bims-mecosi 2026-04-05 papers

bims-mecosi

Biomed News

on Membrane contact sites

Issue of 2026–04–05
eleven papers selected by
Verena Kohler, Umeå University

Small molecule modulation of organelle membrane contact sites.
Plasmodium falciparum Niemann-Pick Type C1-Related protein relies on its physicochemical properties for membrane contact site localization required for cholesterol homeostasis.
SERCA2 Dysfunction Drives Vascular Calcification via Coupling with TSPO-MCU at Mitochondria-Associated Endoplasmic Reticulum Membranes.
A bridge-like lipid transfer protein is critical for generation of invasive stages in malaria parasites.
Ca 2+ influx through ER-plasma membrane contacts is required for brown fat thermogenesis and metabolic health.
Endoplasmic Reticulum Geometry Dictates Neuronal Bursting via Calcium Store Refill Rates and Exposes Selective Neuronal Vulnerability.
The P23H Rhodopsin Mouse Model Reveals a Novel Interaction Between the Endoplasmic Reticulum and Connecting Cilium Rootlet Within Photoreceptors.
Intercompartmental communication in senescence.
4-OI improves mitochondria-associated endoplasmic reticulum membrane dysfunction by regulating MFN2 through Nrf2 transcription and alleviates airway inflammation in asthma exposed to PM2.5 early in life.
Complement 5a receptor 2 attenuates diabetic kidney disease by promoting mitochondria-associated endoplasmic reticulum membrane formation mediated by PSS-MFN2 interaction.
Newfoundland Mutation TMEM43-p.S358L Causes Impaired Cardiac Energy Metabolism and Mitochondrial Function Through Altered Protein Interaction.

Trends Pharmacol Sci. 2026 Mar 30. pii: S0165-6147(26)00041-6. [Epub ahead of print]

Small molecule modulation of organelle membrane contact sites.

Minjeong Ko, Jiho You, Eunwoo Cho, Ho Jeong Kwon.

  Organelle membrane contact sites (MCSs) regulate calcium exchange, lipid transfer, metabolism, and cellular stress responses. Dysregulation of MCSs contributes to diverse diseases, yet pharmacological strategies that directly modulate contact architecture remain limited. Recent advances in chemoproteomics and live-cell imaging demonstrate that small molecules can remodel organelle contacts by modulating the conformational states of tethering proteins, coordinating associated effector and regulatory assemblies, and reshaping organelle networks. Here, we propose a pharmacological framework that classifies MCS modulators as stabilizers or destabilizers and review representative compounds, highlighting their molecular mechanisms and emerging therapeutic candidates. We further discuss advanced technologies for visualizing MCS dynamics and identifying small molecule-induced proteoforms. This review positions MCSs as actionable drug targets and outlines future directions for organelle-focused pharmacology.

Keywords:  chemoproteomics; drug discovery; membrane contact sites (MCSs); organelle communication; proteoforms; small molecule modulators

DOI:  https://doi.org/10.1016/j.tips.2026.02.008
bioRxiv. 2026 Mar 26. pii: 2026.03.25.714277. [Epub ahead of print]

Plasmodium falciparum Niemann-Pick Type C1-Related protein relies on its physicochemical properties for membrane contact site localization required for cholesterol homeostasis.

Ananya Ray, Eva S Istvan, Daniel E Goldberg, Matthias Garten.

