bims-mecosi 2026-05-31 papers

bims-mecosi

Biomed News

on Membrane contact sites

Issue of 2026–05–31
twenty papers selected by
Verena Kohler, Umeå University

Protocol for the in vivo quantification of mitochondria-associated ER membranes in Caenorhabditis elegans.
MICOS and MIMAS, multifunctional assemblies linking mitochondrial biogenesis, architecture, and function.
Mitochondria-associated membranes in heart failure: from molecular mechanisms to therapeutic targets.
Organelle regulation of ferroptosis after intracerebral hemorrhage.
Mitochondria-ER contact sites (MERCS) in the cell cycle: molecular architecture and functional remodeling across cellular states.
Membrane bridges and nanodomain partitioning govern membrane protein targeting to lipid droplets.
Disruption of ER-mitochondria contact sites by coronavirus replication organelles sustains viral replication via NSP3 stabilization.
Malic Enzyme 2 Regulates Dynamin-Related Protein 1-Dependent Mitochondrial Fission and Mitochondria-Associated Membranes to Drive Odontogenic Differentiation: An In Vitro and In Vivo Study.
MFN2 Overexpression Attenuates Coal Dust-Induced Pulmonary Fibrosis by Modulating MAMs Integrity and Cell Apoptosis.
Exploring Replicative Senescence and Oxidative Stress-Induced Remodelling of Mitochondrial-Associated Membranes in Human Skin Fibroblasts.
Patulin induces crosstalk between ferroptosis and the endoplasmic reticulum-MAMs-mitochondria axis in the kidney.
A lipid droplet - plasma membrane contact site is conserved across the angiosperm lineage.
Redox control at the ER-mitochondria interface in kidney transplantation: MAM-centered stress signaling and translational organoid platforms.
Disruption of Fructose 1,6-Bisphosphatase 2 Proximity to MIC60 Correlates with Mitochondrial Ultrastructural Changes.
Ubiquitin-dependent mitochondrial protein degradation ensures seedling emergence by regulating ER-mitochondrial interaction and mitophagy.
FLVCR1-related diseases: from clinical heterogeneity to mechanistic insights.
Cell Structure Segmentation in TEM Images of Murine Skin Melanoma Cells by Deep Learning Model.
Holistic therapeutic philosophy: Boost a cascade communication between endoplasmic reticulum-mitochondria-lysosome to overload intracellular Ca2+ and initiate chemoimmunotherapy.
ITPR1 Maintains Mitochondrial Redox Homeostasis to Drive Glioblastoma Progression Through Recruitment and Activation of DRP1.
The Role of Sigmar1 in Autophagy Regulation and Disease Therapy.

STAR Protoc. 2026 May 22. pii: S2666-1667(26)00245-5. [Epub ahead of print]7(2): 104592

Protocol for the in vivo quantification of mitochondria-associated ER membranes in Caenorhabditis elegans.

Fivos Borbolis, Konstantinos Palikaras.

  Mitochondria-associated membranes (MAMs) are specialized contact sites between the endoplasmic reticulum and mitochondria, with multiple functional aspects. Here, we present a confocal microscopy-based protocol for quantifying the area of MAM-like domains in intestinal cells of the nematode Caenorhabditis elegans using organelle-specific fluorescent reporters. We describe steps for worm synchronization, microscope setup, sample preparation, and image acquisition. We then detail procedures for manual single-image analysis and scalable automated batch processing, enabling robust quantification of ER-mitochondria contacts across experimental conditions. For complete details on the use and execution of this protocol, please refer to Roussos et al.1.

Keywords:  Cell Biology; Model Organisms; microscopy

DOI:  https://doi.org/10.1016/j.xpro.2026.104592
Protein Sci. 2026 Jun;35(6): e70653

MICOS and MIMAS, multifunctional assemblies linking mitochondrial biogenesis, architecture, and function.

Patrick Horten, Kuo Song, Nikolaus Pfanner, Heike Rampelt.

  Mitochondrial cristae architecture is central for optimal oxidative phosphorylation and a healthy mitochondrial physiology. The intricate architecture of the inner mitochondrial membrane relies on protein complexes that compartmentalize the membrane by imposing membrane curvature, forming membrane contact sites or membrane subdomains, regulating the partitioning of mitochondrial proteins between the different subcompartments and thereby enabling functional asymmetry, and by governing membrane dynamics. Studies in recent years have expanded our understanding of the machineries and mechanisms underlying the manifold functions of the inner membrane. This review focuses on the mitochondrial contact site and cristae organizing system (MICOS), a protein complex that stabilizes the narrow entry gates of cristae, and on a novel inner membrane megacomplex, the mitochondrial multifunctional assembly (MIMAS), as well as on their roles in organizing the inner membrane.

