bims-mecosi 2026-03-22 papers

bims-mecosi

Biomed News

on Membrane contact sites

Issue of 2026–03–22
sixteen papers selected by
Verena Kohler, Umeå University

STIM1 and endoplasmic reticulum-plasma membrane contact sites oscillate independently of calcium-induced calcium release.
Lipid overload triggers PERK-ALCAT1-mediated mitophagy failure in hepatocytes.
Excessive ER-mitochondria coupling: A DRP1-driven mechanism underlying mitochondrial dysfunction and impaired autophagy in stress-induced depression-like behavior in mice.
Melatonin promotes skeletal muscle mitochondria-associated endoplasmic reticulum membrane contacts and restores organellar membrane integrity and phospholipid composition in Zücker diabetic fatty rats of both sexes.
Atrazine increases hepatic inflammation and injury via endoplasmic reticulum (ER) stress mediated excessive formation of mitochondria-associated membranes (MAMs) and activation of the cGAS-STING pathway.
Parkinson's disease-associated PLA2G6 protects IP3R1 protein to control ER-mitochondria tethering and Ca2+ transfer.
ATG2A connects lipid droplets and the ER to regulate lipid storage.
Endosomes as Central Hubs of Interorganellar Communication and Cellular Homeostasis.
Lysosomal phosphoinositide turnover acts upstream of RagGTPase-mTORC1 and controls muscle growth.
Proximity Labelling-Based Proteomics Identifies Antiviral Host Factors Associated With the Potexvirus Replicase.
Dietary semen cuscuta improves laying performance by stabilizing mitochondria-associated membranes (MAMs) and inhibiting granulosa cell apoptosis in laying hens.
Non-muscle tropomyosins inhibit Myosin-19 and dynamically localize to mitochondrially-associated actin filaments.
Mitofusin 2 Is Required for the Maturation of Embryonic Stem Cell-Derived Cardiomyocytes via a GRP75-Dependent Suppression of the ROS/PI3K/AKT/mTOR Axis.
Mitochondria acidify lysosomes through membrane contacts.
Magnaporthe oryzae MoPh1 perceives ER stress and promotes adaptive responses via a plasma membrane-to-vacuole pathway.
Ironing out COPD: ferroptosis-driven immune dysregulation, metabolic rewiring, and precision therapeutic opportunities.

Open Biol. 2026 Mar 18. pii: 250220. [Epub ahead of print]16(3):

STIM1 and endoplasmic reticulum-plasma membrane contact sites oscillate independently of calcium-induced calcium release.

Ding Xiong, Cheesan Tong, Suet Yin Sarah Fung, Samantha McClellan, Yang Yang, Jeffery Yong, Min Wu.

  Calcium (Ca²+) release from intracellular stores, Ca²+ entry across the plasma membrane and their coordination via store-operated Ca²+ entry (SOCE) are critical for receptor-activated Ca²+ oscillations. However, the precise mechanism of Ca²+ oscillations and whether their control loop resides at the plasma membrane or intracellularly remains unresolved. By examining the dynamics of stromal interaction molecule 1 (STIM1), an endoplasmic reticulum (ER)-localized Ca²+ sensor that activates the Orai1 channel on the plasma membrane for SOCE, in mast cells, we found that a significant proportion of cells exhibited STIM1 oscillations with the same periodicity as Ca²+ oscillations. These cortical oscillations, shared with ER-plasma membrane (ER-PM) contact site proteins, were only detectable using total internal reflection fluorescence microscopy. Notably, STIM1 oscillations could occur independently of Ca²+ oscillations. Simultaneous imaging of cytoplasmic Ca²+ and ER Ca²+ with CEPIA1er revealed that receptor activation does not deplete ER Ca²+, whereas receptor activation without extracellular Ca²+ influx induces cyclic ER Ca²+ depletion. However, under such non-physiological conditions, cyclic ER Ca²+ oscillations lead to sustained STIM1 recruitment, indicating that oscillatory Ca²+ release is neither necessary nor sufficient for STIM1 oscillations. Using optogenetic tools to manipulate ER-PM contact site dynamics, we found that persistent ER-PM contact sites reduced the amplitude of Ca²+ oscillations without alteration of oscillation frequency. Together, these findings suggest an active cortical mechanism governs the rapid dissociation of ER-PM contact sites, thereby controlling amplitude of oscillatory Ca²+ dynamics during receptor-induced Ca²+ oscillations.

