bims-mecosi 2026-10-25 papers

bims-mecosi

Biomed News

on Membrane contact sites

Issue of 2026–10–25
nine papers selected by
Verena Kohler, Umeå University

Endoplasmic reticulum-mitochondria contact sites in benign prostatic hyperplasia: evidence integration and mechanistic hypotheses.
GRP75-dependent SIMPA mediates inter-organellar quality control.
Lipid droplet targeting at single-molecule resolution.
Polycystin-2 functions as a calcium leak channel under endoplasmic reticulum stress to protect against myocardial ischemia.
Polystyrene nanoplastics impair mitochondrial function, quality control, and ER-mitochondria crosstalk in HeLa cells.
Lipid droplet-mitochondria crosstalk in osteoarthritis: linking lipid routing to metabolic mismatch.
Ginsenoside Rb1 ameliorates stress urinary incontinence by upregulating SIRT1 to preserve mitochondrial homeostasis and MAM integrity.
Natural products targeting mitochondrial homeostasis: a four-dimensional framework integrating dynamics, mitophagy, pharmacokinetics, and translational safety.
Acetochlor Induces Nephrotoxicity in Chicken through IP3R1-GRP75-VDAC1-Mediated Stabilization of Mitochondria-Associated MAMs and the Regulation of Apoptosis and Autophagy, an Effect That Is Mitigated by Omega-3 Fatty Acids.

Front Immunol. 2026 ;17 1945942

Endoplasmic reticulum-mitochondria contact sites in benign prostatic hyperplasia: evidence integration and mechanistic hypotheses.

Lei Liu, Minhao Fu, Zhenting Wang.

  Benign prostatic hyperplasia (BPH) is a common chronic and progressive disease in ageing men. Its pathobiology involves androgen-signaling remodeling, chronic inflammation, oxidative stress, metabolic disturbance, and dysregulated cell fate control; however, the organelle-level communication that connects these processes remains insufficiently defined. Endoplasmic reticulum (ER)-mitochondria contact sites, commonly referred to as mitochondria-associated membranes (MAMs), are dynamic membrane contact platforms that coordinate ER stress with mitochondrial homeostasis. Through the regulation of Ca²+ transfer, lipid metabolism, mitochondrial dynamics, autophagy, inflammatory signaling, and cell death, MAMs may provide a structural and functional interface linking several pathological features of BPH. In this review, we integrate evidence from BPH studies, including GRP78 upregulation, mitochondrial reactive oxygen species (ROS) accumulation, NLRP3 inflammasome activation, DRP1-associated abnormalities in mitochondrial dynamics, and resistance to apoptosis. On this basis, we discuss the mechanistic hypothesis that MAM remodeling may contribute to the chronic progression of BPH. Current evidence does not support defining MAMs as direct pathogenic drivers of BPH. Rather, positioning MAMs as an organelle-communication framework that links ER stress, mitochondrial injury, and tissue hyperplasia may help explain the pathological heterogeneity of BPH and identify candidate targets for future investigation.

Keywords:  ageing; benign prostatic hyperplasia; endoplasmic reticulum stress; inflammation; mitochondria-associated membranes; mitochondrial dysfunction; oxidative stress

DOI:  https://doi.org/10.3389/fimmu.2026.1945942
Nature. 2026 Oct 21.

GRP75-dependent SIMPA mediates inter-organellar quality control.

Fan Yu, Lingyu Jiang, Hanyu Liu, Song Yang, Yuan Yuan, Hongzhen Jin, Jinming Liu, Xi Liu, Yu Dong, Dongfeng Ren, Jie Kang, Yan Huang, Qi Meng, Feng Bai, Yanjun Li, Shuoguo Li, Huadong Liu, Wei Zhao, Jia Xiao, Quan Chen.