Keywords:  cristae; membrane organization; metabolism; mitochondria; respiratory chain

DOI:  https://doi.org/10.1002/pro.70653
Front Physiol. 2026 ;17 1797296

Mitochondria-associated membranes in heart failure: from molecular mechanisms to therapeutic targets.

Shuning Li, Yanjie Lian, Xiaolei Lai, Juju Shang, Wenlong Xing, Hongxu Liu.

  Mitochondria-associated endoplasmic reticulum membranes (MAMs) serve as pivotal functional contact sites linking mitochondria and the endoplasmic reticulum, playing a role in orchestrating various cellular life activities, including calcium homeostasis, mitochondrial quality control, endoplasmic reticulum stress, lipid synthesis and transport, inflammation and innate immunity, apoptosis, autophagy, ferroptosis, and oxidative stress. Recent research has demonstrated that the structural and functional dysregulation of MAMs significantly contributes to the onset and progression of heart failure. This review systematically examined the molecular composition, structural features, and dynamic regulatory mechanisms of MAMs, emphasizing their central roles in the pathophysiological processes of heart failure, such as calcium homeostasis imbalance, mitochondrial dynamics disorders, endoplasmic reticulum stress, metabolic reprogramming, and inflammatory and immune responses. We proposed an in-depth analysis of the differential manifestations of MAMs across distinct heart failure phenotypes (HFrEF and HFpEF) and summarized potential therapeutic strategies targeting MAMs, along with the challenges encountered in their clinical translation. Finally, we proposed a novel research paradigm for MAMs based on multi-omics integration and artificial intelligence, offering a theoretical foundation for the development of precise treatment plans for heart failure.

Keywords:  calcium homeostasis; heart failure; mitochondria-associated endoplasmic reticulum membranes; organelle interaction; therapeutic target

DOI:  https://doi.org/10.3389/fphys.2026.1797296
Redox Biol. 2026 May 21. pii: S2213-2317(26)00212-0. [Epub ahead of print]94 104214

Organelle regulation of ferroptosis after intracerebral hemorrhage.

Na Zhou, Yang Du, Yinuo Wang, Xingquan Zhao, Yi Ju.

  Intracerebral hemorrhage (ICH) is a devastating form of acute cerebrovascular disease characterized by high mortality and long-term disability, posing a substantial public health burden. Ferroptosis has emerged as a pivotal mechanism underlying secondary brain injury (SBI) after ICH, driven by reactive iron accumulation, amplification of lipid peroxidation (LPO) cascades, and disruption of cellular antioxidant defenses. Despite growing evidence supporting its involvement, the precise regulatory networks governing ferroptosis after ICH remain to be fully clarified. This review integrates recent advances to delineate how mitochondria, the endoplasmic reticulum (ER), lysosomes, lipid droplets (LDs), peroxisomes, the Golgi apparatus, and inter organelle membrane contact sites (MCSs) contribute to ferroptosis after ICH. We further summarize current therapeutic strategies targeting ferroptosis from an organelle-centered perspective and highlight its potential as a promising avenue for future intervention.

Keywords:  Ferroptosis; Intracerebral hemorrhage; Membrane contact sites; Mitochondria; Organelles

DOI:  https://doi.org/10.1016/j.redox.2026.104214
BMC Biol. 2026 May 27.

Mitochondria-ER contact sites (MERCS) in the cell cycle: molecular architecture and functional remodeling across cellular states.

Eduardo Silva-Pavez, Bruno Torres-Gonzalez, Michelle Sotomayor, Benjamín Cartes-Saavedra, Dorian V Ziegler, Yessia Hidalgo-Fadic, Ulises Ahumada-Castro.

  Mitochondria-endoplasmic reticulum (ER) contact sites (MERCS) are nanoscopic, dynamic platforms integrating metabolism, signaling, and stress responses to regulate cell fate. These nanoscopic interfaces remodel continuously to meet the demands of proliferating, quiescent, and senescent cells. We synthesize evidence that MERCS actively coordinate local Ca2+ signaling, non-vesicular lipid transfer, and proteostasis to shape mitochondrial function and cellular homeostasis. We discuss how MERCS architecture changes across the cell cycle and during arrest, distinguishing adaptive from maladaptive remodeling, and consider therapeutic potential in aging and age-related disease.

Keywords:  Calcium signaling; Cell-cycle regulation; Cellular senescence; Lipid transfer; Mitochondria–ER contact sites

DOI:  https://doi.org/10.1186/s12915-026-02645-0
Nat Cell Biol. 2026 May 26.

Membrane bridges and nanodomain partitioning govern membrane protein targeting to lipid droplets.

Arda Mizrak, Jacob Kæstel-Hansen, Jessica Matthias, J Wade Harper, Nikos S Hatzakis, Robert V Farese, Tobias C Walther.