Keywords:  calcium oscillations; dynamical systems; endoplasmic reticulum calcium imaging; optogenetics

DOI:  https://doi.org/10.1098/rsob.250220
iScience. 2026 Mar 20. 29(3): 115068

Lipid overload triggers PERK-ALCAT1-mediated mitophagy failure in hepatocytes.

Wenli Zhao, Yangguang Bao, Lei Liu, Yixin Gu, Xuran Liu, Óscar Monroig, Tingting Zhu, Peng Sun, Douglas R Tocher, Qicun Zhou, Min Jin.

  Mitochondria-associated endoplasmic reticulum membranes (MAMs), contact sites between the endoplasmic reticulum (ER) and mitochondria, are critical for calcium signaling and lipid metabolism. However, how MAMs contribute to mitochondrial dysfunction in lipid overload-induced fatty liver remains unclear. Here, using teleost fish as a model, we showed that high-fat diets promoted the aggregation of PERK and ALCAT1 at MAMs, causing mitochondrial calcium overload and membrane depolarization, and impairing PINK1/Parkin-dependent mitophagy. Acetylation of PERK at lysine 388 facilitated its binding to ALCAT1, while activation of SIRT1 by resveratrol induced site-specific deacetylation of PERK, disrupted PERK-ALCAT1 interaction, and restored mitophagy and mitochondrial integrity. These findings revealed a conserved SIRT1-PERK-ALCAT1 signaling axis linking ER stress to mitophagy failure and identified a potential nutritional intervention to alleviate lipid-induced hepatic injury. This mechanism is conserved across species and offers a basis for controlling metabolic dysfunction-associated steatotic liver disease (MASLD) in teleosts and potentially other vertebrate systems.

Keywords:  Lipid; Metabolic flux analysis; Molecular network

DOI:  https://doi.org/10.1016/j.isci.2026.115068
Redox Biol. 2026 Mar 10. pii: S2213-2317(26)00119-9. [Epub ahead of print]92 104121

Excessive ER-mitochondria coupling: A DRP1-driven mechanism underlying mitochondrial dysfunction and impaired autophagy in stress-induced depression-like behavior in mice.

Jia-Rui Zhang, Jia-Yan Zhang, Qing-Ya Sun, Chang Chen, Jing-Wei Yang, Nan Cheng, Zi-Wen Guo, Ruo-Nan Shuang, Wei Gu, Meng-Ying Zhai, Jin-Ao Duan, Wei-Wei Tao.

   BACKGROUND: Depression is a common psychiatric disorder characterized by heightened stress exposure and disruptions in neuronal signaling. Growing evidence suggests that mitochondrial dysfunction contributes to its pathophysiology. In particular, mitochondrial dynamics regulated by Dnm1l/Drp1 are critical for neuronal homeostasis, and their dysregulation may lead to cellular impairment. Additionally, mitochondrial-endoplasmic reticulum contact sites (MERCs) are crucial for maintaining cellular function and require precise regulation. However, the role of Drp1 in modulating MERC structure and function in the context of depression remains unclear.
METHODS: We quantified protein changes via 4D-FastDIA proteomics. MERC alterations were examined using transmission electron microscopy (TEM) and proximity ligation assay (PLA). Mitochondrial metabolism was assessed with the Seahorse XF Analyzer. Autophagy was visualized through tyramine signal amplification and Imaris-based 3D reconstruction. The causal relationship was tested using Vglut2-Cre mice combined with specific flox-virus mediated Drp1 manipulation and pharmacological inhibition of autophagy. Depression-like behaviors were evaluated after chronic social defeat stress (CSDS).
RESULTS: Drp1 activation disrupts mitochondrial-endoplasmic reticulum contact sites (MERCs), leading to mitochondrial dysfunction and impaired autophagy, and ultimately promoting depressive-like behaviors. Inhibiting the MERC tethering protein GRP75 or enhancing mitophagy pharmacologically alleviated these neuronal and behavioral deficits. These findings identify Drp1-mediated MERC disruption as a key mechanism in depression and suggest therapeutic strategies targeting MERC integrity and autophagy.
CONCLUSION: Our results provide novel mechanistic evidence that Drp1-mediated dysfunction at MERCs and impaired mitochondrial quality control contribute to the pathogenesis of depression. These findings underscore the importance of endoplasmic reticulum-mitochondrial crosstalk in depression and suggest potential therapeutic targets for modulating cellular resilience in stress-related disorders.

