bims-mecosi Biomed News
on Membrane contact sites
Issue of 2026–07–26
six papers selected by
Verena Kohler, Umeå University
  1. ER-mitochondria contact sites and organelle stress in asthma.
  2. Tripartite ER-mitochondria-lipid droplets contact sites control adipocyte metabolic flexibility.
  3. Disruption of mitochondria-associated ER membranes: a novel mechanism for high-salt diet-exacerbated hemorrhagic shock-induced lymphatic dysfunction.
  4. When calcium crosstalk turns ferroptotic: the SERCA2-VDAC1 axis in AKI.
  5. Trimethylamine N-oxide activates cardiac fibroblasts transformation through NLRP3 inflammasome activation with changes in mitochondrial dynamics and ER-mitochondrial contact under ER stress.
  6. Mechanisms and Therapeutic Strategies Targeting the Reversible Phosphorylation-Endoplasmic Reticulum Stress Network in Diabetic Cardiomyopathy.
  1. Mol Biol Rep. 2026 Jul 22. pii: 1236. [Epub ahead of print]53(1):
    ER-mitochondria contact sites and organelle stress in asthma.
    Sihao Zhu, Xinxin Xing, Jia Zheng, Hai Wang.
      Mitochondria-associated endoplasmic reticulum membranes (MAMs), functional domains within endoplasmic reticulum (ER)-mitochondria contact sites, provide spatial domains through which ER-derived Ca²⁺ signals are coupled to mitochondrial metabolism, redox balance, and stress adaptation. In asthma, this concept is relevant because many disease-associated stimuli, including allergens, cytokines, oxidative stress, infection-related signals, and mechanical stress, disturb both ER and mitochondrial homeostasis. However, MAMs should not be used as a general label for all ER stress or mitochondrial dysfunction. Their unique value lies in explaining how selected stress signals are organized at sites of ER-mitochondria communication. This review critically evaluates whether MAM-related mechanisms contribute to asthma pathogenesis and where the current evidence remains indirect. The strongest asthma-relevant support is found in monocyte/macrophage-centered inflammatory responses, in which ER-mitochondria Ca²⁺ transfer, mitochondrial stress, and inflammasome activation may be functionally connected. In airway epithelial cells and airway smooth muscle cells (ASMCs), available studies more consistently support mitochondrial dysfunction, Ca²⁺ dysregulation, oxidative stress, barrier injury, cell death, and remodeling-related responses, but direct evidence that these changes are initiated by defined MAM remodeling remains limited. We therefore distinguish MAM-specific mechanisms from MAM-adjacent ER or mitochondrial stress responses across different asthma-relevant cell types. By organizing the literature around ER-to-mitochondria Ca²⁺ transfer, contact-site remodeling, mitochondrial stress signaling, and cell type-specific inflammatory or remodeling outcomes, this review highlights both the potential importance and the current limitations of MAM biology in asthma. Future studies should combine structural assessment of ER-mitochondria contacts with functional readouts of Ca²⁺ transfer, mitochondrial redox state, mitophagy, inflammasome activation, and disease-relevant cellular phenotypes. Such work will be essential to determine whether MAMs are causal regulators of asthma pathology or stress-responsive interfaces associated with broader organelle dysfunction.
    Keywords:  Asthma; ER–mitochondria contact sites; Mitochondria-associated endoplasmic reticulum membranes; NLRP3 inflammasome; Organelle stress
    DOI:  https://doi.org/10.1007/s11033-026-12441-2
  2. EMBO J. 2026 Jul 22.
    Tripartite ER-mitochondria-lipid droplets contact sites control adipocyte metabolic flexibility.
    Marie Palard, Gilliane Chadeuf, Maxime Carpentier, Clotilde C N Renaud, Samuel Frey, Mikael Croyal, Rola Shaaban, Samy Hadjadj, Chloe Cloteau, Naima El Khallouki, Perrine Bomme, Soazig Le Lay, Manuel Majrouh, Perrine Paul-Gilloteaux, Alexandre Humbert, Christine Durand, Nicolas Bertocchini, Laurence Dubreil, Yoann Combot, Antria Antreou, Cedric Le May, Simon Ducheix, Bertrand Cariou, Francesca Giordano, Jennifer Rieusset, Abdou Rachid Thiam, Xavier Prieur.
