bims-mecosi 2025-10-19 papers

bims-mecosi

Biomed News

on Membrane contact sites

Issue of 2025–10–19
nine papers selected by
Verena Kohler, Umeå University

Analyzing Endolysosome-Mitochondria Membrane Contact Sites by Thin Section TEM of Human Fibroblasts.
Regulation of endoplasmic reticulum-mitochondria transfer and its importance in GBM.
The role of mitochondria-endoplasmic reticulum crosstalk in colorectal cancer.
Enhanced mitochondria-associated membrane formation in Fuchs endothelial corneal dystrophy: a novel link between endoplasmic reticulum stress and mitochondrial dysfunction.
Influence of a mitochondria-associated membranes (MAMs) linker protein on coronary calcification: Commentary on "GRP75 inhibition attenuates arterial calcification" by Heyn J et al. Atherosclerosis 2025.
Organelle abnormalities in Alzheimer's disease.
The Ultrastructural Properties of the Endoplasmic Reticulum Govern Microdomain Signaling in Perisynaptic Astrocytic Processes.
Mitochondrial MFN2 integrates the function of multiple organelles to regulate metabolic dysfunction-associated steatotic liver disease: mechanisms and therapeutic insights.
Emerging roles and therapeutic implications of lipid droplet protein perilipin 2 in liver disease.

Methods Mol Biol. 2026 ;2976 119-134

Analyzing Endolysosome-Mitochondria Membrane Contact Sites by Thin Section TEM of Human Fibroblasts.

Claudia Parra-Ruiz, Carlos Enrich, Silvana Zanlungo.

  Membrane contact sites (MCS) are dynamic nanoregions of close apposition between two different organelles, functioning as discrete lipid or ion transfer sites. This new concept in cell biology involves unique proteins at both membrane sites, named tethers, and emerges in early observations by transmission electron microscopy (TEM). Currently, this technique still constitutes a valuable tool for MCS visualization and quantification. In the last decade, Lysosomal Storage Diseases (LSD) have been instrumental in studying the MCS between lysosomes (Ly), or endolysosomes (EL), and other organelles in close proximity such as mitochondria or the endoplasmic reticulum (ER). At present, the analysis of composition, functioning, and alterations/rewiring of MCS in health and disease represents an innovative area of research for designing therapeutic strategies in a variety of pathologies. Here, we describe procedures for chemical fixation using the Flat Embedding technique to characterize and quantify the MCS between LE/Lys and mitochondria in human fibroblasts by thin-section TEM.

Keywords:  Flat embedding; Image analysis; Lysosomal storage diseases; Lysosomes; Membrane contact sites; Mitochondria; Transmission electron microscopy-chemical fixation

DOI:  https://doi.org/10.1007/978-1-0716-4844-5_10
Int J Cancer. 2025 Oct 17.

Regulation of endoplasmic reticulum-mitochondria transfer and its importance in GBM.

Jinyi Zhao, Tian Li, Yue Jing, Haoran Yang, Xuemei Ma, Mengyu Liu.

  The traditional view of organelles as isolated functional entities is increasingly being replaced by a perspective that emphasizes dynamic connections. In particular, the membrane contact site between mitochondria and endoplasmic reticulum, mitochondrial associated endoplasmic reticulum membrane (MAM), has been extensively studied. MAM, as a key intracellular signaling hub, regulates various key activities including lipid metabolism, mitochondrial function, calcium ion homeostasis, and cell survival and apoptosis. Given its central role in maintaining cellular homeostasis, increasing evidence suggests that dysfunction of the endoplasmic reticulum mitochondrial axis may be associated with tumorigenesis, particularly in glioblastoma. This review aims to summarize the current understanding of the role and underlying mechanisms of MAM.

Keywords:  ER; GBM; MAM; carcinogenesis; mitochondria

DOI:  https://doi.org/10.1002/ijc.70173
Genes Dis. 2026 Jan;13(1): 101766

The role of mitochondria-endoplasmic reticulum crosstalk in colorectal cancer.

