs), ceramides, cholesterol, fatty acids, and triglycerides in renal cells, thereby addressing a gap between previous reviews on renal lipotoxicity and those focusing on MAM-dependent calcium signaling in kidney diseases. Key mechanisms include impaired PL transfer with disrupted cardiolipin remodeling, ceramide-associated mitochondrial injury, defective fatty acid oxidation, and acyl-CoA synthetase long-chain family member 4-mediated PL peroxidation, leading to renal ferroptosis. Direct evidence for MAM-regulated lipid droplet degradation in the kidney is limited; thus, findings from non-renal cells are differentiated from kidney-specific observations. MAM-associated proteins have emerged as potential therapeutic targets in preclinical studies. However, renoprotective effects of sodium-glucose cotransporter 2 inhibitors and glucagon-like peptide-1 receptor agonists related to MAMs remain indirect and necessitate validation. Restoring the structural and functional integrity of MAMs could represent a promising strategy to mitigate lipid-induced renal injury.

Keywords:  ELD; MAM; kidney; lipotoxicity; mitochondria dysfunction; oxidative stress

DOI:  https://doi.org/10.1042/BSR20260413
Anal Chem. 2026 Aug 25. 98(33): 24473-24488

Tunable Chemical and Optical Modulation of ER-Plasma Membrane Contact-Site Geometry, Dynamics, and Protein Recruitment with High-Fidelity Visualization.

Shaoqing Zhang, Jinyu Fei, Yuanmin Zheng, Ruobo Zhou.

Endoplasmic reticulum-plasma membrane (ER-PM) contact sites are dynamic membrane interfaces that regulate essential cellular processes, including calcium signaling and lipid homeostasis. Emerging evidence suggests that contact-site geometry and organization critically influence these functions, yet existing tools cannot systematically manipulate individual geometric parameters while providing high-fidelity visualization in living cells. Here, we develop complementary chemical and optical platforms for inducible ER-PM contact-site reconstitution. A nontoxic, reversible abscisic acid-inducible system based on the plant-derived ABIcs/PYLcs pair and a rapidly reversible optogenetic iLID/SspB system enable robust visualization and dose-dependent control of contact-site assembly and disassembly. Increasing inducer dose selectively increases contact-site density and total contact area per cell without substantially changing the average size of individual contact sites. In contrast, systematic variation of tether length or tether abundance selectively increases average contact-site size and total contact area without altering contact-site density, providing orthogonal strategies to modulate contact-site density and size. Importantly, engineered contact sites recruit ER-PM contact-site-associated proteins, including MAPPER, Kv2.1, and Stromal Interaction Molecule 1 (STIM1), demonstrating key organizational features of native ER-PM contacts. MAPPER recruitment is maintained across tether lengths tested, whereas Kv2.1/STIM1 recruitment depends strongly on tether length, with longer tethers promoting recruitment by increasing intermembrane spacing. In contrast, varying tether abundance has little effect on protein recruitment, revealing distinct roles for intermembrane spacing and tether density in organizing ER-PM contact sites. Together, this work establishes a quantitative platform for engineering ER-PM contact sites with defined geometric properties and provides a framework for investigating how membrane contact-site architecture regulates cellular function.

DOI: https://doi.org/10.1021/acs.analchem.6c03857
J Cell Biol. 2026 Oct 05. pii: e202511193. [Epub ahead of print]225(10):

Ceramide transfer protein regulates G-protein-coupled phospholipase signalling in photoreceptors.

Shirish Mishra, Ali Khan, Vaisaly R Nath, Tejaswini Manoj, Thejaswini Balavali Gangadhar, Preethi Alex, Amruta Naik, Ujjaini Dasgupta, Padinjat Raghu.

Non-vesicular lipid transfer at membrane contact sites (MCS) is proposed as a key principle in eukaryotic cells. While several lipid transfer proteins (LTPs) are localized at MCS, their physiological significance is poorly understood. Ceramide transfer protein (CERT) transfers ceramide between membranes in vitro. However, evidence for the in vivo significance of CERT function is limited. We find that loss of dcert, the only gene encoding CERT in Drosophila, results in elevated levels of short-chain ceramides along with reductions in the levels of its metabolite phosphoethanolamine ceramide in photoreceptors. Physiological analysis showed a reduced electrical response to light stimulation in dcert mutants. dcert mutants showed a reduction in the rate of phosphatidylinositol 4,5-bisphosphate (PIP2) resynthesis following light-induced phospholipase C (PLC) stimulation, associated with reduced ER-plasma membrane MCS density and function of the MCS-localized protein RDGB. Together, our findings suggest that CERT function regulates G-protein-coupled PLC signalling through modulation of MCS function in vivo.