Mitochondria are bound by a double membrane and are semiautonomous organelles, rendering them highly vulnerable to global and internal proteostatic stress1. Multiple surveillance mechanisms at proteostatic and inter-organellar levels have evolved to maintain mitochondrial integrity and cellular health2-7. However, the precise mechanisms by which proteostatic damage relays stress signals across organelles and how the quality surveillance machinery coordinates these functions remain unknown. Here we report that under proteostatic stress, damaged mitochondrial proteins are sequestered to form stress-induced mitochondrial protein aggregates (SIMPAs) that activate specific quality control mechanisms in a spatially confined manner without perturbing the mitochondrial network. Quantitative proteomic and correlative light-electron microscopy analysis revealed that SIMPA mediates inter-organellar communication via mitochondria-endoplasmic reticulum contact sites or mitochondrial-associated membranes. Mechanistically, GRP75 coordinates SIMPA biogenesis and focally activates endoplasmic reticulum unfolded protein response pathways via mitochondria-endoplasmic reticulum contact sites or mitochondrial-associated membranes for the targeted clearance of SIMPAs. Functionally, in both cellular and liver disease models, we found that a GRP75-dependent SIMPA signalling cascade attenuates mitochondrial stress and preserves mitochondrial integrity under proteotoxic stress. Overall, we show that SIMPAs, functioning as protein condensates, serve as a central cross-compartment communication hub for mitochondrial quality control, supporting cellular and organismal fitness.

DOI: https://doi.org/10.1038/s41586-026-10733-y
Trends Cell Biol. 2026 Oct 21. pii: S0962-8924(26)00209-6. [Epub ahead of print]

Lipid droplet targeting at single-molecule resolution.

Veijo T Salo, Elina Ikonen.

  Lipid droplet proteins can move from the endoplasmic reticulum to droplets through persistent membrane connections. A new single-molecule study reveals that accumulation is not only about access: protein sequence features tune residence on the droplet surface, revealing how confined mobility can lead to accumulation on the organelle (Mizrak et al.).

Keywords:  endoplasmic reticulum; lipid droplets; membrane contact sites; protein targeting; seipin; single-molecule tracking

DOI:  https://doi.org/10.1016/j.tcb.2026.10.003
Cell Rep. 2026 Oct 20. pii: S2211-1247(26)01245-3. [Epub ahead of print]45(11): 118166

Polycystin-2 functions as a calcium leak channel under endoplasmic reticulum stress to protect against myocardial ischemia.

Virdjinija Vuchkovska, Sanjeet Paluru, Ryne M Knutila, Djamilla Simoens, Karla M Márquez-Nogueras, Elisabeth DiNello, Quan Cao, Jonathan A Kirk, Ivana Y Kuo.

  Endoplasmic reticulum (ER) stress activates the unfolded protein response (UPR) to enhance metabolism and restore homeostasis by increasing mitochondrial calcium at mitochondrial-endoplasmic reticulum contact sites (MERCs). Unresolved ER stress is deleterious and contributes to the severity of diseases such as myocardial infarction (MI). The identity of the MERC calcium source and its interplay with the UPR is unclear. We find that ER-localized polycystin-2 (PC2), a calcium channel, is upregulated in cardiomyocytes with MI. Cardiomyocyte PC2-knockout mice with MI exhibit worsened heart function and decreased PERK. ER stress induces a PC2-facilitated adaptive ER calcium leak and PC2 localization to MERCs. PC2 requires PERK phosphorylation for mitochondrial calcium transfer. PC2 mutations impair ER calcium leak, restored by full-length PC2 expression. Thus, PC2 functions in a PERK-dependent manner under ER stress to provide mitochondrial calcium, and its upregulation is cardioprotective in MI.

Keywords:  CP: cell biology; ER stress; MERCs; MI; PC2; PERK; calcium leak; cardiomyocytes

DOI:  https://doi.org/10.1016/j.celrep.2026.118166
Front Toxicol. 2026 ;8 1907794

Polystyrene nanoplastics impair mitochondrial function, quality control, and ER-mitochondria crosstalk in HeLa cells.