Lanshu Xiao, Yao Wei, Yiping Qin, Bianqin Guo.

  Colorectal cancer (CRC) is a significant health burden globally, with the third highest incidence and the second highest mortality among all types of cancer. Understanding the mechanisms underlying CRC progression is crucial for advancing therapeutic strategies. Organelles are essential components of cells and play a critical role in the initiation and progression of cancer. Over the past decades, numerous studies have demonstrated that mitochondria and the endoplasmic reticulum (ER) can communicate through signaling pathways, thereby regulating cellular homeostasis and function in both normal and cancer cells. This interaction primarily occurs through mitochondria-associated endoplasmic reticulum membranes (MAMs). MAMs, as key nodes in cancer initiation and progression, are also potential vulnerabilities of cancer cells, offering promising opportunities for cancer treatment. Recent research further emphasizes the close association between MAMs and CRC in terms of proliferation, apoptosis, and invasion. To deepen our understanding of the interactions and mechanisms between mitochondria and the ER in CRC, this review, for the first time, synthesizes the research advancements concerning the crosstalk between these organelles in CRC. It innovatively identifies potential targets associated with MAMs, aiming to uncover novel therapeutic strategies for CRC.

Keywords:  CRC; ER; MAMs; Mitochondria; Therapeutic strategy

DOI:  https://doi.org/10.1016/j.gendis.2025.101766
Jpn J Ophthalmol. 2025 Oct 15.

Enhanced mitochondria-associated membrane formation in Fuchs endothelial corneal dystrophy: a novel link between endoplasmic reticulum stress and mitochondrial dysfunction.

Saki Matusmoto, Saori Kadoya, Yuna Horiuchi, Hirokazu Okuda, Keita Miyadai, Yu Shima, Robert D Young, Andrew J Quantock, Ursula Schlötzer-Schrehardt, Friedrich Kruse, Noriko Koizumi, Naoki Okumura.

   PURPOSE: To investigate the presence and characteristics of mitochondria-associated membranes (MAMs) in Fuchs endothelial corneal dystrophy (FECD) and to assess the relationship between endoplasmic reticulum (ER) stress and MAM formation in corneal endothelial cells, given the established roles of mitochondrial dysfunction and ER stress in FECD pathogenesis.
STUDY DESIGN: Experimental laboratory investigation.
METHODS: Corneal endothelial tissues from FECD patients and controls were examined by use of transmission electron microscopy to evaluate the ultrastructural features of mitochondria-ER contacts. An established FECD cell model was used for immunofluorescence colocalization analysis and protein expression profiling. Experimental models of protein misfolding (MG132) and direct ER stress induction (tunicamycin) were implemented to explore the relationship between ER stress and MAM formation.
RESULTS: The FECD specimens exhibited extensive mitochondria-ER contacts with evident tethering complexes and distances reduced to <20 nm when compared with normal corneal endothelium. Quantitative analysis showed significantly increased mitochondria-ER colocalization in iFECD cells (P <0.01). The FECD cell model showed significant upregulation of MAM-associated proteins, including GRP75, Mfn1, Mfn2, Sigma1 receptor, VDAC, and IP3R. MG132 and tunicamycin treatments both increased MAM formation while activating all UPR pathways.
CONCLUSIONS: This study provides the first evidence of enhanced MAM formation in FECD and identifies ER stress as a key driver of this structural change. While these findings suggest a potential role for MAMs in linking ER stress and mitochondrial dysfunction in FECD pathogenesis, further investigation is needed to clarify whether such changes are protective adaptations or whether they contribute to disease progression.

Keywords:  Endoplasmic reticulum stress; Fuchs endothelial corneal dystrophy; Mitochondria-associated membranes; Mitochondrial dysfunction; Unfolded protein response

DOI:  https://doi.org/10.1007/s10384-025-01288-y
Atherosclerosis. 2025 Oct;pii: S0021-9150(25)01395-4. [Epub ahead of print]409 120497

Influence of a mitochondria-associated membranes (MAMs) linker protein on coronary calcification: Commentary on "GRP75 inhibition attenuates arterial calcification" by Heyn J et al. Atherosclerosis 2025.