Numerous metabolic enzymes translocate from the endoplasmic reticulum (ER) membrane bilayer to the lipid droplet (LD) monolayer, where they perform essential functions. Mislocalization of certain LD-targeted membrane proteins, including HSD17B13 and PNPLA3, is implicated in metabolic dysfunction-associated steatotic liver disease. However, the mechanisms governing the trafficking and accumulation of ER proteins on LDs remain poorly understood. Here using minimal fluorescence photon fluxes nanoscopy and highly inclined and laminated optical single-molecule tracking combined with machine learning, we show that HSD17B13, GPAT4 and the model cargo 'LiveDrop' diffuse at comparable speeds in the ER and on LDs, but become nano-confined upon reaching the LD surface. Mechanistic dissection of LiveDrop targeting revealed that this confinement, along with protein accumulation on LDs, depends on specific residues within its targeting motif. These residues mediate preferential interactions with nanoscale membrane domains, suggesting that LD-targeted proteins selectively partition into distinct lipid-protein environments that transiently alter local motion and concentrate them at the LD surface. Single-molecule trajectories further revealed bidirectional trafficking of LiveDrop across seipin-containing ER-LD bridges, providing direct evidence for lateral protein transfer across membrane contact sites. These findings establish nanodomain-based confinement as a key mechanism driving selective protein accumulation on LDs and reveal how membrane bridges between organelles facilitate protein sorting.

DOI: https://doi.org/10.1038/s41556-026-01963-3
EMBO J. 2026 May 28.

Disruption of ER-mitochondria contact sites by coronavirus replication organelles sustains viral replication via NSP3 stabilization.

Xinyue Zheng, Liqiao Hu, Xubing Long, Zhilei Zhao, Rongrong Chen, Rong Bai, Buyun Tian, Maoge Zhou, Binbin Ding, Tao Xu, Zonghong Li.

Coronaviruses establish infection by reorganizing the host endoplasmic reticulum (ER) to form double-membrane vesicles (DMVs), which function as viral replication platforms. However, the role of other cellular organelles in this process remains incompletely understood. Here, we uncover a self-reinforcing cycle between viral replication organelles and mitochondrial damage that sustains coronavirus replication. We show that DMV formation disrupts ER-mitochondria contact sites (ERMCs), causing mitochondrial damage. This injury initiates a feed-forward mechanism wherein mitochondria release the matrix enzyme ECHS1 into the cytosol. Cytosolic ECHS1 then binds and stabilizes the DMV inducer protein NSP3 by blocking its K963 ubiquitination via the host E3 ligase RBBP6, thereby promoting further DMV formation. Disrupting this cycle, either through enhanced ER-mitochondria tethering or targeted interference with ECHS1-NSP3 binding, effectively suppresses viral replication. Our findings reveal that coronaviruses exploit an inter-organellar feedback loop linking mitochondrial damage to DMV formation, identifying new potential therapeutic targets for inhibition of coronaviral replication.

DOI: https://doi.org/10.1038/s44318-026-00816-x
Biomolecules. 2026 Apr 30. pii: 664. [Epub ahead of print]16(5):

Malic Enzyme 2 Regulates Dynamin-Related Protein 1-Dependent Mitochondrial Fission and Mitochondria-Associated Membranes to Drive Odontogenic Differentiation: An In Vitro and In Vivo Study.

Jingzhou Li, Qianyi Shi, Xinyue Sheng, Haozhen Ma, Qianyi Deng, Yifan He, Fuping Zhang, Fang Huang.

  The differentiation of dental papilla cells (DPCs) into functional odontoblasts is critical for dentinogenesis, yet the role of mitochondrial dynamics remains unclear. Here, we investigated the functional role of mitochondrial fission and mitochondria-associated endoplasmic reticulum membranes (MAMs) in the odontogenic differentiation of DPCs. Using in vitro differentiation models combined with confocal microscopy, transmission electron microscopy, and gain- and loss-of-function approaches, we found that odontogenic induction triggered early mitochondrial fragmentation and increased MAM formation. Dynamin-related protein 1 (DRP1) mediated mitochondrial fission, which in turn regulated MAM architecture and promoted differentiation. Malic enzyme 2 (ME2) acted as an upstream regulator, facilitating DRP1 recruitment and organizing MAM integrity. Notably, disruption of the ME2-DRP1-MAM axis impaired dentin formation both in vitro and in vivo, either by ME2 knockdown or pharmacological inhibition of DRP1 (Mdivi-1). These findings establish the ME2-DRP1-MAM axis as a critical metabolic-organellar switch driving odontoblast differentiation, providing new mechanistic insights into dentinogenesis and identifying potential therapeutic targets for dentin-pulp complex regeneration.

Keywords:  dental papilla cells; dynamin-related protein 1; malic enzyme 2; mitochondria-associated endoplasmic reticulum membranes; mitochondrial fission; odontogenic differentiation

DOI:  https://doi.org/10.3390/biom16050664
Toxics. 2026 Apr 30. pii: 391. [Epub ahead of print]14(5):

MFN2 Overexpression Attenuates Coal Dust-Induced Pulmonary Fibrosis by Modulating MAMs Integrity and Cell Apoptosis.