The Niemann-Pick Type C1-Related protein of the malaria parasite Plasmodium falciparum , PfNCR1, is a promising anti-malarial drug target facilitating cholesterol homeostasis at the interface of the malaria parasite with its host-red blood cell. PfNCR1 is localized to otherwise functionally uncharacterized regions covering ∼half of the host-parasite interface. These regions are defined by exceptionally narrow membrane contact sites, leaving only ∼3-4 nm vertical aqueous space in between the membranes. Determining the origin and functional consequence of localization to the closely apposed membrane is central for our understanding of PfNCR1 as drug target but also offers a window into the mechanism of the group of homologous proteins, associated with congenital conditions and cancer. Here we define the mechanism of PfNCR1's membrane contact site localization and its implication for cholesterol transport. We identified a 141 amino acid long (amphipathic) helix - linker - (amphipathic) helix domain ("HLH domain") unique to Plasmodium spp. , that is necessary for efficient localization of PfNCR1 to the narrow membrane contact sites. Mechanistically, we show that this localization relies on the HLH domain's physicochemical properties. GPI-anchoring the isolated HLH domain or a version of the HLH domain in which the helices are replaced by the amphipathic helix of human ATG3 are sufficient to target a fluorescent protein to regions of endogenous PfNCR1. Functionally, we demonstrate that the degree of PfNCR1 localization to narrow contact sites qualitatively correlates with its ability to maintain cholesterol homeostasis, linking PfNCR1's membrane contact to its recognized transport function. Collectively, the results establish the HLH domain as key element for PfNCR1's localization and effectiveness in cholesterol transport while also opening avenues to probe the narrow membrane contact site regions with engineered proteins.

DOI: https://doi.org/10.64898/2026.03.25.714277
Pharmacol Res. 2026 Apr 01. pii: S1043-6618(26)00092-7. [Epub ahead of print] 108177

SERCA2 Dysfunction Drives Vascular Calcification via Coupling with TSPO-MCU at Mitochondria-Associated Endoplasmic Reticulum Membranes.

Shixian Pi, Wanling Liu, Junyong Zhao, Hui Chen, Xianbin Luo, Shaofa Wu, Jiarou Song, Xun Chen, Xue Li, Wenjian Luo, Yirui Wang, Chuan Liu, Jun Ren, Tian Li, He Liu, Xiaoyong Tong, Zhexue Qin.

  Vascular calcification arises from osteogenic transdifferentiation of vascular smooth muscle cells (VSMC) driven by disordered calcium signaling. Sarcoplasmic/ER calcium ATPase 2 (SERCA2) maintains intracellular calcium homeostasis. Irreversible oxidation of SERCA2 Cys674 (C674) indicates SERCA2 dysfunction. The impact of SERCA2 dysfunction on vascular calcification remains poorly understood. Here, we demonstrate that oxidized SERCA2 C674, a SERCA2 dysfunction marker, was elevated in the calcified arteries of mice and chronic kidney disease (CKD) patients. Heterozygous SERCA2 Cys674Ser knock-in (SKI) mice, a SERCA2 dysfunction model, exhibited aggravated aortic calcification in cholecalciferol (VitD3)-overloaded and 5/6 nephrectomy-induced CKD mice. SERCA2 dysfunction exacerbates calcification, mitochondrial impairment and calcium overload in cultured VSMC. Mechanistically, SERCA2 dysfunction increased mitochondria-associated endoplasmic reticulum membrane (MAM) formation. Furthermore, outer-mitochondrial translocator protein (TSPO) was identified to facilitate SERCA2 coupling to the IP3R1-Grp75-VDAC1-MCU complex at MAM. TSPO knockdown alleviated SERCA2 dysfunction-induced MAM formation and vascular calcification in SKI mice and cultured SKI VSMC, while TSPO overexpression aggravated these effects. Inhibition of the downstream mitochondrial calcium uniporter (MCU) reduced mitochondrial calcium overload and thus alleviated the pro-calcific effects of TSPO in SKI VSMC. In conclusion, SERCA2 dysfunction promotes TSPO-dependent MAM formation, which couples SERCA2 to the IP3R1-Grp75-VDAC1-MCU complex, causing mitochondrial impairment and calcium overload. This study uncovers the pivotal role of SERCA2 during vascular calcification, delineates the novel components of the MAM complex, and highlights potential therapeutic targets of vascular calcification.

Keywords:  SERCA2; mitochondria-associated endoplasmic reticulum membranes; mitochondrial calcium uniporter; translocator protein; vascular calcification

DOI:  https://doi.org/10.1016/j.phrs.2026.108177
Nat Commun. 2026 Mar 28. pii: 3030. [Epub ahead of print]17(1):

A bridge-like lipid transfer protein is critical for generation of invasive stages in malaria parasites.

Andrés Guillén-Samander, Nika Perepelkina, Vendula Horáčková, Hannah M Behrens, Hely O Rodriguez Cruz, Joëlle Paolo Mesén-Ramírez, Ana Ribeiro-Holbein, Per Haberkant, Frank Stein, Tobias Spielmann.

