bims-mecosi 2026-09-20 papers

bims-mecosi

Biomed News

on Membrane contact sites

Issue of 2026–09–20
ten papers selected by
Verena Kohler, Umeå University

Mitochondria‑associated endoplasmic reticulum membranes in degenerative musculoskeletal disorders: Mechanistic evidence and therapeutic perspectives (Review).
Role of mitochondria-associated endoplasmic reticulum membranes in hepatic ischemia-reperfusion injury: Molecular architecture, pathological remodeling, and therapeutic prospects.
Mitochondria-associated endoplasmic reticulum membranes in canine and feline diabetic kidney disease: mechanistic links and nutritional implications.
Mitochondria-endoplasmic reticulum-lipid droplet crosstalk in lipid metabolic reprogramming in type 2 diabetes mellitus.
VPS13D protects against alcohol- associated steatohepatitis by regulating organelle contacts and VLDL secretion.
Proximity labeling: A powerful tool for mapping protein interactions.
Spatiotemporal redistribution of HMGB1 shapes organelle interactome dysfunction and informs precision pharmacological targeting in diabetic vascular disease.
Loss of Ca2+ Signaling Fidelity During Aging: Mitochondrial Dysfunction, Senescence, and Cognitive-Motor Decline.
Neuro-glial lipid imbalance in a Drosophila model of amyotrophic lateral sclerosis 8.
Prospective associations of premature senescence, inflammation, and MERCSs in the cardioprotective effect of CBD in HFpEF.

Mol Med Rep. 2026 Nov;pii: 309. [Epub ahead of print]34(5):

Mitochondria‑associated endoplasmic reticulum membranes in degenerative musculoskeletal disorders: Mechanistic evidence and therapeutic perspectives (Review).

Shilong Meng, Xinlei Fu, Yawei Xu, Zhiliang Peng, Xu Zhang, Yanguang Cao, Binbin Tang, Xiaolin Shi, Kang Liu.

  Mitochondria‑associated endoplasmic reticulum membranes (MAMs) are specialized endoplasmic reticulum (ER) membrane domains at ER‑mitochondrial contact sites that coordinate Ca²+ transfer, lipid exchange, mitochondrial quality control and cellular stress responses. In osteoporosis, intervertebral disc degeneration, osteoarthritis and sarcopenia/skeletal muscle atrophy, altered ER‑mitochondrial communication has been linked to recurrent disturbances in Ca²+ homeostasis, mitochondrial function, ER stress, inflammatory signaling and cell fate. However, evidence for MAM involvement varies markedly in directness and biological context. This narrative review compares these evidence patterns and their therapeutic implications across degenerative musculoskeletal disorders. Direct structural and causal evidence is most developed in intervertebral disc degeneration and selected osteoarthritis models; osteoporosis is supported mainly by studies of MAM‑associated regulators and functional pathways, whereas sarcopenia‑specific mechanisms remain largely informed by aging muscle and related experimental models. The direction and consequences of contact remodeling also vary with cell type, metabolic state and disease stage, arguing against a uniform gain‑ or loss‑of‑contact model. Interventions targeting contact‑site regulators or MAM‑related Ca²+ and mitochondrial pathways have shown preclinical benefit, but MAM‑specific target engagement and human validation remain limited. Progress will require paired structural and functional assessment together with validation in clinically characterized human tissues and patient‑derived systems.

Keywords:  ER‑mitochondrial contacts; endoplasmic reticulum stress; ferroptosis; mitochondrial dysfunction; mitochondria‑associated endoplasmic reticulum membranes; musculoskeletal degeneration; organelle communication

DOI:  https://doi.org/10.3892/mmr.2026.14020
Tissue Cell. 2026 Sep 07. pii: S0040-8166(26)00634-8. [Epub ahead of print]104(Pt 2): 103939

Role of mitochondria-associated endoplasmic reticulum membranes in hepatic ischemia-reperfusion injury: Molecular architecture, pathological remodeling, and therapeutic prospects.

