bims-mecosi 2026-10-18 papers

bims-mecosi

Biomed News

on Membrane contact sites

Issue of 2026–10–18
eleven papers selected by
Verena Kohler, Umeå University

TM6SF2 acts at ER membrane contact sites to enable RAB7-dependent endolysosomal VLDL secretion and maintain Golgi structure.
Mitochondria-Endoplasmic Reticulum Crosstalk in Pancreatic β-Cell Stress: A Driver of Diabetes.
Organelle localization and trafficking of ether lipids: Current evidence and open questions.
Membrane contact activation of Piezo2 drives lysosome-mitochondrion Ca2+ transfer and signaling in Trypanosoma cruzi.
Organelle Crosstalk: Mitochondria and Endoplasmic Reticulum in Macular Degeneration.
Mechanisms of lipid droplet-mitochondria interactions and their roles in diseases.
Mitofusin 2 orchestrates mitochondrial metabolic homeostasis and suppresses cutaneous squamous cell carcinoma by stabilizing ER-mitochondria contacts.
Sequential stage-specific administration of Bushen-Tiaojing decoctions II and III ameliorates mitochondrial dysfunction in ovarian granulosa cells of COH mice by regulating GRP75-mediated MAM homeostasis.
Lipid Transporter TMEM24/C2CD2L Plays Essential Roles in Retinal Photoreceptor Survival by Regulating Calcium Signaling and Synaptic Transmission.
A Review of Nuclear-Organellar Communication in Response to Heat Stress.
A Novel NO Donor 3A72 Activates Mitochondrial-Associated Endoplasmic Reticulum Membrane Structures to Induce Ferroptosis in Triple-Negative Breast Cancer.

Cell Rep. 2026 Oct 15. pii: S2211-1247(26)01195-2. [Epub ahead of print]45(10): 118116

TM6SF2 acts at ER membrane contact sites to enable RAB7-dependent endolysosomal VLDL secretion and maintain Golgi structure.

Emad Heidary Arash, Marko Groeger, James P Grenert, Torsten Wittmann, Robert L Raffai, Jacquelyn J Maher, Holger Willenbring.

  Although a loss-of-function variant of TM6SF2 is a highly penetrant risk factor for steatotic liver disease, including progression to cirrhosis and cancer, its normal function is largely unknown. Here we show that endoplasmic reticulum (ER)-localized TM6SF2 forms membrane contact sites (MCSs) with late endosomes/lysosomes, where it activates the small GTPase RAB7 to enable an endolysosomal route for selective secretion of lipid-rich very low-density lipoprotein (VLDL) particles. In accord, TM6SF2 and RAB7 deficiency similarly cause endolysosomal VLDL retention and accumulation of enlarged late endosomes/lysosomes. TM6SF2 further binds to VAMP-associated protein (VAP) ER-anchor proteins to maintain MCSs between the ER, endosomes, and the trans-Golgi network, with TM6SF2 deficiency causing Golgi fragmentation and disruption of cGAS-STING signaling known to prevent cirrhosis and cancer by clearing senescent hepatocytes. Our findings establish TM6SF2 as an ER-MCS component that enables endolysosomal VLDL secretion and maintains Golgi structure, which suggests that TM6SF2 loss of function causes liver disease through steatosis-dependent and independent mechanisms.

Keywords:  CP: cell biology; Golgi; RAB7; TM6SF2; VAP; cGAS-STING; endoplasmic reticulum; late endosomes/lysosomes; membrane contact sites; steatotic liver disease

DOI:  https://doi.org/10.1016/j.celrep.2026.118116
Cells. 2026 Sep 23. pii: 1733. [Epub ahead of print]15(19):

Mitochondria-Endoplasmic Reticulum Crosstalk in Pancreatic β-Cell Stress: A Driver of Diabetes.

Sara Anjum Niinuma, Ashleigh Suzu-Nishio Takemoto, William Junior Khalil, Alexandra E Butler, Abu Saleh Md Moin.