Malaria blood stages build and maintain an intricate system of membranes during their cycle of rapid growth and schizogony (daughter-cell formation), requiring precise mechanisms of lipid synthesis and trafficking. Lipid transfer proteins (LTPs) at ER membrane contact sites (MCSs) have emerged as key for lipid distribution processes but remain largely unexplored in protozoans. Here we use the ER adapter VAP to identify essential mechanisms of lipid transfer at ER-MCSs in P. falciparum. One PfVAP-interacting LTP is the bridge-like PfVPS13L1, which allows bulk flow of lipids between two apposed membranes. PfVPS13L1 bridges the ER with the nascent inner membrane complex (IMC), a de novo-generated organelle required for schizogony. Its loss-of-function reduces IMC growth and leads to smaller anucleated progeny, impairing schizogony. Our data supports a model in which VPS13L1 is critical for the formation of apicomplexan invasive stages by mediating bulk transfer of lipids from the ER to the growing IMC.

DOI: https://doi.org/10.1038/s41467-026-70887-1
bioRxiv. 2026 Mar 23. pii: 2026.03.20.712802. [Epub ahead of print]

Ca 2+ influx through ER-plasma membrane contacts is required for brown fat thermogenesis and metabolic health.

J Zhou, C Dogan, L L Artico, K Rodrigues, S Hakam, T Kim, V Xu, K Lapenta, M Kang, D M Jorgens, S B Widenmaier, G Parlakgul, A P Arruda.

Brown adipose tissue (BAT) exhibits exceptional metabolic plasticity, rapidly increasing energy expenditure to sustain thermogenesis during cold exposure. This high metabolic activity imposes substantial demands on cellular systems, requiring robust adaptive mechanisms to maintain homeostasis and prevent cellular stress. Yet, the pathways that support and coordinate these adaptive responses in brown adipocytes remain incompletely understood. Here, we identify a cold-induced adaptive program in BAT characterized by the formation of endoplasmic reticulum-plasma membrane (ER-PM) contact sites and the activation of store-operated calcium entry (SOCE), which is essential for maintaining brown adipocyte health during thermogenic activation. Cold exposure enhances ER-PM contacts and upregulates the expression of STIM and Orai proteins, key mediators of SOCE. Loss of STIM in brown adipocytes disrupts intracellular Ca²⁺ homeostasis and induces aberrant aggregation of ER membranes. STIM deficiency also impairs cold-induced mitochondrial fission resulting in hyperfused mitochondria with reduced oxidative capacity, independently of UCP1 abundance. Importantly, mice lacking STIM in BAT exhibit impaired lipid oxidation, are cold intolerant and develop exacerbated peripheral insulin resistance when challenged with a high-fat diet. Together, these findings identify ER-PM remodeling and STIM-mediated SOCE as a central regulator that links organelle architecture to brown adipocyte function and contributes to whole-body metabolic homeostasis.

DOI: https://doi.org/10.64898/2026.03.20.712802
Adv Sci (Weinh). 2026 Mar 31. e21101

Endoplasmic Reticulum Geometry Dictates Neuronal Bursting via Calcium Store Refill Rates and Exposes Selective Neuronal Vulnerability.

Valentina Davi, Pierre Parutto, Yuyi Zhang, Tasuku Konno, Cecile Crapart, Raquel Pereira, John P Franklin, Mosab Ali Awadelkareem, Daniel C Maddison, Michael J Devine, Edgar R Gomes, Joseph Chambers, Elena Koslover, Edward Avezov.