Florence Gizard, Nassim Mohamedi.

Heyn et al. provided the first evidence of a key role for a MAM component, the Glucose-regulated protein 75 (GRP75), in coronary calcification. The underlying mechanisms involve the GRP75 effect on MAM integrity and matrix mineralization in calcifying vascular smooth muscle cells (SMCs). These innovative data open up new avenues for biomedical research on atherosclerosis, and possibly other chronic and/or rare diseases.

DOI: https://doi.org/10.1016/j.atherosclerosis.2025.120497
Organelle. 2025 ;3

Organelle abnormalities in Alzheimer's disease.

Ju Gao, Lauren Vicuna, Xinglong Wang.

  Alzheimer's disease (AD) is the most common cause of dementia, pathologically characterized by extracellular amyloid plaques and intracellular neurofibrillary tangles. While these pathological hallmarks remain central to our understanding of AD, they do not fully explain the complex cellular failures observed throughout the disease course. Neurons are highly specialized and polarized cells that depend on an integrated and dynamic network of specialized subcellular compartments named organelles to maintain structure, metabolism, and communication. Given these critical roles, organelle dysfunction is increasingly recognized as a key contributor to AD pathogenesis. Structural and functional impairments in conventional organelles, including mitochondria, endoplasmic reticulum (ER), lysosomes, Golgi apparatus, and peroxisomes, are consistently observed in AD brains and experimental models. These impairments are believed to cause energy failure, disrupted proteostasis, intracellular trafficking defects, and elevated oxidative and ER stress. In parallel, abnormalities in membraneless organelles (MLOs) further compromise RNA regulation, protein synthesis, and cellular stress responses. Additionally, perturbed communication between organelles, such as at mitochondria-associated ER membranes (MAMs), lipid droplets, and primary cilia, further exacerbates signaling imbalances and neuronal vulnerability. In this review, we not only provide a comprehensive overview of abnormalities in both membrane-bound and membraneless organelles in AD, emphasizing how their dysfunction contributes to cellular stress, impaired homeostasis, and neurodegeneration, but also discuss how disruptions in organelles intersect with amyloid, tau, and other AD-associated pathologies to intensify disease progression. A deeper understanding of organelle dysfunction in AD may provide new mechanism insights and advance the development of effective disease modifying interventions.

Keywords:  Alzheimer’s disease; amyloid plaques; endoplasmic reticulum stress; liquid-liquid phase separation; membraneless organelles; mitochondria; organelle dysfunction; tau pathology

DOI:  https://doi.org/10.61747/0ifp.202503005
Glia. 2025 Oct 16.

The Ultrastructural Properties of the Endoplasmic Reticulum Govern Microdomain Signaling in Perisynaptic Astrocytic Processes.

Audrey Denizot, Marı́a Fernanda Veloz Castillo, Pavel Puchenkov, Corrado Calì, Erik De Schutter.

  Astrocytes are now widely accepted as key regulators of brain function and behavior. Calcium (Ca2+) signals in perisynaptic astrocytic processes (PAPs) enable astrocytes to fine-tune neurotransmission at tripartite synapses. As most PAPs are below the diffraction limit, their content in Ca2+ stores and the contribution of the latter to astrocytic Ca2+ activity is unclear. Here, we reconstruct hippocampal tripartite synapses in 3D from a high-resolution electron microscopy (EM) dataset and find that 75% of PAPs contain some endoplasmic reticulum (ER), a major calcium store in astrocytes. The ER in PAPs displays strikingly diverse shapes and intracellular spatial distributions. To investigate the causal relationship between each of these geometrical properties and the spatiotemporal characteristics of Ca2+ signals, we implemented an algorithm that generates 3D PAP meshes by altering the distribution of the ER independently from ER and cell shape. Reaction-diffusion simulations in these meshes reveal that astrocyte activity is governed by a complex interplay between the location of Ca2+ channels, ER surface-volume ratio, and spatial distribution. In particular, our results suggest that ER-PM contact sites can act as local signal amplifiers if equipped with IP3R clusters but attenuate PAP Ca2+ activity in the absence of clustering. This study sheds new light on the ultrastructural basis of the diverse astrocytic Ca2+ microdomain signals and on the mechanisms that regulate neuron-astrocyte signal transmission at tripartite synapses.