Keywords:  Depression; Mitochondrial-endoplasmic reticulum contact sites (MERCs); Mitochondrion; Mitophagy; drp1

DOI:  https://doi.org/10.1016/j.redox.2026.104121
Cell Commun Signal. 2026 Mar 17.

Melatonin promotes skeletal muscle mitochondria-associated endoplasmic reticulum membrane contacts and restores organellar membrane integrity and phospholipid composition in Zücker diabetic fatty rats of both sexes.

Diego Salagre, Marina Villalón-Mir, Jennifer Rieusset, Ahmad Agil.



Keywords:  Cardiolipin; Endoplasmic reticulum; Melatonin; Mitochondria; Mitochondria-associated membrane; Obesity; Phosphatidylcholine; Phosphatidylethanolamine; Skeletal muscle; Type 2 diabetes

DOI:  https://doi.org/10.1186/s12964-026-02799-y
Environ Pollut. 2026 Mar 13. pii: S0269-7491(26)00329-5. [Epub ahead of print] 127959

Atrazine increases hepatic inflammation and injury via endoplasmic reticulum (ER) stress mediated excessive formation of mitochondria-associated membranes (MAMs) and activation of the cGAS-STING pathway.

Zi-Jun Sun, Guan-Yue Shan, Hui Wan, Yu-Xin Zhang, Zhi-Cheng Gao, Wen-Na Shi, Lei Lv, Wei-Qun Yan, Hai-Jun Li.

  Despite its widespread application as a triazine herbicide, atrazine (ATR) poses significant health threats, with the mechanisms underlying its induction of hepatic inflammation still not fully elucidated. Our research delineates a mechanistic cascade in which ATR exposure is associated with endoplasmic reticulum (ER) stress induction, which in turn stimulates the excessive generation of mitochondria-associated membranes (MAMs). This event is associated with mitochondrial calcium inundation, augmented generation of mitochondrial reactive oxygen species (mtROS), and the cytosolic translocation of mitochondrial DNA (mtDNA). Subsequently, cytosolic mtDNA may operates as a damage-associated molecular pattern (DAMP), which engages the cGAS-STING pathway and nucleates NLRP3 inflammasome assembly, ultimately provoking a severe hepatic inflammatory response. These findings were consistently validated through both in vitro experiments and mouse models. Furthermore, inhibition of ER stress with 4-PBA significantly reduced MAMs over-assembly and alleviated mitochondrial dysfunction. Scavenging mitochondrial ROS with MitoQ also effectively attenuated downstream inflammatory activation. Overall, this study identifies a novel mechanistic pathway of ATR-induced hepatotoxicity: ER stress-MAMs-mitochondrial damage-mtDNA release-cGAS-STING-NLRP3 inflammation, providing new insights into the toxicology of environmental chemicals and suggesting potential therapeutic strategies for pollutant-induced liver injury.

Keywords:  Atrazine; cGAS; endoplasmic reticulum (ER) stress; liver injury; mitochondria-associated endoplasmic reticulum membranes (MAMs)

DOI:  https://doi.org/10.1016/j.envpol.2026.127959
Nat Commun. 2026 Mar 19.

Parkinson's disease-associated PLA2G6 protects IP3R1 protein to control ER-mitochondria tethering and Ca2+ transfer.