  The endoplasmic reticulum (ER)'s continuous morphology is tightly controlled by ER-shaping proteins, whose genetic or expression defects drive a spectrum of neurodegenerative disorders from Hereditary Spastic Paraplegia to Alzheimer's disease. Why perturbations in ER morphology manifest specifically in neurons remains unknown. Here, by coupling visualisation of global sub-Hz firing bursts to ER ultrastructural manipulations in human inducible Pluripotent Stem Cells (hiPSC)-derived cortical neurons, alongside physical simulations, we establish a key ER structure-function principle: neuronal ER architecture dictates Ca2+ replenishment speed. Altering ER structure hinders network ER luminal connectivity and Ca2+ propagation from refill points at plasma membrane contact sites, impairing the ER's capability to supply repetitive Ca2+ bursts. The ER morpho-regulatory control of Ca2+ refill speed thus constitutes a switch on neuronal activity. Further, perturbed ER shape also abolishes Ca2+ firing and contraction in primary skeletal muscle cells. These results expose the selective vulnerability of Ca2+-firing cells to ER structural disruptions, rationalizing ER dysfunction in neurodegeneration and unveiling a new role for the continuous ER morphology that could apply universally to Ca2+-firing cells.

Keywords:  calcium oscillations; endoplasmic reticulum Ca2+ refill; endoplasmic reticulum morphology; human iPSC‐derived neurons; modelling; neurodegenerative diseases ; neuronal firing

DOI:  https://doi.org/10.1002/advs.202521101
Invest Ophthalmol Vis Sci. 2026 Mar 02. 67(3): 57

The P23H Rhodopsin Mouse Model Reveals a Novel Interaction Between the Endoplasmic Reticulum and Connecting Cilium Rootlet Within Photoreceptors.

Sergey S Novoselov, Bernardo S Mendes, Andrea Martello, Silene Wavre-Shapton, Monica Aguila, Rosellina Guarascio, Kalliopi Ziaka, Dalila Bevilacqua, Gergana Metodieva, Philip J Luthert, Jun Yang, Metodi V Metodiev, Philip J Reeves, Clare E Futter, Michael E Cheetham, Thomas Burgoyne.

Purpose: Photoreceptors are highly polarized sensory neurons containing a modified cilium known as the outer segment. This cilium has a rootlet that spans the length of the metabolically active inner segment and anchors the outer segment to the remainder of the photoreceptor. The full function and reasons for such a long rootlet in photoreceptors are not well understood. To gain deeper insight, we characterized the membrane associated with the rootlet.
Methods: Proteomic analysis was performed on immunopurified wild-type (WT) and P23H rhodopsin knock-in mouse retina. Images of mouse and human retina were acquired by transmission electron microscopy and electron tomography and protein localization in mouse retina determined by immunofluorescence and immunoelectron microscopy.
Results: In homozygous P23H knock-in mouse retinas, misfolded rhodopsin retained in the endoplasmic reticulum (ER) prior to degradation was found to be closely associated with rootletin and mitochondrial proteins. This observation helped reveal that the ER forms extensive interactions with the rootlet, running alongside it throughout the inner segment. Furthermore, the ER branches from the rootlet to make contact with mitochondria, Golgi, and the plasma membrane. Human rod photoreceptors had similar rootlet:ER interactions within the proximal inner segment, but differed from mouse, as the rootlet within the distal inner segment mainly interacted with mitochondria.
Conclusions: These findings suggest that the rootlet plays a critical role in organizing intracellular architecture by serving as a kind of "scaffold" that supports ER positioning and allowing it to branch and form membrane contact sites with other cellular membranes.

DOI: https://doi.org/10.1167/iovs.67.3.57
FEBS Open Bio. 2026 Mar 30.

Intercompartmental communication in senescence.

Krystyna Mazan-Mamczarz, Eleanor J Wind, Jixiang Leng, Myriam Gorospe.

  Cellular senescence represents a response to sublethal damage, characterized by persistent growth arrest and a robust pro-inflammatory trait, the senescence-associated secretory phenotype (SASP). Senescent cells accumulate in the body with age, promoting tissue dysfunction and age-related disease. In addition to profound reprogramming of gene expression patterns, senescent cells undergo broad remodeling of cellular compartments, including the plasma membrane, nucleus, endoplasmic reticulum (ER), Golgi apparatus, endolysosomal system, mitochondria, biomolecular condensates, and cytoskeleton. These changes alter the intracellular communication networks required for homeostasis. Here, we review how senescence alters (i) vesicular trafficking along secretory, endocytic, and autophagic routes, (ii) interorganelle contact sites such as those among mitochondria, ER, and lysosomes to modulate lipid and calcium exchange, and (iii) diffusion and transport of regulatory signals across the cytosol and membranes. We discuss how the impaired crosstalk among compartments increases ROS, exacerbates proteostatic stress, impairs clearance of damaged components, and activates p53/p21, p16/Rb, cGAS-STING, NF-κB, and mTOR pathways, enhancing apoptosis resistance and the SASP. Finally, we highlight emerging technologies to study the senescent organelle 'interactome' and identify therapeutic vulnerabilities in age-associated declines and diseases linked to senescence. Impact statement We synthesize evidence that cellular senescence arises not only from gene expression changes but also from disrupted interorganelle communication. We discuss defects in vesicle trafficking and organelle contact sites that redefine senescence as failure of the organellar interactome, highlighting future mechanistic work and therapeutic opportunities in age-related disease.