Luo He, Ting Yang, Zhengda Lou, Junfeng Luo.

  Mitochondria-associated endoplasmic reticulum membranes (MAMs) are dynamic platforms that integrate calcium signaling, lipid metabolism, mitochondrial dynamics, autophagy, and oxidative stress. In hepatic ischemia-reperfusion injury (HIRI), MAMs act as a structural-functional hub that amplifies the cascade from ischemic stress to reperfusion injury. In this review, we analyze the main tethering networks of MAMs and their pathological remodeling in HIRI, such as the uncoupling of the structure, opening of the mitochondrial permeability transition pore (mPTP) induced by Ca2 + overload, aggravation of endoplasmic reticulum (ER) stress, defective mitophagy, and a vicious loop of reactive oxygen species (ROS)/lipid peroxidation. Direct molecular and interventional evidence has proved the causal link between dysfunction of MAMs and the progression of HIRI. The state of MAMs determines whether hepatocytes undergo repair or irreversible injury. Based on these insights, a novel clinical strategy is proposed: targeting MAMs through a multi-level framework of "structural stabilization-calcium modulation-mitophagy restoration," delivered during perioperative windows such as organ preservation and machine perfusion. This framework elevates MAMs from a mechanistic concept to a monitorable, stratifiable, and actionable therapeutic node, offering a translational direction for protecting high-risk and marginal liver grafts in transplantation and hepatectomy.

Keywords:  Calcium signaling; Endoplasmic reticulum stress; Hepatic ischemia-reperfusion injury; Mitochondria-associated endoplasmic reticulum membranes; Mitophagy; Therapeutic targets

DOI:  https://doi.org/10.1016/j.tice.2026.103939
Front Vet Sci. 2026 ;13 1848289

Mitochondria-associated endoplasmic reticulum membranes in canine and feline diabetic kidney disease: mechanistic links and nutritional implications.

Qingwen Yang, Yu Sun, Li Zuo, Maosen Xu, Suwen Tan, Zhihao Wang, Mingzheng Han.

  Diabetic kidney disease in dogs and cats is clinically relevant but mechanistically underdefined, and the dietary management of diabetic pets is still dominated by empirical control of glycemia, body weight, and renal nutrient load. Mitochondria-associated endoplasmic reticulum membranes (MAMs) are dynamic contact domains that coordinate calcium transfer, lipid exchange, ER stress, mitochondrial quality control, inflammatory signaling, and cell death. This review first summarizes the veterinary clinical context of canine and feline diabetic kidney disease, including proteinuria, microalbuminuria, hypertension, chronic kidney disease, and species-specific differences in diabetes pathophysiology. It then integrates MAM biology into core renal injury modules involving structural tethering proteins, the IP3R-GRP75-VDAC-MCU/MICU1 calcium axis, lipid metabolic enzymes, PERK/GRP78-mediated ER stress, mPTP opening, mitophagy, and inflammatory amplification. Because direct MAM evidence in diabetic dogs and cats remains limited, the MAM-related pathways discussed here are presented as hypotheses inferred from rodent DKD models, human cell lines, and broader metabolic-disease studies rather than as confirmed mechanisms in companion animals. Finally, we discuss how MAM-centered mechanisms may guide the development of functional prescription diets incorporating EPA/DHA, medium-chain triglycerides, L-carnitine, taurine, magnesium, N-acetylcysteine, antioxidants, resveratrol, and selected plant extracts, provided that efficacy and safety are validated using species-specific renal endpoints. This perspective may support a transition from empirical formulation to mechanism-informed precision nutrition for diabetic dogs and cats.

Keywords:  diabetes mellitus; food development; functional therapeutic diets; kidney disease; mitochondria-associated endoplasmic reticulum membrane

DOI:  https://doi.org/10.3389/fvets.2026.1848289
J Lipid Res. 2026 Sep 15. pii: S0022-2275(26)00176-8. [Epub ahead of print] 101146

Mitochondria-endoplasmic reticulum-lipid droplet crosstalk in lipid metabolic reprogramming in type 2 diabetes mellitus.

