bims-mecosi 2026-06-21 papers

bims-mecosi

Biomed News

on Membrane contact sites

Issue of 2026–06–21
nine papers selected by
Verena Kohler, Umeå University

Dissecting mitochondria-nucleus contact sites using SPLICS reveals a distributed and dynamic tethering network.
Alzheimer's Disease and MERC Dysfunction: Integrating Mechanisms, Biomarkers, and Therapeutic Strategies.
Miro1 mutations disrupt cellular calcium homeostasis via dysregulation of mitochondria-ER-contact-sites, rendering iPSC-derived neurons more susceptible to lipid peroxidation.
Ubiquitin and ubiquitin-like modifications in the endoplasmic reticulum stress response.
Ultrastructural evidence of autophagy-related processes and mitochondrial remodeling in the myxozoan parasite Henneguya piaractus.
Lipophagy in disease: signaling control, organelle communication, and therapeutic opportunities.
Rewiring Mitochondrial Phosphatidylethanolamine Metabolism Identifies New and Unaccounted Trafficking Steps.
Targeting intracellular cholesterol imbalance rescues sarcomere-ER contact site signaling and ER remodeling in dilated cardiomyopathy.
Dendrobine alleviates lung injury in septic mice by inhibiting mitochondrial-endoplasmic reticulum crosstalk-mediated NLRP3 inflammasome activation.

Biol Direct. 2026 Jun 17.

Dissecting mitochondria-nucleus contact sites using SPLICS reveals a distributed and dynamic tethering network.

Adamantia Deligiannopoulou, Lucia Barazzuol, Caterina Peggion, Elena Poggio, Michelangelo Campanella, Marisa Brini, Tito Calì.

  Mitochondria-nucleus contact sites (also known as nucleus-associated mitochondria, NAMs) are emerging as important platforms for inter-organelle communication; however, their molecular organisation and regulation remain poorly understood. Here, we use split-GFP-based contact site sensors (SPLICSS-P2ANU-MT) to quantitatively dissect the contribution of candidate tethering proteins to the formation of short-range mitochondria-nucleus contacts in HeLa cells. Through systematic overexpression and downregulation approaches, we identify TOM70, MFN2, AKAP95, and the catalytic subunit of PKA as positive modulators of contact formation when individually overexpressed. In contrast, loss-of-function experiments reveal a selective role for TOM70, whose downregulation significantly reduces contact site abundance, whereas depletion of other candidates has limited effects. These results suggest that mitochondria-nucleus contacts are not maintained by single dominant tethers but instead rely on the coordinated contribution of multiple proteins. To further investigate cooperative mechanisms, we performed co-expression experiments. Among the combinations tested, TSPO in conjunction with either the regulatory or catalytic subunits of PKA significantly increased contact site formation, indicating that specific protein partnerships are required to establish functional tethering. Overall, our data support a model in which mitochondria-nucleus contact sites are heterogeneous and regulated by a network of interacting factors rather than a single structural component. These findings highlight the complexity of inter-organelle communication and underscore the importance of dissecting both individual and combinatorial roles of contact site components to understand their functional relevance.

Keywords:  NAM; Organelle communication; Protein kinase A (PKA) and TSPO; SPLICSS; TOM70

DOI:  https://doi.org/10.1186/s13062-026-00870-9
Mol Neurobiol. 2026 Jun 18. pii: 701. [Epub ahead of print]63(1):

Alzheimer's Disease and MERC Dysfunction: Integrating Mechanisms, Biomarkers, and Therapeutic Strategies.

Mohd Kashif, Dhriti Majumder.

  Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder, characterized by progressive cognitive decline, memory loss, and neuronal dysfunction. The pathological hallmarks are characterized by extracellular amyloid-β (Aβ) plaques, intracellular tau tangles, neuroinflammation, and synaptic failure. However, these only partially explain disease onset and progression. Recent evidence highlights mitochondria-endoplasmic reticulum contact sites (MERCs) as crucial hubs of cellular homeostasis, integrating calcium exchange, lipid metabolism, redox balance, and autophagy regulation. Dysregulation of MERC signaling is emerging as a central contributor to AD pathogenesis. MERCs orchestrate processes that intersect with amyloidogenic processing, tau hyperphosphorylation, mitochondrial dysfunction, and impaired clearance of protein aggregates. Aberrant tethering protein expression, disrupted calcium transfer, and altered lipid trafficking at MERCs have been reported in both familial and sporadic AD models, underscoring their pathogenic relevance. Moreover, MERCs influence neuroinflammatory cascades and synaptic remodeling, bridging molecular alterations with clinical manifestations. This review synthesizes current knowledge on MERC biology in the context of AD, highlighting molecular mechanisms, disease-specific perturubations, and therapeutic opportunities. In this review, we discussed pharmacological and genetic interventions targeting MERCs, including small molecules, natural compounds, and nanotechnology-based approaches. Taken together, this review outlines open research questions and future directions, underscoring MERC signaling as a promising frontier for therapeutic innovation in AD.

Keywords:  Alzheimer’s disease; Calcium signaling; Interorganelle communication; Lipid metabolism; Mitochondria–endoplasmic reticulum contact sites (MERCs)

DOI:  https://doi.org/10.1007/s12035-026-06009-1
Neurobiol Dis. 2026 Jun 18. pii: S0969-9961(26)00237-8. [Epub ahead of print] 107492

Miro1 mutations disrupt cellular calcium homeostasis via dysregulation of mitochondria-ER-contact-sites, rendering iPSC-derived neurons more susceptible to lipid peroxidation.

Anna E Bartalis, Jack Genschmar, Julia C Fitzgerald, Andreas Hermann, Dajana Grossmann.

  The pathogenesis of Parkinson's disease is multifactorial, but disruption of calcium and iron is a common feature. The mitochondrial Rho GTPase Miro1 is a component of the mitochondrial-endoplasmic reticulum contact sites and a key regulator of calcium homeostasis. Heterozygous variants in the Miro1-encoding gene RHOT1 were identified in Parkinson's disease patients. Neurons harboring Parkinson's disease-associated variants show defects in mitochondrial calcium regulation and mitochondria-ER contact sites organization which we hypothesize to contribute to neuronal vulnerability. However, the exact mechanism is not fully understood. We systematically assessed the role of Miro1 and its different domains by using a set of isogenic lines with gene edited mutations S156A and K572R in PINK1/Parkin regulatory elements and the Parkinson's disease-associated mutation R272Q. This showed us a general role of Miro1 in the regulation of cellular calcium homeostasis and the regulation of mitochondrial-ER contact sites, but more importantly, a domain-specific involvement of local calcium distribution, impaired store operated calcium entry and vulnerability to ferroptosis. These findings indicate that Miro1-mutant specific impairments in cellular calcium handling contributes to neuronal vulnerability via mitochondria-ER contact sites and provides further insights in the mechanism how impaired regulation of Miro1 impacts neurons in the context of Parkinson's disease.

Keywords:  Calcium; Ferroptosis; Lipid peroxidation; MERCS; Miro1; Parkinson's disease

DOI:  https://doi.org/10.1016/j.nbd.2026.107492
FEBS J. 2026 Jun 16.

Ubiquitin and ubiquitin-like modifications in the endoplasmic reticulum stress response.

Tony Avril, Matthieu Le Gallo, Elodie Lafont.

  The endoplasmic reticulum (ER) is a cellular organelle frequently subjected to stress under both physiological and pathological circumstances, associated with the accumulation of mis/unfolded proteins in its lumen. To cope with this stress, cells have evolved an adaptive program called the unfolded protein response (UPR), whose primary function is to restore ER proteostasis. When the stress is prolonged, the UPR can also trigger cell death. The UPR controls multiple machineries involved in pre-emptive quality control (QC) of proteins prior to ER entry, ribosome-associated QC, protein folding within the ER, protein degradation through various processes, and export from the ER for secretion. Because the UPR and the machineries it controls play fundamental roles in determining cell fate, they are finely regulated, including through post-translational modifications (PTMs). In this review, we focus on the role of the ubiquitin and ubiquitin-like PTMs in the regulation and mediation of ER proteostasis. We specifically focus on three core processes: the UPR, ER-associated ribosome QC and ER-associated degradation. Lastly, we briefly discuss how Ub and Ubl also control the integrated stress response and the formation of inter-organelle membrane contact sites and thus act as general regulators of responses to cellular stresses beyond ER proteotoxicity.