  Pancreatic β-cell failure is central to the pathogenesis of type 2 diabetes (T2D), developing when chronic metabolic stress overwhelms the adaptive capacity of these cells. Because insulin biosynthesis and glucose-stimulated secretion depend on tightly coordinated organelle function, crosstalk between the endoplasmic reticulum (ER) and mitochondria strongly influences β-cell fate. The two organelles are physically coupled at mitochondria-associated membranes (MAMs), contact sites that synchronize ER Ca2+ release with mitochondrial Ca2+ uptake and adenosine triphosphate (ATP) production, and that help regulate redox balance, autophagy, mitophagy and the unfolded protein response. This review draws together evidence on three questions. First, which stresses converge on the β-cell: ER stress, oxidative stress and dysregulated autophagy and mitophagy. Second, how ER-mitochondria crosstalk sustains β-cell health through Ca2+ handling and the proteins that maintain MAM integrity, including inositol 1,4,5-trisphosphate (IP3) receptors, voltage-dependent anion channel 1 (VDAC1), mitofusin 2 (Mfn2) and the ER stress sensors IRE1α and PERK. Third, how glucolipotoxic and inflammatory stress remodels these contacts and pushes communication towards a maladaptive state marked by mitochondrial Ca2+ overload, ROS accumulation, defective organelle quality control, cellular senescence and apoptosis. We contrast rodent and human data, where MAM composition and glucotoxic responses diverge, and consider therapeutic strategies, such as incretin-based agents and the mitochondrial-derived peptide MOTS-c, that target this interface to preserve β-cell function in diabetes.

Keywords:  MAMs; mitochondrial-associated membranes; β-cell dysfunction; β-cell stress

DOI:  https://doi.org/10.3390/cells15191733
Biochimie. 2026 Oct 12. pii: S0300-9084(26)00241-5. [Epub ahead of print]

Organelle localization and trafficking of ether lipids: Current evidence and open questions.

Denise Kummer, Katrin Watschinger.

  Ether glycerophospholipids are abundant and functionally versatile membrane lipids whose defining sn-1 ether (plasmanyl), or vinyl ether (plasmenyl, plasmalogen) linkage, and polyunsaturated sn-2 chains provide membranes with unique biophysical and signaling properties. Biogenesis is partitioned between two organelles: peroxisomes establish the sn-1 ether linkage and deliver 1-O-alkyl intermediates to the endoplasmic reticulum, where headgroup addition and remodeling occur. Introduction of the vinyl ether double bond by plasmanylethanolamine desaturase then yields plasmalogens. Emerging evidence indicates that ether lipids are unevenly distributed across cellular membranes, reflecting both local metabolic control and selective trafficking. Biosynthetic intermediates are delivered from peroxisomes to the endoplasmic reticulum via ACBD4/5-VAPA/B membrane contact sites, which also couple ether lipid-flux to cholesterol homeostasis. At the plasma membrane, ATP8B2 flippase enforces inner leaflet enrichment of plasmalogens, linking their molecular shape to membrane curvature, raft organization, and signaling. Beyond these core sites, additional pools of ether lipids are detected in the Golgi, mitochondria, endolysosomal system, lipid droplets, and the nucleus, where they are proposed to support membrane organization, and trafficking, yet their organelle-specific functions and transport mechanisms remain poorly defined. In this review we summarize the current knowledge about cellular and subcellular distribution of ether lipids, their biosynthesis, remodeling, degradation, and intracellular trafficking. We also highlight recent methodological advances enabling organelle-resolved lipidomics and live-cell tracking of ether lipids and outline open questions regarding contact-site identity and regulation, transport specificity between plasmanyl and plasmenyl species, and pathophysiological mislocalization mechanisms.

Keywords:  Endoplasmic reticulum; Lipid transfer proteins; Membrane contact sites; Peroxisome; Plasmalogens

DOI:  https://doi.org/10.1016/j.biochi.2026.10.004
Proc Natl Acad Sci U S A. 2026 Oct 20. 123(42): e2627551123

Membrane contact activation of Piezo2 drives lysosome-mitochondrion Ca2+ transfer and signaling in Trypanosoma cruzi.

Guozhong Huang, Roberto Docampo.

  Calcium ion (Ca2+) transfer from other organelles is central to mitochondrial metabolism and cell survival, yet how mechanical forces regulate interorganelle communication remains unclear. Here we report a lysosome-to-mitochondrion pathway in Trypanosoma cruzi, the etiologic agent of Chagas disease, mediated by the mechano/osmosensitive channel TcPiezo2. Using ultrastructural, biochemical, and live-cell superresolution imaging, we define lysosome-mitochondrion contact sites (LMCs) that enable direct Ca2+ transfer. TcPiezo2 triggers Ca2+ release, which generates perilysosomal nanodomains that drives mitochondrial Ca2+ uptake via the voltage-dependent anion channel and the mitochondrial Ca2+ uniporter complex. Disruption of TcPiezo2-dependent Ca2+ transfer impairs mitochondrial metabolism, perturbs redox homeostasis, induces autophagy, and eventually leads to parasite death. These findings establish LMCs as a signaling platform that directly regulates interorganelle Ca2+ transfer and mitochondrial bioenergetics.