Xinyi Fang, Jiaqi Gao, Yan Wang, Jiaxing Tian, Xiaolin Tong.

  Type 2 diabetes mellitus (T2DM) is characterized by progressive metabolic reprogramming in which lipid metabolism imbalance links nutrient excess to insulin resistance, organelle stress, and tissue dysfunction. Although mitochondria, the endoplasmic reticulum (ER), and lipid droplets (LDs) each have established roles in metabolic homeostasis, how their coordinated interactions govern lipid remodeling in T2DM remains incompletely defined, owing in part to the technical difficulty of resolving these highly dynamic contact sites in space and time. In this Review, we integrate current evidence on mito-ER-LD interactions in T2DM, spanning advances in omics, imaging, and biochemical approaches, and summarize their structural organization, regulatory machinery, tissue-specific remodeling, and therapeutic modulation. Emerging data identify this tri-organelle network as a central metabolic interface that couples phospholipid synthesis and trafficking, calcium flux, mitochondrial dynamics, LD biogenesis and turnover, fatty-acid oxidation, autophagy, and stress signalling. Disruption of this network, including mitochondria-associated ER membrane (MAM) instability, altered balance between cytoplasmic and peridroplet mitochondria, and pathological LD expansion, reprograms lipid handling across liver, adipose tissue, skeletal muscle, and pancreatic β cells, thereby promoting lipotoxicity, oxidative and ER stress, mitochondrial dysfunction, β-cell failure, and systemic insulin resistance. Notably, glucose-lowering drugs and lifestyle interventions may exert part of their metabolic benefit by restoring organelle crosstalk and re-establishing lipid homeostasis. Together, this Review positions mito-ER-LD contact sites not simply as structural interfaces, but as core nodes that regulate lipid metabolic reprogramming in T2DM, thereby providing a mechanistic framework for targeting organelle crosstalk in metabolic disease.

Keywords:  Type 2 diabetes mellitus; lipid metabolic reprogramming; membrane contact sites; mitochondria-associated ER membranes; mitochondria-endoplasmic reticulum-lipid droplet interactions; organelle crosstalk

DOI:  https://doi.org/10.1016/j.jlr.2026.101146
Hepatology. 2026 Sep 14.

VPS13D protects against alcohol- associated steatohepatitis by regulating organelle contacts and VLDL secretion.

Chen Zhang, Nicholas Dunn, Yan Xie, Nicholas O Davidson, Wei Zhong, Wen-Xing Ding, Hong-Min Ni.

   BACKGROUND: Organelle contact sites are critical for intracellular signaling, membrane dynamics, and organelle quality control. Here we examined the role of VPS13D, a bridge-like lipid transport protein, in alcohol-induced liver injury and defined the mechanisms by which VPS13D regulates lipid metabolism at organelle contact sites.
APPROACH AND RESULTS: Liver-specific Vps13d knockout (LKO) mice and matched wild-type (WT) mice were subjected to chronic-plus-binge ethanol feeding. RNA-seq and metabolomic analyses were performed to investigate changes in hepatic gene expression and metabolism. Biochemical, microscopic, and histological analyses were performed to examine organelle contacts and liver injury. Liver samples from patients with alcohol-associated hepatitis (AH) showed decreased VPS13D expression and mitochondrial-ER contact sites. Binge ethanol-fed Vps13d LKO mice developed more severe steatosis, inflammation and liver injury, with increased progenitor cells, compared with WT mice. Ethanol-fed Vps13d LKO mice exhibited decreased mitochondria-ER contact sites and peroxisome content, with increased lysosome damage and ER stress compared with WT mice. Metabolomic analysis revealed altered hepatic phospholipid homeostasis, with increased hepatic phosphatidylethanolamine (PE) and decreased phosphatidylcholine (PC) abundance, along with decreased phosphatidylethanolamine N-methyltransferase (PEMT) expression, resulting in impaired hepatic VLDL secretion in ethanol-fed Vps13d LKO mice. Adenovirus-mediated hepatic PEMT expression increased VLDL secretion and decreased steatosis and liver injury in ethanol-fed Vps13d LKO mice.
CONCLUSIONS: Loss of hepatic VPS13D disrupts mitochondria-ER contact sites, decreasing hepatic PC content and VLDL secretion, promoting ethanol-induced steatosis, progenitor cell accumulation, and liver injury. ER-mitochondrial contact disruption and altered phospholipid homeostasis may be pathogenic drivers in AH.