Zhi-Hao Lin, Nai-Jia Xue, Yi Liu, Feng Zhang, Xiao-Li Si, Ran Zheng, Lu-Yan Gu, Yao-Lin Li, Yi Fan, Jun Tian, Wolfgang H Oertel, Hyemyung Seo, Jia-Li Pu, Bao-Rong Zhang.

Mutations in the phospholipase A2 group VI (PLA2G6) gene have been linked to autosomal recessive Parkinson's disease (PD), yet the molecular mechanisms remain poorly understood. This study provides the in vitro and in vivo evidence, specifically in dopaminergic neurons derived from patients with PD, that PLA2G6 loss-of-function disrupts the mitochondria-associated endoplasmic reticulum (ER) membrane (MAM), a critical regulator of Ca2+ transfer and energy homeostasis. This study demonstrates that the PLA2G6 protein localizes to the MAM and physically associates with the IP3R1-GRP75-VDAC1 complex. PLA2G6 deficiency destabilizes this complex, accelerating IP3R1 degradation, which in turn reduces ER-mitochondria contacts and impairs Ca2+ transfer. Notably, introducing a MAM linker restores the phenotypes caused by PLA2G6 loss. In iPSCs-derived dopaminergic neurons from patients with PD harboring PLA2G6 mutations, the structural and functional disruption of the MAM is further confirmed, underscoring its role in PD pathogenesis. These findings uncover the pivotal function of PLA2G6 within the MAM and suggest that modulating inter-organelle contacts could be a therapeutic strategy for correcting PD's ion channel dysfunction and energy imbalances.

DOI: https://doi.org/10.1038/s41467-026-70752-1
Autophagy. 2026 Mar 18. 1-2

ATG2A connects lipid droplets and the ER to regulate lipid storage.

Helin Elhan, Justin L Korfhage, Thomas J Melia, Abdou Rachid Thiam.

  The endoplasmic reticulum (ER) must carefully regulate the levels of nonmembrane lipids such as diacylglycerol (DAG), phosphatidic acid (PA), and triacylglycerol (TAG) to maintain membrane integrity and prevent lipotoxic stress. While ATG2A is well known as a lipid transfer protein essential for autophagosome formation, its role at lipid droplet (LD) contact sites has remained unclear. In our recent work, we show that ATG2A functions beyond its typical role in autophagy as a key regulator of lipid storage, transferring DAG, TAG, and PA from the ER to LDs and recruiting the TAG synthesis enzyme DGAT2 to promote LD expansion. Without ATG2A, lipids accumulate in the ER, leading to smaller, more numerous nucleated LDs rather than proper growth. Notably, ATG2A-mediated DAG transfer recruits DGAT2 to LD surfaces, enabling local TAG synthesis that prevents nonmembrane lipid accumulation in the ER. This cooperative process reveals ATG2A's dual role in both autophagy and lipid storage, highlighting an unexpected link between autophagy machinery and lipid storage.

Keywords:  ATG2A; DGAT2; ER quality control; diacylglycerol; lipid droplets; lipid transfer

DOI:  https://doi.org/10.1080/15548627.2026.2645161
Protein Cell. 2026 Mar 18. pii: pwag018. [Epub ahead of print]

Endosomes as Central Hubs of Interorganellar Communication and Cellular Homeostasis.

Yao Feng, Bo Zhou, Zihan Lu, Muyin Guo, Shaohui Zhang, Songlin Wang, Mo Chen.

  Endocytosis mediates the internalization of extracellular cargo via vesicular trafficking, enabling targeted delivery to specific organelles and maintaining cellular homeostasis. Endosomes function as dynamic hubs that orchestrate intracellular communication. While they primarily internalize material from the cell surface, their role extends far beyond passive transport. Through continuous cycles of sorting, fusion, and fission, endosomes engage in extensive crosstalk with other organelles via three fundamental modes: vesicle-mediated cargo transport, membrane contact site-mediated non-vesicular exchange, and signaling and mechanical coupling. These interorganellar interactions enable the transfer of metabolites, lipids, and signals, positioning endosomes as central regulators of cellular homeostasis. While interest in these contacts is growing, a systematic understanding of their roles is still needed. This review explores the protein machinery involved, examines how endosome-organelle contacts coordinate transport and remodeling, and discusses their impact on homeostasis and disease when dysregulated. We underscore the importance of the endosomal communication network in adaptive responses and provide perspectives for targeting endosome-related pathologies.