Keywords:  Golgi; SASP; endoplasmic reticulum; interorganellar communication; organelles; senescence

DOI:  https://doi.org/10.1002/2211-5463.70236
Inhal Toxicol. 2026 Mar 28. 1-16

4-OI improves mitochondria-associated endoplasmic reticulum membrane dysfunction by regulating MFN2 through Nrf2 transcription and alleviates airway inflammation in asthma exposed to PM2.5 early in life.

Jiaxin Xu, Lei Wang, Rui Zhou, Siwei Wang, Juan Li.

   BACKGROUND: Asthma is a disease that still lacks effective preventive measures with distinctive pathologicfeatures, particularly inflammation, oxidative stress, apoptosis and endoplasmic reticulum (ER) stress. 4-Octyl itaconate (4-OI) has been reported to possess immunomodulatory, anti-inflammatory and antioxidant properties.
METHODS: In this study, we evaluated the efficacy of 4-OI in airway inflammation and oxidative lung injury in asthmatic mice exposed to PM2.5 using the ovalbumin (OVA)+ PM2.5-induced asthma model in BALB/c mice. In addition, we further evaluated the role of 4-OI in protecting BEAS-2B cells from PM2.5 induction using an in vitro model of asthma.
RESULTS: The results showed that 4-OI attenuated airway inflammatory cell infiltration and the levels of mouse whole lung lavage fluid inflammatory factors, and decreased the levels of MDA and ROS, while increasing the activity of SOD. Meanwhile, in in vitro experiments, it was further demonstrated that 4-OI transcriptionally regulated MFN2 via Nrf2, which reduced the intracellular and mitochondrial ROS content, and the fluorescence intensities of Mito Tracker Red+ calnexin+ and MFN2+PERK+ were also significantly reduced. Fluo-3 AM experiment showed that 4-OI reduced Ca2+ concentration by regulating MFN2 through Nrf2 transcription. In addition, the protein expression of MFN1, MFN2, Bcl-2, and pro-Caspase3 was significantly elevated and that of PERK, GRP78, CHOP, Caspase12, Bax, and cleaved-Caspase3 was significantly decreased by Western Blot.
CONCLUSIONS: In summary, our research demonstrated found that 4-OI improved the dysfunction of mitochondria-associated endoplasmic reticulum membranes by modulating MFN2 via Nrf2 transcription, thereby reducing the inflammatory response in asthmatic airways during early exposure to PM2.5.

Keywords:  4-OI; MFN2; Nrf2; PM2.5; mitochondrial dysfunction

DOI:  https://doi.org/10.1080/08958378.2026.2650614
Cell Discov. 2026 Mar 31. pii: 24. [Epub ahead of print]12(1):

Complement 5a receptor 2 attenuates diabetic kidney disease by promoting mitochondria-associated endoplasmic reticulum membrane formation mediated by PSS-MFN2 interaction.

Yi-Yang Zhao, Yi-Hui Wang, Zi-Han Li, Dong-Yuan Chang, Lin Nie, Ming-Hui Zhao, Sydney Chi Wai Tang, Min Chen.