Keywords:  Autophagy; lipid droplet; mitochondria; peroxisome; steatosis

DOI:  https://doi.org/10.1097/HEP.0000000000001847
Biosens Bioelectron. 2026 Sep 13. pii: S0956-5663(26)00859-6. [Epub ahead of print]315 119226

Proximity labeling: A powerful tool for mapping protein interactions.

Hua-Qian Yin, Shiwu Zhang, Shu-Lin Liu, Zhi-Gang Wang.

  Protein-protein interactions (PPIs) are fundamental to cellular regulation, and their dysregulation contributes to numerous diseases. Conventional approaches for studying PPIs often lack sufficient spatial and temporal resolution and are limited in capturing weak, transient, or context-dependent molecular associations. Proximity labeling (PL) technologies address these limitations by using labeling enzymes or photocatalysts targeted to specific proteins, subcellular compartments, membranes, or other biological locations to generate reactive intermediates that covalently label nearby biomolecules in living systems, thereby providing an unbiased view of protein neighborhoods and molecular proximity landscapes. This review summarizes recent advances in enzyme-based and photocatalytic proximity labeling (PPL) platforms. We discuss whole-enzyme systems, with emphasis on their engineering optimization and applications in dynamic interactome mapping, organelle organization, and signaling regulation. Split-enzyme strategies are further reviewed as conditional labeling approaches that improve spatial specificity for studying inducible interactions and membrane contact sites. In addition, emerging PPL platforms based on metal complexes, organic chromophores, and genetically encoded photocatalysts are highlighted for their light-controlled activation and expanded applicability in genetically inaccessible systems. Finally, we compare the advantages, limitations, and suitable applications of different PL technologies and discuss future challenges, including improving biological compatibility, expanding tissue applications, and integrating PL with advanced omics and computational approaches.

Keywords:  Enzyme-based proximity labeling; Photocatalytic proximity labeling; Protein–protein interactions; Proximity labeling; Spatiotemporal proteomics

DOI:  https://doi.org/10.1016/j.bios.2026.119226
Pharmacol Res. 2026 Sep 16. pii: S1043-6618(26)00382-8. [Epub ahead of print]233 108467

Spatiotemporal redistribution of HMGB1 shapes organelle interactome dysfunction and informs precision pharmacological targeting in diabetic vascular disease.

Yang Chen, Juan Xiao, Hai-Bo Si.

  Diabetic vascular complications arise from persistent metabolic stress, chronic low-grade inflammation, and progressive loss of coordinated organelle homeostasis. HMGB1 is increasingly recognized as a context-dependent mediator linking metabolic stress with cellular responses, with its functions shaped by subcellular localization, redox state, and post-translational modification. Nuclear HMGB1 supports chromatin homeostasis, cytosolic HMGB1 participates in stress- and autophagy-related responses, and extracellular HMGB1 acts as a redox-sensitive damage-associated molecular pattern. Chronic glucotoxic, lipotoxic, oxidative, and endoplasmic reticulum stress are associated with shifts among these HMGB1 pools involving nuclear export, unconventional secretion, receptor-mediated signaling, and context-dependent re-entry. This spatiotemporal redistribution is linked to changes within the organelle interactome, including mitochondria-associated endoplasmic reticulum membranes (MAMs), mitochondrial quality control, endolysosomal homeostasis, and lipid-handling organelles, with reported associations across vascular, cardiac, retinal, renal, neurovascular, and platelet-neutrophil contexts. In diabetic models, the strongest available evidence currently concerns HMGB1-associated lysosomal injury and extracellular receptor signaling, whereas several MAM-, mitophagy-, and re-entry-related mechanisms remain context dependent. This spatial perspective may help define pharmacological strategies by distinguishing disease-associated extracellular or cytosolic HMGB1 pools from homeostatic nuclear HMGB1. Integrating HMGB1 localization, molecular state, organelle context, and cell type provides a spatial framework for developing more selective interventions in diabetic vascular disease.