Keywords:  Cellular homeostasis; Endocytosis; Endosome; Interorganellar communication; Membrane contact sites

DOI:  https://doi.org/10.1093/procel/pwag018
Nat Metab. 2026 Mar 18.

Lysosomal phosphoinositide turnover acts upstream of RagGTPase-mTORC1 and controls muscle growth.

Melanie Picot, Nesrine Hifdi, Mathilde Vaucourt, Melanie Mansat, Peng Li, Isabel Singer, Gaëtan Chicanne, Alexandre Stella, Shen Kuang, Caterina Miceli, Nathaniel F Henneman, Bernard Payrastre, Marie Vandromme, Odile Schiltz, Ivan Nemazanyy, Mariana E G de Araujo, Ganna Panasyuk, Julien Viaud, Michael Lämmerhofer, Karim Hnia.

Lysosomes act as metabolic signalling hubs that integrate nutrient availability to coordinate anabolic and catabolic programmes. Mechanistic target of rapamycin complex 1 (mTORC1) is activated at the lysosomal surface by amino acids through RagGTPases recruited by the lysosomal adaptor and MAPK and mTOR activator complex, yet the contribution of lysosomal lipid composition to this pathway remains unclear. Here we identify lysosomal phosphoinositides, PI3P and PI(3,5)P2, as key regulators of lysosomal adaptor and MAPK and mTOR activator complex stability and dynamics at the lysosome. These lipid pools are controlled by the phosphoinositide 3-phosphatase MTM1, mutated in myotubular myopathy, via endoplasmic reticulum-lysosome membrane contact sites. Under endoplasmic reticulum stress, MTM1-dependent phosphoinositide remodelling suppresses RagGTPase-mTORC1 signalling, thereby regulating anabolic-catabolic balance during myogenic differentiation. Restoring mTORC1 activity or lysosomal phosphoinositide homeostasis rescues Rag-dependent signalling and muscle growth in cellular and mouse models of myopathy, uncovering a lysosome-centred metabolic checkpoint with direct disease relevance.

DOI: https://doi.org/10.1038/s42255-026-01484-1
Mol Plant Pathol. 2026 Mar;27(3): e70239

Proximity Labelling-Based Proteomics Identifies Antiviral Host Factors Associated With the Potexvirus Replicase.

Yi-Chen Chang, Sae Takatsuka, Aki Eguchi, Nobumitsu Sasaki, Yoshiyuki Itoh, Miki Hisada, Tsutomu Arie, Ken Komatsu.

  Plant positive-strand RNA viruses establish viral replication complexes (VRCs) by remodelling intracellular membranes, primarily the endoplasmic reticulum (ER) and recruiting host proteins to these structures. To identify ER-associated host proteins involved in potexvirus replication, we developed a multi-control proximity labelling approach using TurboID-fused constructs that localise to the cytosol, the ER lumen and the ER membrane. This strategy enabled specific identification of host factors that are proximal to the methyltransferase (MET) domain of Plantago asiatica mosaic virus (PlAMV) replicase, distinguishing them from general ER-associated proteins. Our proximity labelling identified 33 host factors associated with the PlAMV MET domain, 28 of which showed exclusive enrichment compared to all three controls. Subcellular localization prediction revealed that MET-proximal proteins predominantly associate with chloroplasts, the cytosol and mitochondria rather than the ER. This suggests that the MET domain localises to specialised ER membrane subdomains interfacing with multiple organelles. Functional analysis of three selected candidates, calcyclin-binding protein (NbCBP), remorin1.5 (NbREM1.5) and calcium-sensing receptor (NbCAS), revealed their antiviral roles. Virus-induced gene silencing of these factors significantly enhanced PlAMV accumulation. Co-immunoprecipitation demonstrated physical interactions between the three host factors and the MET domain, while confocal microscopy revealed their relocalization to specific subcellular sites during co-expression with MET. These results demonstrate that potexvirus VRCs interact with diverse host factors from multiple organelles, providing new insights into plant-virus interaction networks.