DOI: https://doi.org/10.1083/jcb.202511193
Pharmacol Res. 2026 Aug 31. pii: S1043-6618(26)00343-9. [Epub ahead of print]232 108428

Crosstalk between UPR and mitochondria: The triad of ER-mitochondria contacts, Ca²⁺, and ROS.

Ester Zito, György Hajnóczky.

  Endoplasmic reticulum (ER) stress is triggered by several cellular perturbations causing protein misfolding, and activates the unfolded protein response (UPR), an initially adaptive signaling network that aims to restore ER and cellular homeostasis. Growing evidence indicates that UPR signaling extends beyond ER proteostasis, influencing mitochondrial function and bioenergetics through ER-mitochondria contact sites (ERMCs). The CHOP-ERO1A-IP3R axis has a primary role in recruiting mitochondria to adaptive UPR. However, its sustained activation renders UPR signaling maladaptive, leading to mitochondrial dysfunction through both outer mitochondrial membrane permeabilization (OMMP) and mitochondrial permeability transition pore (mPTP) opening, ultimately contributing to irreversible cell injury and disease pathogenesis. Here, we examine the molecular mechanisms that govern adaptive and maladaptive UPR signaling and discuss how these ER-centered responses impinge on mitochondrial and cellular physiology. We analyze three major drivers of coupling mitochondrial function to UPR signaling: (i) enhanced ERMCs, (ii) IP3R-mediated Ca²⁺ transfer from the ER to mitochondria, and (iii) bidirectional ROS/H₂O₂ exchange between the two organelles. We also discuss unresolved questions in the field and technological advances, including approaches to investigate ERO1-dependent redox nanodomains, ERO1 inhibitors and engineered ERMC linkers, that are advancing our understanding of ER-mitochondria crosstalk and revealing potential therapeutic opportunities. These insights may inform precision medicine strategies for diseases driven by chronic ER stress and mitochondrial dysfunction.

Keywords:  CHOP; Ca²⁺ handling; ER stress; ERO1; ER–mitochondria contact sites (ERMCs); IP₃ receptor (IP₃R); Mitochondrial permeability transition pore (mPTP); Pharmacological therapy; Unfolded protein response (UPR)

DOI:  https://doi.org/10.1016/j.phrs.2026.108428
J Inflamm Res. 2026 ;19 627857

Spatial-Bioenergetic-Immune Axis in Type 2 Diabetes Mellitus-Associated Sarcopenia: A Review from Pathogenesis to Targeted Reconstruction.

Lingfeng Wu, Hong Ye, Xiaofeng Wang, Qinggang Ding, Wenlong Zhang.

  Type 2 diabetes mellitus (T2DM)-associated sarcopenia extends beyond isolated metabolic dysregulation; consequently, standard glucose-centric therapeutic strategies are insufficient to arrest myofibrillar atrophy. In this review, we characterize this pathogenesis through a novel spatial-bioenergetic-immune axis, stratifying disease progression across three hierarchical levels. First, within the tissue niche, the proliferation of CD90⁺ fibro-adipogenic progenitors (FAPs) establishes a pro-inflammatory microenvironment, driving extracellular matrix fibrosis that physically constrains the myogenic niche. Second, at the subcellular organelle level, kinase-driven structural disruption of mitochondria-associated endoplasmic reticulum membranes (MAMs) induces calcium dyshomeostasis and oxidative stress, culminating in bioenergetic collapse and NLRP3 inflammasome assembly. Third, at the immune-nuclear axis, retrograde signaling-exacerbated by GSDMD-mediated sarcolemmal permeabilization-induces sustained transcriptional repression of core myogenic programs. Synthesizing these spatial mechanisms, we propose a comprehensive clinical paradigm. By integrating microenvironmental modulation (SGLT2 inhibitors/GLP-1RAs), structural mechanotransduction (HIIT), and epigenetic rejuvenation (15-PGDH inhibitors), we advocate for a transition toward precision clinical management of T2DM-associated sarcopenia, aimed at arresting skeletal muscle degeneration and preserving physical functional capacity.

Keywords:  NLRP3 inflammasome; anabolic resistance; fibro-adipogenic progenitors; lipotoxicity; mitochondria-associated ER membranes

DOI:  https://doi.org/10.2147/JIR.S627857
Mol Plant Pathol. 2026 Sep;27(9): e70331

The ER-Golgi Lipid Exchanger PsORP1 Is Essential for Phytophthora sojae Development and Is Blocked by Oxathiapiprolin via Its OSBP-Related Domain (ORD).