Giuseppe Petito, Maria Teresa Gentile, Arianna Cuomo, Angelo Fusco, Sara Falvo, Maria Della Valle, Gianluca D'Abrosca, Carla Isernia, Roberto Fattorusso, Maria Emanuela Errico, Antonia Lanni, Gaetano Malgieri, Rosalba Senese.

   Introduction: Polystyrene nanoplastics (PS-NPs) represent persistent environmental contaminants derived from the degradation of plastic debris and are increasingly detected in biological systems, raising concerns regarding their potential effects on human health. Emerging evidence suggests that, following cellular internalization, PS-NPs can induce intracellular stress responses and interfere with mitochondrial homeostasis, highlighting mitochondria as key targets of nanoplastic-induced cellular dysfunction. This study aimed to investigate the effects of PS-NPs on mitochondrial function in HeLa cells. Particular attention was devoted to Mitochondrial Quality Control (MQC) pathways, including the mitochondrial Unfolded Protein Response (UPRmt), a stress-adaptive mechanism that remains poorly characterized in response to nanoplastic exposure in human cellular model. In addition, the study examined the functional crosstalk between the Endoplasmic Reticulum and mitochondria.
Methods: HeLa cells were exposed to PS-NPs, and mitochondrial bioenergetics, oxidative stress, mitochondrial membrane potential, cellular ATP levels, extracellular lactate levels, and calcium homeostasis were assessed using functional assays. MQC-related pathways, including UPRmt, mitochondrial biogenesis, dynamics, autophagy/mitophagy, and ER stress responses, were evaluated through biochemical, molecular, and imaging approaches.
Results: Our results demonstrate that PS-NP exposure induces mitochondrial dysfunction, characterized by impaired mitochondrial coupling, mitochondrial membrane depolarization, increased H2O2 levels in cell lysates, and altered cellular redox homeostasis. Moreover, PS-NPs disrupt MQC processes, leading to an imbalance in the mechanisms that maintain mitochondrial homeostasis, including modulation of UPRmt-associated proteins and dysregulation of ER-mitochondria communication via Mitochondria-Associated Membranes (MAMs).
Conclusion: Collectively, these data advance our understanding of PS-NP toxicity by identifying alterations in MQC systems and ER-mitochondria crosstalk as key events in nanoplastic-induced cellular stress. These findings provide novel mechanistic insights into nanoplastic toxicity and highlight the potential impact of environmental PS-NP exposure on cellular homeostasis and human health.

Keywords:  HeLa cells; mitochondria associated membranes (MAMs); mitochondrial dysfunction; mitochondrial unfolded protein response (UPRmt); nanoplastics (NPs); oxidative stress

DOI:  https://doi.org/10.3389/ftox.2026.1907794
Front Mol Biosci. 2026 ;13 1973436

Lipid droplet-mitochondria crosstalk in osteoarthritis: linking lipid routing to metabolic mismatch.

Gang Meng, Ruijie Hou, Ping Dong, Qiannan Chen, Xueyuan Li, Kai Hu, Zixuan Du, Rong Wang, Zhaoxin Zhong.

  Osteoarthritis (OA) is a whole-joint disease characterized by metabolic reprogramming beyond structural degeneration. Increasing evidence indicates that lipid droplets (LDs) regulate lipid storage, mobilization and intracellular lipid routing, while alterations in mitochondrial metabolism determine the capacity of chondrocytes to adapt to metabolic stress. However, LD accumulation alone is insufficient to define metabolic dysfunction, as it may represent either adaptive buffering or maladaptive retention. This review proposes a lipid flux-mitochondrial capacity matching framework to integrate lipid handling with mitochondrial oxidative capacity, redox regulation and quality control. We discuss how excessive lipid flux relative to mitochondrial capacity may promote oxidative stress, lipid peroxidation, ferroptosis, senescence and extracellular matrix disruption, whereas balanced lipid utilization supports chondrocyte homeostasis. Current evidence on LD biology, fatty acid oxidation, mitophagy and whole-joint metabolic communication is summarized, with clear distinction between direct OA evidence and findings from other cellular systems. Although organelle contact sites such as PLIN5-FATP4, PLIN3-VDAC3 and ESYT1/2-VAPB represent potential regulators of lipid routing, their functional relevance in OA chondrocytes remains to be established. Future studies integrating isotope tracing, metabolic flux analysis and dynamic organelle imaging are required to clarify how lipid routing and mitochondrial capacity jointly regulate OA progression.