Keywords:  Diabetic vascular disease; HMGB1; Organelle interactome; Precision pharmacology; Redox regulation; Spatiotemporal redistribution

DOI:  https://doi.org/10.1016/j.phrs.2026.108467
Mech Ageing Dev. 2026 Sep 14. pii: S0047-6374(26)00094-1. [Epub ahead of print] 112242

Loss of Ca2+ Signaling Fidelity During Aging: Mitochondrial Dysfunction, Senescence, and Cognitive-Motor Decline.

Sergio Linsambarth, Alejandra Lopez-Moroni, Cesar Casanova, Simon Alarcon, Loreto Araos, Andrea Puebla-Huerta, Fabian Jaña, Alenka Lovy, Carlos Villalobos, J Cesar Cárdenas.

  Aging is characterized by a progressive decline in cellular homeostasis that ultimately compromises tissue integrity, regenerative capacity, and organismal function. Among the molecular processes increasingly recognized as central regulators of aging, intracellular Ca2+ signaling has emerged as a major determinant of metabolic adaptation, stress responses, inflammation, and cell fate. Ca2+ controls essential biological functions in virtually every tissue. Importantly, the remarkable versatility of Ca2+ signaling depends on the precise spatial and temporal coordination of channels, pumps, exchangers, buffering proteins, and organelle contact sites that together generate highly organized intracellular Ca2+ microdomains. During aging, the quality of this signaling progressively deteriorates. Altered activity of plasma membrane channels, defective endoplasmic reticulum (ER) Ca2+ handling, impaired mitochondrial buffering, oxidative stress, and chronic inflammation collectively destabilize intracellular Ca2+ homeostasis. These alterations converge on mitochondrial dysfunction, one of the central hallmarks of aging, leading to bioenergetic decline, excessive reactive oxygen species production, cellular senescence, and impaired tissue adaptation. In the nervous system, disrupted Ca2+ signaling contributes to synaptic dysfunction, neuroinflammation, and neuronal vulnerability associated with cognitive decline and neurodegenerative disease. In skeletal muscle, defective Ca2+ handling impairs excitation-contraction coupling, mitochondrial metabolism, and regenerative capacity, thereby promoting sarcopenia and motor decline. In this review, we discuss how aging remodels the cellular Ca2+ signaling toolkit across neuronal and muscular systems, with particular emphasis on mitochondrial dysfunction, senescence and inter-organelle communication. Finally, we examine therapeutic strategies aimed at restoring Ca2+ signaling fidelity as potential interventions to preserve tissue function and extend healthspan.

Keywords:  Channels; MERCs; mitochondria; neurodegeneration; sarcopenia

DOI:  https://doi.org/10.1016/j.mad.2026.112242
Acta Neuropathol Commun. 2026 Jul 27. pii: 189. [Epub ahead of print]14(1):

Neuro-glial lipid imbalance in a Drosophila model of amyotrophic lateral sclerosis 8.

Lovleen Garg, Kriti Chaplot, Gowhith Kuppili, Shweta Tendulkar, Jomon Joseph, Siddhesh Kamat, Girish Ratnaparkhi.