Xiaofei Liu, Chengcheng Li, Guangda Shao, Qin Peng, Haixia Wang, Jianqiang Miao, Xili Liu.

  Oxysterol-binding protein (OSBP)-related proteins (ORPs) are indispensable eukaryotic lipid transporters and promising targets for pharmaceutical and agrochemical exploitation. Among ORP family members across kingdoms, oomycete ORP1 constitutes a phylogenetically distinct subtype that evolved independently in oomycetes, which is markedly divergent from ORP homologues in animals, plants and fungi. Oxathiapiprolin, the first commercial fungicide targeting OSBP family proteins, specifically acts on oomycete ORP1 and exhibits robust inhibitory efficacy against diverse Phytophthora pathogens and downy mildews. Nevertheless, the molecular function of oomycete ORP1 and the inhibitory mechanism of oxathiapiprolin remain poorly defined. Here, we demonstrate that PsORP1 of Phytophthora sojae specifically localises to ER-Golgi membrane contact sites (MCSs) and is indispensable for vegetative growth and asexual/sexual development of P. sojae. In vitro liposome reconstitution assays confirmed that the conserved C-terminal OSBP-related domain (ORD) of PsORP1 mediates canonical phosphatidylserine (PS)/phosphatidylinositol 4-phosphate (PI4P) counter-transport. Biochemical binding assays further verified that oxathiapiprolin directly interacts with the ORD of PsORP1 and competitively blocks PS/PI4P lipid exchange. Collectively, this study demonstrates that PsORP1 localises to ER-Golgi MCSs and mediates ORD-dependent PS/PI4P counter-transport, which is essential for P. sojae development, and elucidates that oxathiapiprolin directly targets the ORD to competitively block this lipid exchange, providing a structural framework for rational design of next-generation OSBP-targeting inhibitors against oomycetes.

Keywords:   Phytophthora sojae ; OSBP‐related protein; PS/PI4P exchange; mode of action; oxathiapiprolin

DOI:  https://doi.org/10.1111/mpp.70331
Redox Biol. 2026 Aug 20. pii: S2213-2317(26)00359-9. [Epub ahead of print]97 104360

Hypertensive mt. tRNAIle4263A>G mutation orchestrates vascular senescence and apoptosis by activation of mitochondria-ER interplay.

Nian Cao, Haijing Zhao, Zhengfeng Wu, Shuanglei Li, Wei Tong, Lihao Jin, Ming Wu, Jie Liu, Aihong Liu, Meng Wang, Changfu Liu, Yuqi Liu, Yundai Chen.

  The pathogenic mechanism underlying diseases caused by mitochondrial DNA (mtDNA) mutation, including hypertension, persists as an unresolved global challenge. Although mutation-induced mitochondrial defects have been well characterized, how these mito-perturbations are converted into critical intermediary signaling cascades and contribute to diseases remain unknown. Here, using human induced pluripotent stem cell (hiPSC)-derived vascular organoids (VOs) and vascular cells, the hypertensive mt. tRNAIle4263A > G mutation was identified to induce vascular senescence, apoptosis and vascular-specific dysfunction through mitochondria-endoplasmic reticulum (ER) interaction. For the first time, this study mapped the transcriptional reprogramming landscape of human VOs carrying this mutation. Through systematic screening and functional validation, ER stress was screened out, together with downstream mitochondria-associated ER membranes-mitochondrial Ca2+ overload resulting in vascular abnormality. Pathological reactive oxygen species (ROS) elevation, driven by tRNAIle destabilization and bioenergetic failure, acts as the primary instigator of maladaptive ER stress activation in this cascade. Pharmacological targeting of this axis-using mito-Tempol (a mitochondria-targeted ROS scavenger), Tauro Ursodeoxycholic Acid (an ER stress inhibitor), or RU265 (a highly-selective mitochondrial calcium uniporter inhibitor)-rescues vascular abnormality. This study highlights mt. tRNAIle4263A > G mutation orchestrates vascular pathology through ROS induced activation of inter-organelle communication, resolving a long-standing knowledge gap between mtDNA mutations and diseases and establishing therapeutic nexuses for mtDNA mutation-related cardiovascular diseases.

Keywords:  Hypertension; Mitochondria-associated endoplasmic reticulum membranes; Mitochondrial Ca(2+) overload; ROS; Vascular organoids; mt.DNA mutation

DOI:  https://doi.org/10.1016/j.redox.2026.104360