Keywords:  Piezo channel; calcium; lysosomes; membrane contact sites; mitochondria

DOI:  https://doi.org/10.1073/pnas.2627551123
J Ophthalmol Res. 2026 Sep;9(3): 60-67

Organelle Crosstalk: Mitochondria and Endoplasmic Reticulum in Macular Degeneration.

Iffat Alam, Ayeshah Hussain, Devendra K Agrawal.

  Age-related macular degeneration (AMD) is a leading cause of irreversible vision loss characterized by progressive retinal pigment epithelium (RPE) dysfunction, mitochondrial damage, oxidative stress, and chronic inflammation. While mitochondrial dysfunction is a known contributor to AMD, the contribution of the endoplasmic reticulum (ER) has not been fully explored. Mitochondrial associated membranes (MAMs) are regions of the mitochondria which are in direct contact with the ER and are critical areas for regulating essential cellular functions including calcium signaling, mitochondrial dynamics, and apoptosis. Dysfunction of these critical sites may lead to progressive retinal degeneration through the production of reactive oxygen species (ROS), calcium overload, and inflammasome activation in RPE cells. The study was conducted as a comprehensive critical review article on the subject. Findings are reported on the connection between the mitochondria and ER, specifically through MAM dysfunction, in macular degeneration. Overall, this critical review article discusses the pathophysiology of macular degeneration with the mechanistic insights into MAM deregulation and decoding the structural and functional breakdown of MAMs. Understanding the role of MAM-mediated signaling in AMD may identify potential therapeutic targets aimed at restoring mitochondrial resilience and retinal homeostasis.

Keywords:  Age-Related Macular Degeneration (AMD); Endoplasmic Reticulum; Epithelium; Macular Degeneration; Mitochondria; Mitochondrial Associated Membranes (MAMs); Mitochondrial Dysfunction; Organelle Crosstalk; Oxidative Stress; Retinal Pigment Epithelium (RPE)

DOI:  https://doi.org/10.26502/fjor.2644-002400117
Pharmacol Res. 2026 Oct 14. pii: S1043-6618(26)01592-6. [Epub ahead of print]233 109677

Mechanisms of lipid droplet-mitochondria interactions and their roles in diseases.

Yang Ding, Xiao-Hong Xie, Yang-Kun Li, Zhen-Hua Xiao, Zong-Bao Wang, Lin-Xi Chen, Shu-Zhi Wang.

  Lipid droplets (LDs) coordinate cellular lipid utilization, energy homeostasis, redox balance, and autophagy through dynamic inter-organelle communication with mitochondria. This review summarized recent advances in the molecular mechanisms regulating LD-mitochondria interactions and discusses how their dysregulation contributes to disease progression. Accumulating evidence has indicated that the contacts between LD and mitochondria are dynamically regulated through specialized membrane contact sites and protein complexes, such as Perilipin (PLIN) family of proteins, Mitofusin2 (Mfn2), and Rab GTPases. Rather than being a passive structural association, this interaction serves as a regulatory hub that integrates fatty acid (FA) transport, metabolic adaptation, and stress responses. It enables bidirectional regulation of lipid metabolism, allowing cells to flexibly and efficiently switch between lipid storage and FA oxidation in response to metabolic signals. Disruption of this inter-organelle communication impairs intracellular lipid utilization, compromises mitochondrial function, and exacerbates oxidative stress and ferroptosis. Such dysfunction is increasingly recognized as a core mechanism underlying metabolic disorders, cardiovascular diseases and neurodegenerative diseases. In the future, integration of protein regulation, gene editing technologies, and precision therapeutic approaches may enable specific targeting of LD-mitochondria communication, thereby offering new avenues for the treatment of relevant diseases.

Keywords:  Cardiovascular diseases; Lipid droplet; Metabolic diseases; Mitochondria; Neurodegenerative diseases

DOI:  https://doi.org/10.1016/j.phrs.2026.109677
J Bioenerg Biomembr. 2026 Oct 15. pii: 58. [Epub ahead of print]58(1):

Mitofusin 2 orchestrates mitochondrial metabolic homeostasis and suppresses cutaneous squamous cell carcinoma by stabilizing ER-mitochondria contacts.