Keywords:  Plantago asiatica mosaic virus; endoplasmic reticulum; membrane contact sites; proximity labelling; viral replication complex

DOI:  https://doi.org/10.1111/mpp.70239
Poult Sci. 2026 Mar 10. pii: S0032-5791(26)00376-7. [Epub ahead of print]105(6): 106749

Dietary semen cuscuta improves laying performance by stabilizing mitochondria-associated membranes (MAMs) and inhibiting granulosa cell apoptosis in laying hens.

Changqing Si, Ying Chen, Linjie Liu, Shuo Liu, Zhenbiao Zhang, Lihuan Guo, Mengpo Zhao, Yuming Chen, Yuxiang Shi, Wanyu Shi, Shuang Ma.

  The decline in laying performance during late-phase production of hens, primarily due to ovarian aging, poses significant economic challenges to the poultry industry. We have previously identified that Semen Cuscuta (SC), a traditional Chinese herbal medicine, could alleviate reproductive damage in mice, however, the therapeutic potential of SC in aging hens remains largely unexplored. In this study, different doses of SC (1%, 1.5%, or 2%) were dietary supplemented for 4 weeks, and serum, Ileum, ovarian tissues were collected for further detection/examination. Results showed that 1.5% and 2% SC significantly improved laying performance, enhanced systemic antioxidant capacity (increased serum SOD, decreased MDA), and elevated FSH levels. SC also reinforced intestinal barrier integrity, as indicated by improved villus morphology, upregulation of tight junction proteins (Occludin, ZO-1), and reduced serum endotoxin markers (D-LA, LPS). Moreover, SC modulated gut microbiota composition, increased cecal short-chain fatty acids (acetic and butyric acid), and upregulated intestinal specifically short-chain fatty acids (SCFA) receptors (GPR41, GPR43). In the ovary, SC suppressed granulosa cell apoptosis by modulating Bcl-2, Bax, Cleaved Caspase-3, and Cyt c expression. Notably, transmission electron microscopy revealed that SC preserved mitochondrial associated membrane (MAM) structural integrity and normalized the expression of MAM tethering proteins (IP3R, GRP75, VDAC1) in ovary. These findings demonstrate that SC ameliorates ovarian aging and restores laying performance through a dual mechanism: directly stabilizing ovarian MAMs to inhibit apoptosis, and indirectly remodeling gut microbiota to enhance intestinal barrier function and reduce systemic inflammation. This study provides a mechanistic basis for SC as a promising feed additive to improve sustainability in the production of aging hens.

Keywords:  Antioxidant capacity; Gut microbiota; MAMs; Ovarian aging; Semen Cuscuta (SC)

DOI:  https://doi.org/10.1016/j.psj.2026.106749
J Biol Chem. 2026 Mar 17. pii: S0021-9258(26)00247-4. [Epub ahead of print] 111377

Non-muscle tropomyosins inhibit Myosin-19 and dynamically localize to mitochondrially-associated actin filaments.

Cameron P Thompson, Luther W Pollard, Mengqi Xu, Erika L F Holzbaur, E Michael Ostap.

Myosin-19 (Myo19) is a mitochondrially localized actin-based motor important for regulating mitochondrial homeostasis, including the stabilization of mitochondrial-endoplasmic reticulum (mitoER) contact sites. Thus, proper regulation of Myo19 is likely required to maintain mitochondrial health and function, but little is known about regulatory mechanisms. Non-muscle tropomyosins are known to differentially regulate members of the myosin superfamily, leading us to hypothesize that tropomyosins may regulate Myo19-actin filament interactions. Here, we show that the interaction of Myo19 with actin filaments is inhibited by the association of Tropomyosin 3.1 (Tpm3.1) and 1.7 (Tpm1.7) with F-actin. This inhibition is highly cooperative, as both Tpm isoforms induce an all-or-none stalling of Myo19-driven filaments in in vitro gliding assays. In HeLa cells, Tpm3.1 is associated with actin filaments in close proximity to mitochondria. This localization is dynamic, as Tpm3.1 interacts with the mitochondrially-associated actin wave in interphase cells. These findings point toward a tropomyosin-based regulatory mechanism that spatially regulates Myo19 activity in a dynamic manner.