Keywords:  ER stress; ERAD; ER‐ribosomal quality control; endoplasmic reticulum; integrated stress response; ubiquitin; ubiquitin‐like; unfolded protein response

DOI:  https://doi.org/10.1111/febs.70622
J Struct Biol. 2026 Jun 16. pii: S1047-8477(26)00060-2. [Epub ahead of print]218(3): 108344

Ultrastructural evidence of autophagy-related processes and mitochondrial remodeling in the myxozoan parasite Henneguya piaractus.

Kassia Roberta Hygino Capodifoglio, Fernanda Schneberger, Antonio Augusto Mendes Maia, Maria José Tavares Ranzani de Paiva.

  Henneguya piaractus is a myxozoan parasite infecting the gills of Piaractus mesopotamicus, yet its cellular biology remains poorly understood. Here, we investigated mitochondrial organization and the occurrence of autophagy-related processes using an integrated approach combining confocal laser microscopy and transmission electron microscopy. SSU rDNA sequencing (1546 bp) confirmed species identity, showing 99.7% similarity to available H. piaractus sequences. Confocal microscopy revealed clear labeling of nuclei, polar capsules, and valves, whereas no signal indicative of mitochondrial activity was detected in mature myxospores. Ultrastructural analysis showed a plasmodium surrounded by a single membrane with numerous pinocytotic channels and mitochondria with well-developed cristae in the ectoplasmic region. Sporogenesis occurred asynchronously at the periphery, where sporoblasts and immature myxospores were observed. This region also exhibited double-membrane vesicles consistent with autophagosome-like structures, as well as phagophore-like membranes associated with damaged mitochondria. In addition, mitochondria-endoplasmic reticulum contact sites (MERCs) were identified. In contrast, centrally located mature myxospores contained mitochondria lacking cristae. Together, these findings indicate stage-dependent mitochondrial remodeling and suggest an autophagy-related process, possibly involving mitochondrial degradation. However, as these observations are based primarily on morphological evidence, the involvement of canonical autophagy pathways requires further molecular confirmation. This study provides novel insights into organelle dynamics in H. piaractus and contributes to a better understanding of cellular adaptations in myxozoan parasites.

Keywords:  Gills; Myxozoa; Pacu; Phagophore; Serrasalmidae

DOI:  https://doi.org/10.1016/j.jsb.2026.108344
Cell Commun Signal. 2026 Jun 17.

Lipophagy in disease: signaling control, organelle communication, and therapeutic opportunities.

Yu-Yang Du, Xin-Yao Chen, Yue Fang, Qing Wang, Jia-Peng Li, Ting-Ting Guo, Jia-Ni Lin, Jia-Yue Fu, Ming-Li Xie, Li-Jun Hao, Sai Luo.

Lipid droplet (LD) accumulation and impaired lipid mobilization induce lipotoxic stress and contribute to metabolic, cardiovascular, cancer, and neurodegenerative diseases (NDDs). Although LD-selective autophagy (lipophagy) is being increasingly studied, the mechanisms that confer LD specificity and enable tissue- and stage-specific therapeutic modulation remain unclear. Effective lipophagic flux requires coordinated LD coat remodeling, nutrient and energy sensing, and organelle contact. Coat remodeling governs substrate access and droplet recognition. The AMPK-mTORC1-TFEB axis links autophagy induction to lysosome biogenesis and capacity. Endoplasmic reticulum (ER)-LD, mitochondria-LD, and LD-lysosome contact sites facilitate lipid transfer by coupling lysosomal hydrolysis to mitochondrial β-oxidation. Lipophagy is a highly stage- and cell-type-dependent process: it removes excess lipids to protect cells, but its dysregulation can promote inflammation and fibrogenesis or supply substrates to tumors. This review synthesizes mechanistic and translational evidence on lipophagy initiation, regulation, and disease relevance, and identifies the following priorities: robust biomarkers, distinction of cargo-recognition defects from lysosomal dysfunction, and precision interventions tailored to the tissue and disease stage.