Na Zhang, Lulu Liu, Junrong Chen, Yingjie Liu, Shen Yang, Mei Zhang, Yu Xiong, Xin Ma, Yan Wang, Xiaoqiang Han.

  Pneumoconiosis, characterized by progressive pulmonary fibrosis, remains a predominant occupational disease in China, with coal workers' pneumoconiosis (CWP) and silicosis being the primary subtypes. Despite extensive research, its underlying pathogenic mechanisms are not yet fully understood. Mitochondria-associated endoplasmic reticulum (ER) membranes (MAMs) are crucial subcellular microdomains that govern Ca2+ transport, sustain cellular bioenergetics, and maintain systemic homeostasis. Emerging evidence has linked the structural and functional dysregulation of MAMs to the pathogenesis of various fibrotic disorders. Apoptosis, a highly regulated cell death process, is a key driver in pneumoconiosis progression, in which Ca2+ imbalance serves as a critical signaling cascade. Mitofusin 2 (MFN2), a core regulator of MAMs' structural integrity, mediates mitochondrial fusion and directly bridges the ER with the outer mitochondrial membrane, thereby stabilizing ER-mitochondrial coupling. However, whether MFN2 mitigates fibrosis by preserving MAMs' integrity and subsequently suppressing Ca2+-dependent apoptosis remains elusive. In this study, we established SD rat and A549 cell models of CWP. Our results demonstrated that MFN2 expression was downregulated after coal dust exposure, accompanied by MAMs impairment, Ca2+ imbalance, and increased apoptosis, which ultimately drove the pathological progression of pulmonary fibrosis. Notably, MFN2 overexpression restored MAMs' structure and Ca2+ homeostasis, alleviated abnormal apoptosis, and subsequently inhibited fibrosis. This study highlights the importance of the MFN2-MAMs-Ca2+-apoptosis axis and identifies MFN2 as a potential therapeutic target for pneumoconiosis.

Keywords:  Ca2+; MFN2; apoptosis; coal workers’ pneumoconiosis (CWP); mitochondria-associated endoplasmic reticulum membranes (MAMs)

DOI:  https://doi.org/10.3390/toxics14050391
Biomolecules. 2026 May 11. pii: 704. [Epub ahead of print]16(5):

Exploring Replicative Senescence and Oxidative Stress-Induced Remodelling of Mitochondrial-Associated Membranes in Human Skin Fibroblasts.

Anne-Laure Bulteau, Gallic Beauchef, Stéphanie Chanon, Aurélie Vieille-Marchis, Julien Chlasta, Gaël Runel, Juliette Sage, Tanesha Naiken, Lauren Sobilo, Elodie Bossard, Lorene Gourguillon, Carine Nizard, Karl Pays, Laurence Canaple, Beatrice Morio.

  (1) Background: Calcium transfer between the endoplasmic reticulum (ER) and mitochondria through the IP3R-VDAC1 complex at mitochondria-associated ER membranes (MAMs) is essential for cellular homeostasis. Alterations in this signalling axis have been implicated in ageing and cellular senescence. (2) Methods: We developed an in vitro human dermal fibroblast (HDF) model combining replicative senescence and acute oxidative stress to investigate the role of ER-mitochondria coupling in skin ageing and to enable biomolecule screening. (3) Results: In situ proximity ligation assays revealed that replicative senescence significantly increased the number of VDAC1/IP3R complexes per cell (+85% and +72%, p < 0.01), together with elevated cellular reactive oxygen species (+47% and +74%, p < 0.05). Consistently, acute oxidative stress (50 µM t-BHP, 30 min) rapidly increased VDAC1/IP3R complexes (+48%, p < 0.001) and intra-mitochondrial calcium levels (+19%, p < 0.001). These effects persisted for 24 h post-treatment and were associated with impaired mitochondrial function (-27% in the Bioenergetic Health Index, p < 0.05). We also established a flexibility index capturing both acute and long-term adaptations and detecting the protective effects of an orchid extract. (4) Conclusions: ER-mitochondria coupling disruption via the IP3R-VDAC1 complex may contribute to oxidative stress-induced senescence and represent a key mechanism in extrinsic skin ageing.

Keywords:  Bioenergetic Health Index; cytoskeleton physical properties; intra-mitochondrial calcium; mitochondria-ER contact sites; oxidative stress; skin ageing

DOI:  https://doi.org/10.3390/biom16050704
Ecotoxicol Environ Saf. 2026 May 25. pii: S0147-6513(26)00637-8. [Epub ahead of print]319 120308

Patulin induces crosstalk between ferroptosis and the endoplasmic reticulum-MAMs-mitochondria axis in the kidney.