Complement-mediated metabolic disorders are considered important contributors to the pathogenesis of diabetic kidney disease (DKD). This study investigated the non-canonical roles of complement 5a receptor 2 (C5aR2) in metabolism and its underlying molecular mechanisms in DKD. In patients with DKD, we found that C5aR2 expression was upregulated in the tubulointerstitium and correlated with both disease severity and adverse renal outcomes. C5aR2 deficiency in diabetic mice exacerbated the DKD phenotype, including pronounced lipid accumulation, mitochondrial and endoplasmic reticulum (ER) dysfunction, and reduced phosphatidylserine (PS) levels in the kidney. Mechanistically, C5aR2 activated cellular Fos proto-oncogene (c-FOS) nuclear translocation, upregulated phosphatidylserine synthase (PSS) expression, and promoted the interaction between PSS and mitochondrial fusion protein 2 (MFN2), which facilitated mitochondria-associated ER membrane (MAM) formation and PS biosynthesis, improving mitochondrial and ER function. Treatment with the C5aR2-specific agonist P59 ameliorated the DKD phenotype, improved PS homeostasis and MAM formation, and thereby reversed lipid accumulation, ER stress, and mitochondrial dysfunction in db/db mice. Single-cell RNA sequencing (scRNA-seq) analysis revealed that P59 restored Pss expression in injured proximal tubular cells. These results highlight C5aR2 activation as a promising strategy for DKD treatment.

DOI: https://doi.org/10.1038/s41421-026-00873-w
Circ Genom Precis Med. 2026 Apr 01. e005171

Newfoundland Mutation TMEM43-p.S358L Causes Impaired Cardiac Energy Metabolism and Mitochondrial Function Through Altered Protein Interaction.

Sandra Ratnavadivel, Kai Jürgens, Nora Klinke, Anna Gärtner, Joline Groß, Karin Klingel, Anders Malmendal, Stefan Walter, Hanne Boen, Emeline Van Craenenbroeck, René Schramm, Anna Kostareva, Jan Gummert, Astrid Kassner, Heiko Meyer, Achim Paululat, Hendrik Milting.

   BACKGROUND: TMEM43 (transmembrane protein 43) is a ubiquitously expressed 4-transmembrane-protein localized in the endoplasmic reticulum and nuclear lamina. The mutation TMEM43-p.S358L causes ARVC5 (arrhythmogenic right ventricular cardiomyopathy type 5). The TMEM43 function and the pathomechanisms of TMEM43-p.S358L remain poorly understood. We analyzed carrier-derived human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs), human myocardial tissue from TMEM43-wild-type, and TMEM43-p.S358L and identified differentially interacting proteins. We provide evidence for a novel pathomechanism contributing to ARVC5.
METHODS: Microsomes of human wild-type myocardium were separated by sucrose-gradient ultracentrifugation and characterized by mass-spectrometry to identify potential interacting proteins. Proteome and metabolome analyses of a TMEM43-p.S358L explanted human myocardium were performed. hiPSC-derived cardiomyocytes of TMEM43-p.S358L carrier and a corresponding isogenic control were generated. A 3'-end HA-Tag was introduced in TMEM43 for pull-down experiments under optimized conditions. Lipidomics, proteomics, contractility, and ATP-content were measured in hiPSC-CMs.
RESULTS: Pull-down analyses of TMEM43-WT and mutant showed altered interacting proteins involved in metabolic pathways. Lipidomics revealed the accumulation of lipids and decreased lipid metabolism capacity in mutant hiPSC-CMs. The ATP to ADP ratio was lower in mutant hiPSC-CMs and could be associated with diminished contraction frequency. The human TMEM43-p.S358L myocardial proteome revealed altered protein-expression of metabolic pathways comparable to mutant hiPSC-CMs. Metabolic remodeling was also found in the mutant human myocardium. Ultracentrifugation fraction with the highest protein amount of TMEM43 and pull-down experiments of hiPSC-CMs revealed differentially interacting proteins of TMEM43-p.S358L from endoplasmic reticulum and mitochondrial membranes.
CONCLUSIONS: We suggest differential interaction of mutant TMEM43 with proteins of mitochondria and endoplasmic reticulum influences endoplasmic reticulum-mitochondrial contact sites. TMEM43-p.S358L primarily contributes to changes in mitochondrial function affecting lipid homeostasis and energy supply.

Keywords:  lipids; metabolome; mutation; proteome; sucrose

DOI:  https://doi.org/10.1161/CIRCGEN.125.005171