DOI: https://doi.org/10.1186/s12964-026-03016-6
J Lipid Res. 2026 Jun 19. pii: S0022-2275(26)00109-4. [Epub ahead of print] 101083

Rewiring Mitochondrial Phosphatidylethanolamine Metabolism Identifies New and Unaccounted Trafficking Steps.

Rashima Prem, Erica Avery, Juliana M Marquez, Chi Xie, Steven M Claypool.

  The distinct compositions of the two mitochondrial membranes are generated through a combination of phospholipids that mitochondria can make and those they take; both processes depend on a series of distinct lipid trafficking steps. Mitochondria make phosphatidylethanolamine (PE) through the action of the phosphatidylserine decarboxylase Psd1, an intermembrane space (IMS)-facing integral inner membrane (IM) protein. Psd1 has been proposed to act on its endoplasmic reticulum-derived substrate, phosphatidylserine (PS), after its transport to the mitochondrial outer membrane (OM) and either following its Ups2/Mdm35-mediated transport across the IMS to the IM or instead, on the IMS-side of the OM in a process enabled by the mitochondrial contact site and cristae organizing system (MICOS). Here, we implement a two-pronged Psd1 rewiring-based strategy predicted to either 1) circumvent the need for Ups2/Mdm35 and/or MICOS; or 2) selectively ablate the ability of Psd1 to work in trans. Our results with yeast harboring Psd1 targeted to the OM demonstrate that, with respect to mitochondrial PE production, Ups2/Mdm35 and MICOS indeed function within the IMS. Using yeast expressing a topologically inverted Psd1 chimera that faces the matrix, we identify previously unappreciated transbilayer lipid trafficking steps within the IM and show that Psd1 does not operate via a MICOS-organized in trans mechanism. Further, retained flux through inverted Psd1 when both Ups2/Mdm35 and MICOS are absent strongly implicates the existence of a major, yet presently unknown, mediator(s) of lipid movement across the IMS. Collectively, these data suggest a new model of how mitochondrial membrane diversity is established and maintained.

Keywords:  Glycerophospholipids; membrane diversity; metabolic rewiring; mitochondria; phospholipids; phospholipids/biosynthesis; phospholipids/metabolism; phospholipids/trafficking

DOI:  https://doi.org/10.1016/j.jlr.2026.101083
Signal Transduct Target Ther. 2026 Jun 17. pii: 237. [Epub ahead of print]11(1):

Targeting intracellular cholesterol imbalance rescues sarcomere-ER contact site signaling and ER remodeling in dilated cardiomyopathy.

Nadezda Ignatyeva, Cleophas Cheruiyot, Hafiza Nosheen Saleem, Ruheen Wali, Daria Plota, Wenjing Zhang, Sophie Schön, Soeren Brandenburg, Zhengyi Yang, Anna Steyer, Henning Urlaub, Torsten Rasmussen, Jens Mogensen, Julius Ryan D Pronto, Yannic Döring, Michael H Radke, Halyna Shcherbata, Stephan E Lehnart, Andreas Janshoff, Samuel Sossalla, Torben Ruhwedel, Wiebke Moebius, Karl Toischer, Britta Brügger, Volker Haucke, Michael Gotthardt, Niels Voigt, Antje Ebert.