Jiawei Xu, Jiaxuan Ma, Qing Tian, Xinyu Yan, Xiance Sun, Xiaofeng Yao, Ningning Wang, Tianming Qiu, Cong Zhang, Haoyuan Deng, Guang Yang.

  Patulin (PAT), a prevalent mycotoxin. It is widely present in fruits and nuts and causes serious harm to human health. Our prior study found that PAT exposure could trigger ferroptosis, which in turn resulted in severe kidney damage. However, the specific mechanism remained unclear. This research was designed to explore the molecular mechanisms responsible for PAT-induced renal ferroptosis. In vivo, Western blot analysis revealed that PAT exposure activated ferroptosis and endoplasmic reticulum (ER) stress, and reduced the expression of mitochondria-associated endoplasmic reticulum membranes (MAMs)-associated proteins. Specific commercial detection kits revealed a decrease in tissue adenosine triphosphate (ATP) content and an increase in iron content. Transmission electron microscopy (TEM) observation showed that PAT disrupted the structure of MAMs. In vitro, PAT exposure activated the PERK-related ER stress pathway in mouse kidneys and disrupted both the structure of MAMs and normal mitochondrial function. Molecular docking revealed a strong interaction between MFN2 and MFN1. ER stress inhibition in PAT-treated HKC cells elevated MAMs-related protein expression, which in turn restored mitochondrial membrane potential (MMP) and lowered Mitochondrial Reactive Oxygen Species (MtROS) levels. Similarly, MFN2 overexpression restored mitochondrial function and inhibited ferroptosis. Our study demonstrated that ER stress and MAMs integrity lay at the heart of PAT-induced mitochondrial failure and ferroptosis. The results identified a new mechanism through which PAT triggered ferroptosis, offering fresh perspectives on the pathogenesis of mycotoxin-induced kidney injury.

Keywords:  ER stress; Ferroptosis; MAMs; Mitochondrial dysfunction; Patulin

DOI:  https://doi.org/10.1016/j.ecoenv.2026.120308
Protoplasma. 2026 May 23.

A lipid droplet - plasma membrane contact site is conserved across the angiosperm lineage.

Pauline Prüsener, Janis Dabisch, Saskia Baum, Lea Marie Preuss, Jan de Vries, Till Ischebeck.

  In Arabidopsis thaliana, a tethering complex of three proteins, SEED LIPID DROPLET PROTEIN 1 and 2 (SLDP1 and 2) and LIPID DROPLET PLASMA MEMBRANE ADAPTOR (LIPA), binds lipid droplets (LDs) to the plasma membrane (PM). While the physiological function remains unknown, it seems to be conserved across seed plants, as we here observed this tethering of LDs in seedlings of a variety of angiosperms. The analysis of LIPA and SLDP homologs indicated that these proteins emerged in the early period of land plant evolution before seed plants became dominant. LIPA and SLDP are, however, more strongly conserved among seed plants and share distinct amino acid motifs that could be involved in their interaction. We cloned LIPA and SLDP homologs from Arachis hypogaea, Glycine max and Zea mays and transiently expressed them in tobacco pollen tubes, a suitable model system. Here, the LIPAs and SLDPs localised to the PM and LDs, respectively, like their A. thaliana homologs. When coexpressed in pollen tubes, where LDs normally move freely in the cytosol, the LIPAs and SLDPs can tether LDs to the PM indicating that they can interact and constitute a LD-PM contact site. This interaction was even functional across taxon boundaries.

Keywords:  Angiosperms; Lipid droplet; Molecular contact site; Plasma membrane; Pollen tubes; Seedling

DOI:  https://doi.org/10.1007/s00709-026-02215-9
Redox Biol. 2026 May 26. pii: S2213-2317(26)00234-X. [Epub ahead of print]94 104236

Redox control at the ER-mitochondria interface in kidney transplantation: MAM-centered stress signaling and translational organoid platforms.

Baicheng Kuang, Lin Han, Sopheaktra Tan, Sokun Tan, Sopheap Bou, Yuanyuan Zhao, Yan Li, Jiasheng Yu, Nianqiao Gong.

  Kidney transplantation is inevitably accompanied by ischemia-reperfusion injury in which oxidative stress and endoplasmic reticulum (ER) stress act as tightly interconnected drivers of mitochondrial dysfunction, inflammation, and long-term graft failure. Excessive reactive oxygen species disrupt mitochondrial homeostasis, while unresolved ER stress activates maladaptive unfolded protein response signaling, together shaping tubular cell fate. Although these processes have been extensively studied, their spatial and functional integration remains incompletely understood. Growing evidence indicates that oxidative stress and ER stress converge at mitochondria-associated membranes (MAMs), where calcium signaling, redox regulation, and stress-adaptive networks are integrated. However, the dynamic and context-dependent nature of MAM remodeling remains poorly defined and difficult to investigate using conventional experimental systems. In this review, we propose a MAM-centered framework that integrates cellular stress responses, with a particular focus on ischemia-reperfusion in kidney transplantation. We further highlight therapeutic strategies targeting MAM-associated pathways, including mitochondria-directed antioxidants, ER oxidoreductases and structural and signaling proteins of MAM. In parallel, we summarize emerging kidney organoid platforms as human-relevant translational systems for modeling MAM dynamics under controlled conditions. By integrating mechanistic insights with organoid-based investigations, this review bridges a critical gap between molecular understanding and translational application, and offers a conceptual framework for MAM-targeted strategies aimed at improving graft resilience and long-term transplant outcomes.