  Membrane Contact sites (MCS) have emerged as physiologically relevant zones that coordinate inter-organelle communication and cellular function. VAPB, an ER-resident MCS tethering protein, plays a central role in regulating MCSs through its numerous protein interactors, thereby influencing cellular homeostasis. A pathogenic missense VAPBP56S mutation causes familial Amyotrophic Lateral Sclerosis 8 (ALS8) in humans, with progressive degeneration of motor neurons. The precise mechanisms underlying the motor neurodegeneration remain poorly understood. In this study, we examine lipid imbalance in the brain of a Drosophila model of ALS8 (VAPBP58S). Specifically, we find that lipid homeostasis is disrupted in an age-dependent manner. Strikingly, cholesterol esters and sphingolipids show an age-dependent increase, while cholesterol shows a decrease. Intriguingly, from a cellular perspective, despite the accumulation of triacylglycerols (TAGs) in the brains of VAPBP58S animals, the increased neutral lipid species do not correlate with lipid droplets (LDs), which are fewer in density and smaller in size. Lipid imbalance and progressive motor dysfunction in VAPBP58S animals can be reversed by expressing VAPBWT, suggesting a relationship between VAPB activity and lipid flux. To uncover VAPB's role in lipid homeostasis, we modulate VAPB activity in neurons and glia to dissect out tissue-specific roles. We find that both cell types contribute to lipid homeostasis in differential ways. In glia, LD flux is strongly dependent on VAPB activity, a dependence further recapitulated in cultured human cell lines, suggesting evolutionary conservation of the regulatory mechanism. Thus, we hypothesize that lipid dysregulation constitutes a critical pathogenic feature of ALS8, with the VAPBP56S allele disrupting lipid homeostasis in the neuro-glial axis.

Keywords:  Cholesterol; Climbing; Glia; Lipid droplets; Neurodegeneration; VAP33A

DOI:  https://doi.org/10.1186/s40478-026-02391-y
J Mol Med (Berl). 2026 Sep 18. pii: 109. [Epub ahead of print]104(1):

Prospective associations of premature senescence, inflammation, and MERCSs in the cardioprotective effect of CBD in HFpEF.

Alejandro Silva-Palacios, Alejandra María Zúñiga-Muñoz, Elizabeth Soria-Castro, Edith Álvarez-León, Wylly Ramses García-Niño, Gabriela Navarrete-Anastasio, Dilan Raza, Omar Emiliano Aparicio-Trejo, Ricardo Jair Ramírez-Carreto, Verónica Salas-Venegas, Anahí Chavarría, Roger Alexis Maldonado-Ruíz, Hugo Alves-Figueiredo, Gerardo García-Rivas, Cecilia Zazueta.

  Heart failure with preserved ejection fraction (HFpEF) remains a clinical challenge lacking effective therapies. While Cannabidiol (CBD) suggests cardioprotective potential, its efficacy and underlying in HFpEF are poorly understood. This study investigated the effects of CBD on a murine model of HFpEF induced by a high-fat diet and L-NAME for 8 weeks. CBD was administered subcutaneously every three days. Hemodynamic performance was assessed via invasive pressure-volume loops, complemented by histological analysis and oxidative stress markers. Cellular senescence, NLRP3-mediated inflammation and Mitochondria-Endoplasmic Reticulum Contact Sites (MERCSs) were evaluated through immunofluorescence, RT-qPCR, and transmission electron microscopy. CBD treatment failed to reduce cardiac hypertrophy but improves cardiac fibrosis and diastolic dysfunction. These improvements were associated with a marked reduction in senescent cells accumulation and on systemic cytokine levels that may be associated with the senescence-associated secretory phenotype (SASP). Notably, CBD suppressed the NLR3-mediated proinflammatory state by preserving inter-organelle distance and MERCSs integrity. Our findings demonstrate, for the first time, that CBD modulates MERCSs communication to regulate senescence and inflammation in HFpEF. These results position CBD as a promising intervention for mitigating the pathology of HFpEF through the regulation of MERCSs, although the signaling pathways involved in this protective mechanism need to be characterized.

Keywords:  Cannabidiol; Heart failure; Inflammation; MERCSs; Senescence cellular

DOI:  https://doi.org/10.1007/s00109-026-02715-4