Keywords:  fatty acid oxidation; ferroptosis; lipid droplets; lipid flux; mitochondrial metabolism; mitophagy; organelle contact sites; osteoarthritis

DOI:  https://doi.org/10.3389/fmolb.2026.1973436
Front Pharmacol. 2026 ;17 1912811

Ginsenoside Rb1 ameliorates stress urinary incontinence by upregulating SIRT1 to preserve mitochondrial homeostasis and MAM integrity.

Liying Chen, Lingyun Li, Mao Chen, Ya Xiao, Hanyue Li, Xiaoyu Tian, Li Hong, Jianming Tang.

   Introduction: Stress urinary incontinence (SUI) is a prevalent pelvic floor disorder characterized by impaired connective tissue integrity. Oxidative stress-induced mitochondrial dysfunction has been implicated in pelvic floor degeneration. Ginsenoside Rb1 (Rb1), a bioactive component of ginseng, exhibits antioxidant properties; however, its therapeutic effects and underlying mechanisms in SUI remain unclear.
Methods: A vaginal distension (VD)-induced mouse model of SUI and an H2O2-induced oxidative stress model in L929 cells were established to investigate the effects of Rb1. Urodynamic evaluation, histological analysis, mitochondrial functional assays, and SIRT1 inhibition/knockdown experiments were performed to explore the molecular mechanisms.
Results: Rb1 significantly improved bladder leak point pressure, preserved collagen organization, and reduced apoptosis in the anterior vaginal wall of VD mice. Rb1 alleviated oxidative stress by reducing ROS accumulation and restoring mitochondrial homeostasis. Mechanistically, Rb1 upregulated SIRT1 and enhanced mitochondrial biogenesis-associated signaling through the PGC-1α/NRF1/TFAM pathway, while promoting PINK1/Parkin-associated mitophagic signaling. Furthermore, Rb1 maintained mitochondria-associated membrane (MAM) integrity by regulating GRP75 acetylation, thereby reducing excessive ER-mitochondrial calcium transfer, mitochondrial calcium overload, and mtROS accumulation. SIRT1 inhibition or knockdown attenuated these protective effects.
Conclusion: Ginsenoside Rb1 protects against SUI by promoting SIRT1-associated mitochondrial quality control and preserving MAM homeostasis through regulation of GRP75 acetylation. These findings identify the SIRT1-GRP75/MAM axis as a potential therapeutic target for preventing oxidative stress-induced pelvic floor tissue dysfunction.

Keywords:  SIRT1; ginsenoside Rb1; mitochondria-associated membranes; mitochondrial biogenesis; mitophagy; stress urinary incontinence

DOI:  https://doi.org/10.3389/fphar.2026.1912811
Front Pharmacol. 2026 ;17 1911495

Natural products targeting mitochondrial homeostasis: a four-dimensional framework integrating dynamics, mitophagy, pharmacokinetics, and translational safety.

Zhi-Yun Xiang, Xiu-Hua Yang, Wen-Ying Lan, Xin-Yu Xiao, Qun Huang, Lin-Lin Yang.