DOI: https://doi.org/10.1016/j.jbc.2026.111377
Antioxid Redox Signal. 2026 Mar 18. 15230864261426010

Mitofusin 2 Is Required for the Maturation of Embryonic Stem Cell-Derived Cardiomyocytes via a GRP75-Dependent Suppression of the ROS/PI3K/AKT/mTOR Axis.

Zhenping Li, Ka Chun Cheung, Yanxiang Qi, Hin Shing Lam, Xiaoqian Wu, Ellen Ngar-Yun Poon, Suk Ying Tsang.

   AIMS: Pluripotent stem cell-derived cardiomyocytes (PSC-CMs) have the potential for use in cell-based therapy, disease modeling, and drug toxicity testing. However, under the conventional differentiation protocol, PSC-CMs are immature and differ from adult cardiomyocytes in electrophysiological characteristics, calcium kinetics, cellular morphology, metabolism, and gene expression. MFN2 tethers sarcoplasmic reticulum (SR) and mitochondria and mediates their interaction via mitochondria-associated endoplasmic reticulum membranes, which tunes the cytosolic Ca2+ and reactive oxygen species (ROS) signaling. We aim to investigate if MFN2 would regulate murine embryonic stem cell-derived cardiomyocyte (mESC-CM) maturation, and if yes, what are the underlying mechanisms.
RESULTS: MFN2 knockdown caused detrimental effects on mESC-CM maturation in terms of structure, cytosolic calcium kinetics, electrophysiology, and metabolism. Mechanistically, MFN2 knockdown increased proliferative capacity, increased ROS and activated PI3K/AKT/mTOR activity, and these were all reversed by the ROS scavenger N-acetylcysteine. Meanwhile, MFN2 knockdown decreased the IP3R-VDAC coupling mediated by GRP75. Importantly, GRP75 overexpression restored the decreased IP3R-VDAC coupling, reversed the increased cellular ROS, and reversed the increased PI3K/AKT/mTOR activity caused by MFN2 knockdown. Rapamycin, an mTOR inhibitor, reduced the increased proliferative capacity and restored the impaired electrophysiology caused by MFN2 knockdown.
INNOVATION: The current study is the first study to reveal that MFN2-mediated SR-mitochondrial interaction is required for the mESC-CM maturation through the ROS/PI3K/AKT/mTOR axis.
CONCLUSION: MFN2 is required for the maturation of mESC-CMs through GRP75-dependent, mTOR-mediated suppression of proliferative capacity via the ROS/PI3K/AKT pathway. Our findings advance the understanding of PSC-CM maturation and provide novel insight for strategies to promote PSC-CM maturation. Antioxid. Redox Signal. 00, 000-000.

Keywords:  cardiomyocyte maturation; mitochondria; mitofusin 2; pluripotent stem cell-derived cardiomyocytes; sarcoplasmic reticulum

DOI:  https://doi.org/10.1177/15230864261426010
Cell Rep. 2026 Mar 15. pii: S2211-1247(26)00190-7. [Epub ahead of print]45(3): 117112

Mitochondria acidify lysosomes through membrane contacts.

Zhiqi Tian, Rui Chen, Guiqian Fang, Kangqiang Qiu, Weijun Wu, Xintian Shao, Daili Liu, Huilin Que, Xueqian Wang, Ji Gao, Jianyu Zhang, Bidyut Kundu, Qixin Chen, Jun-Lin Guan, Yueguang Rong, Ben Zhong Tang, Kai Li, Yujie Sun, Jiajie Diao.

  The acidic environment within the lysosome lumen is essential for its digestive function. However, the source of protons responsible for acidification has remained elusive. Here, using a molecular probe to monitor lysosomal digestion, we discovered enhanced lysosome content degradation at mitochondria-lysosome contact (MLC) sites, which was caused by lysosomal acidification. Using a mitochondrial probe, we observed a proton flux from mitochondria to lysosomes at these MLC sites. Furthermore, we found that physically bringing mitochondria and lysosomes into close proximity can increase lysosome acidification to enhance content digestion under disease conditions. These findings unveil a crucial physiological role of MLCs in cellular functions.