Keywords:  astrocyte; calcium signaling; computational modeling; electron microscopy; glia; neuroscience; tripartite synapse

DOI:  https://doi.org/10.1002/glia.70091
Biochem Pharmacol. 2025 Oct 12. pii: S0006-2952(25)00688-4. [Epub ahead of print] 117423

Mitochondrial MFN2 integrates the function of multiple organelles to regulate metabolic dysfunction-associated steatotic liver disease: mechanisms and therapeutic insights.

Yibing Wang, Sitong Wan.

  Metabolic dysfunction-associated steatotic liver disease (MASLD) encompasses a wide spectrum of liver diseases with increasing global prevalence. Its hallmarks include aberrant lipid accumulation, inflammation, which leads to liver fibrosis. The efficacious therapies for treating MASLD are limited, and the response rates to antifibrotic drugs are moderate. Understanding the novel mechanisms that regulate the progression of MASLD enables the discovery of drugs with higher response rates and safety. Besides the canonical pathogenic pathways, the dysfunctions in the contact and communication between mitochondria, endoplasmic reticulum (ER) and lipid droplet (LD) causatively drive and promote MASLD. Mitofusin-2 (MFN2) is a mitochondria-bound GTPase that stimulates mitochondrial fusion and is an emerging key factor that suppresses the progression of MASLD and liver fibrosis by maintaining the contact between mitochondria, ER and LD. MFN2 interacts with distinct binding proteins in the ER to facilitate the ER-to-mitochondria transfer of Ca2+ and phosphatidylserine. Moreover, MFN2 is essential for mitochondria-LD contact, which facilitates the lipid transfer and maintains homeostasis. Our analyses indicate that MFN2 is a validated therapeutic target, and exercise elevates the expression of mitochondrial MFN2 to enhance fatty acid oxidation. Regarding translational potential, the advantages and limitations of small-molecule- and peptide-based MFN2 agonists are critically discussed. They effectively induce conformational change and activation of MFN2. We demonstrate that echinacoside and compound 5 are the most promising lead compounds for future development. Evaluation of their anti-MASLD and antifibrotic activities and the combination of them with current therapies and exercise to combat MASLD is warranted in the future.

Keywords:  Agonist; Endoplasmic reticulum; Lipid droplet; MASLD; MFN2; Mitochondria

DOI:  https://doi.org/10.1016/j.bcp.2025.117423
Genes Dis. 2026 Jan;13(1): 101712

Emerging roles and therapeutic implications of lipid droplet protein perilipin 2 in liver disease.

Xuwen Xiang, Jing Chen, Lin Che.

  Lipid droplets (LDs) are dynamic organelles that store neutral lipids when energy is in excess and serve as an energy reservoir during energy deprivation. Altered hepatic lipid metabolism is a critical factor influencing the development of liver disease, such as viral hepatitis, fatty liver disease, and hepatocellular carcinoma. Perilipin 2 (PLIN2) is a protein associated with the metabolism of intracellular LDs and is closely related to the clinical outcome of liver disease. While the impact of PLIN2 on the pathogenesis of liver disease is gradually being recognized, the mechanism of action remains unclear. In this review, we highlight recent advances in the understanding of PLIN2's role in the pathogenesis of liver disease through LD biogenesis, LD contact sites, LD dynamics, and lipophagy. Furthermore, we discuss the current opportunities for PLIN2-targeted therapy for liver disease.

Keywords:  Lipid droplets; Liver disease; Perilipin 2; Small molecular inhibitors; Therapeutic target

DOI:  https://doi.org/10.1016/j.gendis.2025.101712