   Background: Dysregulated mitochondrial dynamics, including fission, fusion, biogenesis, and mitophagy, underlie the pathogenesis of many diseases. Natural products have the potential for multi-target therapy, but insufficient understanding of their mechanisms of action and pharmacokinetic limitations hinder their clinical translation.
Objective: This review proposes a regulatory framework covering the four dimensions of biogenesis, morphology, quality control, and defense, aiming to systematically clarify how natural products regulate mitochondrial function and critically evaluate their translational potential. The framework emphasizes that inter-organelle contact platforms, such as mitochondria-endoplasmic reticulum contact sites (MERCs) and mitochondrial-lysosomal contact sites (MLCs), are key sites through which natural products exert regulatory effects.
Methods: Major scientific databases, including PubMed, Web of Science, and Scopus, were searched, and evidence on mechanisms, pharmacokinetics, and toxicology from preclinical and clinical studies was comprehensively reviewed.
Results: Natural products can selectively regulate key mitochondrial pathways and regulatory nodes, including the AMPK/SIRT1/PGC-1α axis involved in mitochondrial biogenesis, the DRP1 axis involved in mitochondrial fission, and the PINK1/Parkin pathway involved in mitophagy. Representative metabolites include resveratrol, curcumin, and Coptis chinensis-derived alkaloids. A key finding of this review is that the intestinal microbiota plays an important role in converting low-bioavailability precursors, such as tannins, into systemically active metabolites, such as urolithin A (UA), thus inducing mitophagy. Although these metabolites usually show strong activity in vitro, their low oral bioavailability and rapid metabolism lead to significant pharmacokinetic/pharmacodynamic (PK/PD) mismatch, which remains a major obstacle to their clinical translation.
Conclusion: Natural products are powerful multidimensional regulators of mitochondrial homeostasis. In order to fully realize their therapeutic potential, strategies must be adopted to overcome PK/PD mismatch, including the development of targeted delivery systems, in-depth analysis of microbiome-metabolite interactions, and the integration of artificial intelligence and CRISPR-based technological innovation to support precision therapy.

Keywords:  gut microbiota–mitochondria axis; mitochondrial dynamics; mitohormesis; mitophagy; natural products; pharmacokinetics

DOI:  https://doi.org/10.3389/fphar.2026.1911495
J Agric Food Chem. 2026 Sep 23. 74(37): 29532-29549

Acetochlor Induces Nephrotoxicity in Chicken through IP3R1-GRP75-VDAC1-Mediated Stabilization of Mitochondria-Associated MAMs and the Regulation of Apoptosis and Autophagy, an Effect That Is Mitigated by Omega-3 Fatty Acids.

Hongmin Lu, Xin Zhang, Qi Wang, Ruoqi Wang, Yuze Dong, Yutong Yin, Tiantian Guo, Bing Yu, Mingwei Xing.

  Acetochlor (ACT)-induced nephrotoxicity in poultry remains poorly understood. This study investigated the renal toxicity of ACT in chickens and evaluated the protective effects of Omega-3 supplementation using molecular dynamics simulations, Western blotting, and immunofluorescence staining. Prolonged ACT exposure induced renal histopathological damage, mitochondrial swelling, and enhanced endoplasmic reticulum (ER)-mitochondria coupling. Mechanistically, ACT promoted cytosolic calcium ([Ca2+]c) transfer to mitochondria, causing mitochondrial Ca2+ ([Ca2+]mit) overload, excessive mitochondrial ROS generation, mitochondrial permeability transition pore (mPTP) opening, activation of the Bax-Cytc-Caspase3 apoptotic pathway, and impaired autophagic flux. Omega-3 supplementation improved renal function, restricted [Ca2+]mit accumulation, reduced oxidative stress, maintained autophagic flux, and attenuated apoptosis. These findings indicate that inhibition of IP3R-GRP75-VDAC1-mediated [Ca2+]mit overload and oxidative stress, thereby preventing mPTP opening, may mitigate ACT-induced kidney injury and growth impairment. This study provides mechanistic insight into ACT nephrotoxicity and supports Omega-3 as a potential nutritional strategy for reducing related environmental risks.

Keywords:  IP3R-GRP75-VDAC1 complex; Omega-3; acetochlor; apoptosis and autophagy; chicken kidney

DOI:  https://doi.org/10.1021/acs.jafc.6c05123