Dysregulated intracellular lipid metabolism emerged as a driver of heart failure (HF), a leading cause of death worldwide that is frequently caused by dilated cardiomyopathy (DCM). Yet, how defective lipid signaling destabilizes failing cardiomyocytes (CMs) at the molecular level remains elusive. We utilized induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs), patient-derived heart tissue, and living adult CMs to elucidate lipid-dependent endoplasmic reticulum (ER) dysregulation in DCM and HF and identify new therapeutic targets. Lipidomics revealed abnormal intracellular cholesterol in iPSC-CMs carrying DCM-causing mutations in sarcomere proteins (tropomyosin; troponin T). Elevated cholesterol in CMs was found linked to abnormal ER architecture and dysfunction. STED microscopy, electron tomography, and biochemical analyses demonstrated that pathological ER remodeling and abnormal curvature are triggered by loss of ER-sarcomere/cytoskeleton contacts due to sarcomere misalignment in DCM CMs. Mechanistically, this signaling axis levers ER membrane dysfunctions and abnormal cholesterol levels via ER-sarcomere contact sites and operates in a bidirectional manner. Restoring intracellular cholesterol balance rescued ER membrane remodeling, sarcomere-ER contact site signaling, and sarcomere disarray in DCM iPSC-CMs. This ultimately improved the defective contractility of DCM iPSC-CMs, a key feature of failing CMs that contain a misaligned, dysfunctional sarcomere cytoskeleton. We validated this pathomechanism in end-stage DCM hearts and living atrial cardiomyocytes. Our findings suggest that intracellular cholesterol functions as a conserved ER membrane modulator and structural determinant across human CMs. Taken together, we present the lipidomic landscape of DCM and identify defective ER/cholesterol signaling as a disease driver whose therapeutic targeting rescues key functions in failing CMs.

DOI: https://doi.org/10.1038/s41392-026-02731-3
J Pharmacol Sci. 2026 Aug;pii: S1347-8613(26)00027-7. [Epub ahead of print]161(4): 119-129

Dendrobine alleviates lung injury in septic mice by inhibiting mitochondrial-endoplasmic reticulum crosstalk-mediated NLRP3 inflammasome activation.

Shichao Zhang, Kaihang Luo, Xinyue Wei, Cheng Qing, Jianguo Zhang, Huazhang Wei, Yongan Yan, Yuting Yang, Zhenguo Zeng, Shuying Huang.

  Sepsis, a life-threatening disorder driven by a dysregulated host response to infection, is frequently accompanied by acute lung injury (ALI), worsening disease severity, and mortality. Excessive macrophage-mediated inflammation is central to its pathogenesis. Given emerging evidence that mitochondria-endoplasmic reticulum (ER) crosstalk drives inflammatory injury, we investigated whether modulating this interaction could mitigate sepsis-induced damage. Using LPS-stimulated THP-1 macrophages and a murine model of LPS-induced sepsis, we evaluated the anti-inflammatory and organ-protective effects of dendrobine, a bioactive alkaloid from Dendrobium nobile Lindl. Dendrobine suppressed glycolysis-induced mitochondria-ER crosstalk, thereby reducing macrophage-driven inflammation and tissue injury. In vivo, dendrobine lowered circulating interleukin (IL)-1β and IL-18 levels and alleviated ALI. Mechanistically, dendrobine decreased reactive oxygen species production and mitochondrial DNA (mtDNA) release, leading to downregulation of NLRP3 and cleaved caspase-1. These effects stemmed from inhibition of hypoxia-inducible factor-1α (HIF-1α) and hexokinase 2 (HK2)-mediated glycolysis, preventing HK2 dissociation from voltage-dependent anion channel 1 (VDAC1) and disrupting IP3R-GRP75-VDAC1 complex formation. Collectively, these findings demonstrate that dendrobine protects against sepsis-induced organ injury by targeting the IP3R-GRP75-VDAC1-HK2 axis in macrophages, highlighting its therapeutic potential for sepsis.

Keywords:  Acute lung injury(ALI); Dendrobine; Hexokinase2(HK2); Mitochondria-associated endoplasmic reticulum membrane (MAMs); Sepsis

DOI:  https://doi.org/10.1016/j.jphs.2026.05.007