Keywords:  Endoplasmic reticulum stress; Kidney transplantation; Mitochondria-associated membranes; Mitochondrial dysfunction; Organoid; Oxidative stress

DOI:  https://doi.org/10.1016/j.redox.2026.104236
Cells. 2026 May 20. pii: 942. [Epub ahead of print]15(10):

Disruption of Fructose 1,6-Bisphosphatase 2 Proximity to MIC60 Correlates with Mitochondrial Ultrastructural Changes.

Łukasz Pietras, Marta Migocka-Patrzałek, Bartosz Budziak, Dariusz Rakus, Agnieszka Gizak.

  Fructose 1,6-bisphosphatase 2 (FBP2) is a multifunctional protein whose cellular functions depend on its oligomeric state. Forced FBP2 tetramerization has been linked to microtubule disruption and impaired mitochondrial trafficking, accompanied by abnormal mitochondrial morphology. Here, we identify MIC60 (mitofilin), a core element of the mitochondrial contact site and cristae organizing system (MICOS), as a potential mediator of these effects. Using proximity ligation assay, protein crosslinking combined with mass spectrometry, and ultrastructural analysis, we demonstrate that FBP2 is in close proximity to MIC60 under basal conditions and this proximity is reduced upon FBP2 tetramerization or partial FBP2 depletion. Loss of this proximity coincides with marked remodeling of inner-membrane ultrastructure. These findings are consistent with a working model in which dimeric FBP2 contributes to the coordination of microtubule-dependent mitochondrial positioning with MICOS-linked intramitochondrial organization, providing a plausible mechanistic bridge between metabolic cues (AMP/NAD+) and mitochondrial structural integrity.

Keywords:  FBP2; MIC60; cardiomyocyte; mitochondria; mitofilin; ultrastructure

DOI:  https://doi.org/10.3390/cells15100942
Nat Plants. 2026 May 28.

Ubiquitin-dependent mitochondrial protein degradation ensures seedling emergence by regulating ER-mitochondrial interaction and mitophagy.

Zhen Tian, Yawen Huo, Chengyang Li, Qiwei Zheng, Fan Hu, Jing Li, Juncai Ma, Xiaolu Qu, Yunjiang Cheng, Byung-Ho Kang, Patrick Duckney, Pengwei Wang.

Seedling emergence is a pivotal step of plant survival, requiring rapid hypocotyl elongation for soil penetration1,2. This energy-demanding process necessitates active mitochondrial respiration, which inevitably induces oxidative damage3-6. Plants have therefore evolved a quality-control mechanism that selectively removes dysfunctional mitochondria through the mitophagy pathway. Here we identified SPL2, a mitochondrial E3 ligase that is essential for hypocotyl elongation and seedling emergence through degrading mitochondrial outer membrane proteins, such as TRB1 and FIS1A. Intriguingly, these proteins also interact with an endoplasmic reticulum (ER) protein, VAP27-1, forming a complex at the ER-mitochondria contact sites, which is essential for mitophagy initiation. The spl2 mutant exhibits enhanced ER-mitochondrial tethering and mitophagy activation, whereas the overexpression of SPL2 has the opposite effects. The expression of SPL2 increases after light perception, in agreement with the reduced mitophagy. Collectively, our findings reveal mechanistic insights into seedling emergence, which is coordinated through protein ubiquitination, ER-mitochondrial interaction and mitophagy.

DOI: https://doi.org/10.1038/s41477-026-02306-8
Brain Commun. 2026 ;8(3): fcag165

FLVCR1-related diseases: from clinical heterogeneity to mechanistic insights.

Diletta Isabella Zanin Venturini, Deborah Chiabrando.

  Feline Leukemia Virus subgroup-C Receptor 1 (FLVCR1) is an ubiquitously expressed choline and ethanolamine importer that is involved in the control of multiple aspects of cell biology including the regulation of phospholipids metabolism, heme homeostasis, mitochondria-ER contact sites and cellular bioenergetics. Mutations in the FLVCR1 gene cause a spectrum of autosomal-recessive disorders mainly affecting the nervous system. Research conducted in the last decade highlighted the complexity of the clinical features associated with FLVCR1 mutations, ranging from dysfunction of specific sensory modalities to severe neurodevelopmental defects. Despite important progress in understanding the FLVCR1 function, the molecular mechanisms responsible for the disease are still poorly understood and specific treatment for the affected patients is lacking. This review aims to critically examine the current knowledge surrounding FLVCR1-related diseases, from clinical manifestations to the underlying molecular mechanisms. We also propose future directions to advance research and improve patient treatment.