Keywords:  CP: cell biology; lysosome acidification; mitochondria-lysosome contact; proton flux

DOI:  https://doi.org/10.1016/j.celrep.2026.117112
Nat Commun. 2026 Mar 16.

Magnaporthe oryzae MoPh1 perceives ER stress and promotes adaptive responses via a plasma membrane-to-vacuole pathway.

Ziyi Yin, Jiayun Xu, Shijie Ma, Jiazong Liu, Tianfeng Zhao, Yuanchen Li, Yi Wang, Chunyan Liu, Ziming Wang, Yanke Jiang, Haimiao Zhang, Chongchong Lu, Yingying Qin, Ziying Kong, Shi-En Lu, Congming Lu, Yang Li, Xinhua Ding.

During growth and development, cells experience both internal and external stresses, which can exert harmful impacts if they are poorly managed. Endoplasmic reticulum (ER) stress is an internal stress that is induced when protein misfolding or perturbations occur at excess rates, and the conventional response pathways from the ER to the nucleus are activated to address the stress. However, the involvement of the plasma membrane (PM) system in response to this internal stress has been insufficiently investigated. Here, a PM sensor, MoPh1, was observed to perceive stress through ER-PM contact sites and target the autophagosome and vacuole, consequently stimulating the autophagy process and supporting stress relief. The PM-to-vacuole pathway mediated by MoPh1 is independent of the classical ER-to-nucleus pathway and might be highly important in both fungi and plants, as it plays a crucial role in alleviating ER stress and promoting cellular adaptation for cell survival.

DOI: https://doi.org/10.1038/s41467-026-70610-0
Front Immunol. 2026 ;17 1630969

Ironing out COPD: ferroptosis-driven immune dysregulation, metabolic rewiring, and precision therapeutic opportunities.

Feng-Xian Ni, Hui-Hui Chen, Ze-Bo Jiang, Dong-Hui Huang.

  Chronic obstructive pulmonary disease (COPD) is a global health crisis driven by oxidative stress and immune dysregulation. Emerging evidence positions ferroptosis-an iron-dependent cell death driven by iron-catalyzed peroxidation of esterified polyunsaturated fatty acids (PUFAs) in membrane phospholipids-as a pivotal mediator of COPD pathogenesis. This review synthesizes cutting-edge insights into how cigarette smoke (CS) induces mitochondrial fission (via dynamin-related protein 1 (DRP1) phosphorylation) to exacerbate ferroptosis, potentially by enhancing lipid droplet (LD)-mitochondria contact sites and promoting lipid peroxidation in airway epithelial cells. This review further elucidates the complex and context-dependent role of nuclear factor erythroid 2-related factor 2 (Nrf2). While Nrf2 signaling is often suppressed globally in COPD lungs, its dysfunction in macrophages may paradoxically promote ferritinophagy-mediated iron retention through nuclear receptor coactivator 4 (NCOA4), overwhelming ferroprotein (FPN)-mediated iron export and unintentionally fueling ferroptosis. Clinically, plasma malondialdehyde (MDA)-a byproduct of lipid peroxidation-serving as a biomarker of oxidative stress severity, with elevated levels correlating with accelerated lung function decline in COPD patients. Therapeutically, promising targeted strategies are highlighted, such as inhaled exosomes loaded with liproxstatin-1, which can selectively inhibit pulmonary ferroptosis without inducing system immunosuppression. By bridging molecular mechanisms to therapeutic innovation, this review outlines a roadmap for precision medicine in COPD, focusing on the ferroptosis-immune axis to disrupt the self-perpetuating cycle of inflammation and tissue damage.

Keywords:  COPD; ferroptosis; immune-metabolic crosstalk; lipid peroxidation; mitochondrial dynamics; precision inhalation therapy

DOI:  https://doi.org/10.3389/fimmu.2026.1630969