      Adipocyte dysfunction is a major driver of obesity-associated cardiometabolic disease, underscoring the need to understand how lipid storage and mobilization are regulated and disrupted. The ER-anchored protein Seipin governs lipid droplet (LD) biogenesis and ER-LD and ER-mitochondria (MAM) contacts, and its loss impairs calcium transfer and causes lipodystrophy. Here, we investigated whether Seipin coordinates MAM and ER-LD remodeling during adipocyte lipid handling. In subcutaneous adipose tissue from inducible Seipin-knockout mice, electron microscopy and proximity ligation assays revealed that feeding reduces MAMs while increasing ER-LD and mitochondria-LD contacts, a remodeling abolished by Seipin deficiency. Lipid loading elevated tripartite MAM-LD contacts in controls but not knockouts. Fluorescence recovery after photobleaching showed that impaired triglyceride transfer to LDs in Seipin-deficient cells was rescued by the MAM-LD-stabilizing peptide 'Linker-ER-Mi', in a calcium-dependent manner. During adipogenesis and lipid loading, MAM-LD contacts increased, whereas MAM-cytosolic mitochondria contacts declined; however, obesity blunted this remodeling. Furthermore, disrupting membrane contact sites impaired lipid flux, lipolysis, and insulin signaling. Taken together, these findings identify MAM-LD as regulators of adipocyte metabolic flexibility.
    DOI:  https://doi.org/10.1038/s44318-026-00876-z
  3. Shock. 2026 Jul 22.
    Disruption of mitochondria-associated ER membranes: a novel mechanism for high-salt diet-exacerbated hemorrhagic shock-induced lymphatic dysfunction.
    Hong-Li Han, Yang Liu, Yu-Yao Hao, Hai-Ning Zheng, Li-Min Zhang, Hui-Bo Du, Xiao-Qi Yue, Min Gao, Run Li, Yu-Ping Zhang, Chun-Yu Niu, Zi-Gang Zhao.
       BACKGROUND: Although high-salt diet (HSD) impairs cardiovascular function, its impact on the prognosis of hemorrhagic shock (HS) has not been elucidated. Impaired mesenteric lymphatic contractility post-HS contributes to an unfavorable prognosis. Since mitochondria-associated endoplasmic reticulum membranes (MAMs) regulate calcium-dependent contraction, we hypothesized that HSD exacerbates HS-induced lymphatic dysfunction by damaging MAM integrity in lymphatic smooth muscle cells (LSMCs).
    METHODS: Male Wistar rats were fed either a normal diet (ND) or HSD containing 8% NaCl for 8 weeks. A conscious rat model of fixed-pressure HS (40 mmHg for 90 min) with resuscitation was established. The rats were divided into four groups: ND+SS, ND+HS, HSD+SS, and HSD+HS. Additional HS groups were treated with either the IP3R1 inhibitor 2-APB (HSD+HS+2-APB) or the IP3R1 activator CdCl2 (ND+HS+CdCl2). Survival time and in vivo and ex vivo mesenteric lymphatic contractility were assessed. The ultrastructure and protein expression of MAM were analyzed.
    RESULTS: HSD significantly increased blood pressure but not body weight and markedly reduced survival time after HS. HSD alone impaired mesenteric lymphatic contractility and exacerbated HS-induced contractile and reactive dysfunction. HS and HSD independently shortened the contact distance and increased the contact coefficient of MAM in LSMCs, with combined exposure producing the most severe disruption. These structural alterations were accompanied by increased protein expression of IP3R1 and VDAC1. Importantly, therapeutic inhibition of MAM with 2-APB in HSD+HS rats improved survival, restored lymphatic contractility, and normalized MAM structure and protein expression. Conversely, pharmacological aggravation of MAM with CdCl2 in ND+HS rats worsened survival and lymphatic function, paralleling MAM disruption.
    CONCLUSION: Chronic HSD is a risk factor for poor outcomes after HS, worsening both survival and mesenteric lymphatic function by disrupting MAM integrity in LSMCs. Targeting MAM, exemplified by IP3R1 inhibition, represents a novel therapeutic strategy for mitigating shock-induced lymphatic dysfunction, particularly in salt-sensitive populations.
    Keywords:  Hemorrhagic shock; High-salt diet; IP3R1; Lymphatic contractility; Mitochondria-associated endoplasmic reticulum membrane (MAM); Resuscitation
    DOI:  https://doi.org/10.1097/SHK.0000000000002913
  4. Kidney Int. 2026 Aug;pii: S0085-2538(26)00415-1. [Epub ahead of print]110(2): 297-300
    When calcium crosstalk turns ferroptotic: the SERCA2-VDAC1 axis in AKI.
    Yu Ah Hong.
      Organelle communication through endoplasmic reticulum-mitochondrial crosstalk is essential for maintaining cellular homeostasis and is tightly regulated by tethering proteins within mitochondria-associated endoplasmic reticulum membranes. In a recent study published in Kidney International, He et al. identified sarcoplasmic/endoplasmic reticulum Ca2+-ATPase 2 as a key regulator of endoplasmic reticulum-mitochondrial calcium homeostasis in proximal tubules and demonstrated that loss of sarcoplasmic/endoplasmic reticulum Ca2+-ATPase 2 drives voltage-dependent anion channel 1 oligomerization, mitochondrial DNA release, stimulator of interferon genes activation, and ferroptosis in acute kidney injury. This study establishes the sarcoplasmic/endoplasmic reticulum Ca2+-ATPase 2-voltage-dependent anion channel 1 axis as a mechanistic link between mitochondrial calcium dysregulation and ferroptotic tubular injury.