Keywords:  ataxia; microcephaly; neuropathy; pain; retinitis pigmentosa

DOI:  https://doi.org/10.1093/braincomms/fcag165
J Imaging. 2026 May 18. pii: 215. [Epub ahead of print]12(5):

Cell Structure Segmentation in TEM Images of Murine Skin Melanoma Cells by Deep Learning Model.

Mikhail A Genaev, Izabella S Gogaeva, Iuliia S Taskaeva, Nataliya P Bgatova, Mikhail V Kozhekin, Evgeniy G Komyshev, Dmitry A Afonnikov.

  Mitochondria-endoplasmic reticulum contact sites (MERCs) are known as the specialized areas that are involved in a large number of intracellular signaling pathways that regulate Ca2+ homeostasis, lipid transport, mitochondrial dynamics, cell death, and autophagy. Understanding MERC dynamics has important therapeutic implications in cancer, as these contacts regulate fundamental cellular processes and MERCs represent promising targets for therapeutic interventions aimed at improving cancer treatment outcomes. Despite the accumulated data, the role of MERCs in carcinogenesis still remains unknown; thus, it seems promising to search for new tools facilitating the study of MERCs in tumor cells. The structure of MERCs can be examined in great detail using transmission electron microscopy (TEM). Currently, several hundred TEM images are required to obtain reliable data on these contacts. The speed of data processing can be significantly improved by using fast and accurate image analysis techniques based on deep learning models. In this study, five U-Net models with a ResNet34 encoder network were evaluated, including the basic U-Net-Vanilla architecture as well as models incorporating various attention blocks and blocks capturing multilevel image structure, for the segmentation of mitochondria and the endoplasmic reticulum (ER). The best performance on the test dataset was demonstrated by the U-Net-scSE network, with F1 scores of 0.872 for mitochondria and 0.744 for the ER being achieved. Two models were tested for their ability to leverage pre-training on external datasets (Lucchi++, Kasthuri++, and DeepPi-EM). Additionally, models pre-trained on the CEM500K dataset were evaluated after the parameters had been tuned on the data. It was demonstrated by the results that pre-training or the use of pre-trained networks did not lead to an improvement in the IoU and F1 metrics on the test dataset. Subsequent image analysis was conducted to assess two types of MERCs in the segmented images. Finally, the free and user-friendly UltraNet web server was developed for automated analysis of mitochondria, ER, and MERCs using TEM images.

Keywords:  deep learning; endoplasmic reticulum; image segmentation; mitochondria; mitochondria–endoplasmic reticulum contact sites; neural network; transmission electron microscopy

DOI:  https://doi.org/10.3390/jimaging12050215
Mater Today Bio. 2026 Jun;38 103254

Holistic therapeutic philosophy: Boost a cascade communication between endoplasmic reticulum-mitochondria-lysosome to overload intracellular Ca2+ and initiate chemoimmunotherapy.

Yan Su, Hongbao Fang, Wei Hao, Zhong-Hai Ding, Lin Tang, Zheng-Hong Yu, Zhi Su.

  The behaviors of tumor cells relied on the communications between the distinct subcellular organelles through the physical interactions or the released characteristic signals (ions, proteins et al.). Thus, interference with the communications would release the abnormal signals and initiate the improper responses, even the programmed cellular death. Herein, to manipulate the communications between the major suborganelles for the cancer therapy, complex Ru-AM was developed, which could simultaneously accumulate in endoplasmic reticulum (ER), mitochondria (Mito), and lysosome (Lyso). The significant higher rate of mitochondria-associated ER membranes (MAMs) overlay was observed with super-resolution structured illumination microscopy (SIM), resulting in the enhanced Mito-ER contact and Ca2+ release to cytoplasm and Mito. The overloaded mitochondrial Ca2+subsequently evoked the mitophagy with the Mito-Lyso fusion. Moreover, the disruption of intracellular Ca2+ homeostasis was further enhanced with the lysosomal Ca2+ release, due to the lysosomal membrane permeability (LMP), which successfully initiated the immunogenic cell death (ICD). In vivo experiments demonstrated that Ru-AM could effectively inhibit the proliferation of solid tumors and active immune responses. This work not only provided the first metal-based regulator to interfere the intracellular communications between ER-Mito-Lyso, but also demonstrated the effectiveness of the holistic therapeutic philosophy for the cancer chemoimmunotherapy.

Keywords:  Ca2+ overload; Chemoimmunotherapy; Intercellular communications; Metal-based regulator; The holistic therapeutic philosophy

DOI:  https://doi.org/10.1016/j.mtbio.2026.103254
Antioxidants (Basel). 2026 Apr 26. pii: 550. [Epub ahead of print]15(5):

ITPR1 Maintains Mitochondrial Redox Homeostasis to Drive Glioblastoma Progression Through Recruitment and Activation of DRP1.

Shuyan Luo, Mei Tao, Sihan Li, Xingbo Li, Qian Jiang, Quanji Wang, Zihan Wang, Lv Zhou, Kai Shu, Zhuowei Lei, Yimin Huang, Ting Lei.

  Background: Glioblastoma (GBM) exhibits marked cellular heterogeneity and resistance to therapy. Calcium (Ca2+) signaling at endoplasmic reticulum (ER)-mitochondria contact sites has emerged as a key regulator of mitochondrial function and cell fate; however, its lineage-specific role and therapeutic relevance in GBM remain unclear. Methods: ITPR1 expression was analyzed using single-cell and bulk RNA sequencing (RNA-seq) datasets and validated by immunohistochemistry and survival analyses. Functional studies were conducted using genetic silencing or CRISPR-mediated activation of ITPR1, combined with DRP1 knockdown, Ca2+ imaging, transmission electron microscopy, co-immunoprecipitation, mitochondrial fractionation, and mitochondrial functional assays. Therapeutic efficacy was evaluated in orthotopic GBM xenograft models treated with 2-aminoethoxydiphenyl borate (2-APB), temozolomide (TMZ), or their combination. Results: ITPR1 was enriched in mesenchymal-like malignant cell states and associated with higher tumor grade, recurrence, and poor prognosis. ITPR1 knockdown suppressed GBM cell proliferation and tumor growth while promoting intrinsic apoptosis. Mechanistically, loss of ITPR1 impaired ER-to-mitochondria Ca2+ transfer, disrupted ER-mitochondria contacts, and altered mitochondrial ultrastructure. This was accompanied by reduced DRP1 Ser616 phosphorylation and mitochondrial recruitment, as well as decreased autophagy and mitophagy activity. Consequently, ITPR1 knockdown led to mitochondrial depolarization, increased mitochondrial reactive oxygen species (ROS) accumulation, and activation of mitochondria-dependent apoptosis. Conversely, DRP1 knockdown attenuated the mitochondrial and pro-survival effects induced by ITPR1 overexpression. In vivo, combined treatment with 2-APB and TMZ resulted in greater tumor suppression and prolonged survival compared with either treatment alone, accompanied by increased apoptosis and reduced proliferation in tumor tissues. Conclusions: ITPR1 promotes GBM progression by sustaining ER-mitochondria Ca2+ coupling and DRP1-dependent mitochondrial quality control, thereby maintaining mitochondrial homeostasis and cell survival. Targeting inositol 1,4,5-trisphosphate receptor (IP3R)-mediated Ca2+ signaling with 2-APB enhances the therapeutic efficacy of TMZ, suggesting that ITPR1-centered Ca2+ signaling may represent a potential therapeutic vulnerability in aggressive GBM.

Keywords:  2-APB; DRP1; ITPR1; glioblastoma; mitophagy; temozolomide

DOI:  https://doi.org/10.3390/antiox15050550
Int J Mol Sci. 2026 May 17. pii: 4492. [Epub ahead of print]27(10):

The Role of Sigmar1 in Autophagy Regulation and Disease Therapy.

Huanqing Ge, Yusi Lin, Junda Li, Renwen Zhang, Cangcang Xu.

  Sigmar1 is a multifunctional molecular chaperone protein located on the Mitochondria-associated endoplasmic reticulum membranes (MAM). Recent studies have shown that Sigmar1 is not only a regulatory protein involved in cellular stress responses but also plays a significant role in the process of autophagy. It regulates the initiation and progression of autophagy by influencing multiple autophagy-related signaling pathways and interacting with key proteins such as LC3 and GABARAP. This regulation exhibits a dual nature. On one hand, it can induce protective autophagy, helping cells cope with stress such as oxidative stress and endoplasmic reticulum stress, thereby playing a protective role in the progression of diseases such as neurodegenerative disorders and cardiovascular diseases. On the other hand, in certain cancers, Sigmar1 may also promote tumor cell survival through autophagy regulation, thereby exacerbating disease progression. Consequently, developing agonists and antagonists targeting Sigmar1 has become a highly promising therapeutic strategy. This review provides a systematic overview of recent advances in the biological characterization of Sigmar1 and its molecular mechanisms in regulating autophagy. It summarizes the multifaceted roles of Sigmar1 in various diseases and discusses current research progress and the application prospects of Sigmar1 agonists and antagonists, aiming to establish a theoretical foundation for the development of novel Sigmar1-based therapeutic strategies for human diseases.

Keywords:  Sigmar1; agonists and antagonists; autophagy; disease therapy; regulatory mechanism

DOI:  https://doi.org/10.3390/ijms27104492