    DOI:  https://doi.org/10.1016/j.kint.2026.05.005
  5. Mol Cell Biochem. 2026 Jul 20.
    Trimethylamine N-oxide activates cardiac fibroblasts transformation through NLRP3 inflammasome activation with changes in mitochondrial dynamics and ER-mitochondrial contact under ER stress.
    Huimin Wang, Hanlin Liu, Xinnan Meng, Jiantao Song, Yan Jin, Yuanyuan Bai.
      Trimethylamine N-oxide (TMAO), a gut microbiota-derived metabolite, has been linked to cardiovascular diseases. This study aimed to explore the role of TMAO in cardiac fibrosis by examining its effects on the NLRP3 inflammasome, endoplasmic reticulum stress (ERS), mitochondria-associated membranes (MAMs), and mitochondrial dynamics in cardiac fibroblasts (CFs), alongside clinical data from acute myocardial infarction (AMI) patients and unstable angina (UA) patients and AMI animal model data. Plasma TMAO levels were measured in AMI patients and healthy controls. In vitro, CFs were treated with TMAO to assess cellular activation and fibrosis markers. Western blot, immunofluorescence, and RNA sequencing identified key pathways and proteins related to ERS, NLRP3 inflammasome activation, and mitochondrial dynamics. In vivo, Masson's trichrome staining, Hematoxylin-Eosin (HE) staining and Immunohistochemical were used to evaluate the effects of TMAO on AMI mice. Plasma TMAO levels were significantly higher in the AMI group. TMAO promoted cardiac fibroblast activation and fibrosis by increasing α-SMA and Collagen I expression. It induced ERS, marked by elevated GRP78, p-PERK, and CHOP, and upregulated Sigma-1R, enhancing MAM formation. TMAO also altered mitochondrial dynamics via DRP1 phosphorylation and Mfn2 expression. RNA sequencing identified macrophage migration inhibitory factor (MIF) as a key mediator linking TMAO to NLRP3 inflammasome activation. TMAO exacerbates myocardial injury and fibrotic remodeling in AMI mice. TMAO exacerbates cardiac fibrosis via ERS and NLRP3 activation, with implications for mitochondrial dynamics and MAM formation. Elevated TMAO levels in AMI patients underscore its potential as a therapeutic target for ventricular remodeling fibrosis.
    Keywords:  Cardiac fibroblasts; Endoplasmic reticulum stress; MAMs; MIF; NLRP3; TMAO
    DOI:  https://doi.org/10.1007/s11010-026-05658-z
  6. Eur J Pharmacol. 2026 Jul 23. pii: S0014-2999(26)00653-9. [Epub ahead of print] 179171
    Mechanisms and Therapeutic Strategies Targeting the Reversible Phosphorylation-Endoplasmic Reticulum Stress Network in Diabetic Cardiomyopathy.
    Qian-Qian Niu, Tian-Lu Zhu, Bo Xu, Hui-Dan Wang, Chun-Rui Zhang, Kun-Fang Qin, Yu-Ting Xi, Peng Li, Vuanghao Lim, Nik Nur Syazni Binti Nik Mohamed Kamal, Ya-Ling Yin.
      The pathological progression of diabetic cardiomyopathy (DCM) involves multiple interconnected mechanisms, including metabolic reprogramming, oxidative stress, Ca2+ dysregulation, and programmed cell death. Recent studies have shown that reversible protein phosphorylation, endoplasmic reticulum stress (ERS) and the unfolded protein response (UPR) are not independent events, but rather form an interactive network through the dynamic balance mediated by kinases and phosphatases, thereby coordinating cardiomyocyte fate. This review focuses on the reciprocal regulation of reversible phosphorylation and ER stress in diabetic cardiomyopathy and further discusses the role of mitochondria-associated membranes (MAMs) in coupling Ca2+ transfer, oxidative stress, mitochondrial dysfunction, and cell death signaling. Additionally, this review summarizes recent advances in natural bioactive compounds and kinase/phosphatase modulators for targeting these pathological processes, providing insights for mechanistic studies and the optimization of therapeutic strategies for diabetic cardiomyopathy.
    Keywords:  diabetic cardiomyopathy; endoplasmic reticulum stress; mitochondria-associated membranes; reversible phosphorylation; unfolded protein response
    DOI:  https://doi.org/10.1016/j.ejphar.2026.179171
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