Xianpeng Ma, Jing Liu, Xiao Shao, Yupeng Huang, Guangyao Hu.

  This study aimed to elucidate the biological role of Mitofusin 2 (Mfn2) in cutaneous squamous cell carcinoma (cSCC) and evaluate how its regulation of mitochondria-associated membranes (MAMs) may suppress tumor progression by reshaping mitochondrial metabolic homeostasis and apoptosis. We compared Mfn2 expression between normal keratinocytes (HaCaT) and cSCC cells (A431), establishing a stable Mfn2-overexpressing (Mfn2-OE) A431 model. Structural impacts on ER-mitochondrial contacts and MAMs were evaluated using immunofluorescence, STED super-resolution microscopy, TEM, and subcellular fractionation (VDAC1/IP3R/Grp75). Functional assays assessed ER-mitochondrial calcium transport (probes), lipid peroxidation/ROS (C11-BODIPY/DCFH-DA), mitochondrial membrane potential, and ATP levels (JC-1/ATP assays). Mitochondria-dependent apoptosis (Bcl-2/p53/Cytochrome c/Caspase-3) was analyzed via flow cytometry, TUNEL, and Western blot. Phenotypes were assessed using CCK-8, EdU, colony formation, and Transwell assays. In vivo xenografts in nude mice were monitored, with H&E/IHC analysis. Proteomics and untargeted metabolomics (LC-MS) were performed (n = 6/group). Mfn2 protein levels were lower in A431 cSCC cells than in HaCaT keratinocytes. Mfn2-OE enhanced ER-mitochondrial contacts, increased MAMs, and stabilized the VDAC1-Grp75-IP3R complex. This enhanced calcium transport, reduced ROS/lipid peroxidation, stabilized MMP, and decreased ATP. Mfn2-OE inhibited Bcl-2, promoted p53 mitochondrial translocation and Cytochrome c release, activating Caspase cascades. Both in vitro and in vivo, Mfn2-OE suppressed proliferation, invasion, and tumor growth. Proteomics/metabolomics revealed metabolic reprogramming involving energy metabolism, lipid metabolism, and redox balance. Mfn2 may act as a tumor-suppressive regulator in the A431 cSCC model by stabilizing MAMs, remodeling mitochondrial metabolic homeostasis, and activating mitochondria-dependent apoptosis.

Keywords:  Cutaneous squamous cell carcinoma; Mitochondria-associated membranes; Mitochondrial metabolism; Mitofusin 2; Tumor suppression

DOI:  https://doi.org/10.1007/s10863-026-10132-y
J Ethnopharmacol. 2026 Oct 10. pii: S0378-8741(26)01357-7. [Epub ahead of print]374(Pt 2): 122502

Sequential stage-specific administration of Bushen-Tiaojing decoctions II and III ameliorates mitochondrial dysfunction in ovarian granulosa cells of COH mice by regulating GRP75-mediated MAM homeostasis.

Xin Ding, Xiaoying Wen, Wenyan Xiong, Han Liu, Siling Tang, Dandan Li, Yeteng Sun, Xiao Liang, Yancang Duan.

   ETHNOPHARMACOLOGICAL RELEVANCE: Traditional Chinese medicine (TCM) offers a distinct therapeutic approach to infertility. Bushen-Tiaojing Decoctions II (BSTJ-II-D) and III (BSTJ-III-D; collectively, BSTJD) are clinical formulas developed by Professor Huilan Du according to the TCM theory of stage-specific treatment and are widely used in the clinical management of infertility. Previous studies have shown that sequential, stage-specific administration of these formulas can improve mitochondrial energy metabolism and increase pregnancy rates among infertile women undergoing in vitro fertilization and embryo transfer (IVF-ET). However, whether this sequential treatment improves mitochondrial function in ovarian granulosa cells (GCs) by preserving mitochondria-associated endoplasmic reticulum membrane (MAM) homeostasis remains unclear.
AIM OF THE STUDY: Glucose-regulated protein 75 (GRP75) is a key tethering protein that maintains MAM homeostasis. This study aimed to determine whether sequential, stage-specific administration of BSTJ-II-D and BSTJ-III-D ameliorates mitochondrial dysfunction in ovarian GCs by regulating GRP75-mediated MAM homeostasis.
MATERIALS AND METHODS: A controlled ovarian hyperstimulation (COH) mouse model was established, after which animals received BSTJ-II-D and BSTJ-III-D sequentially via oral gavage. A group treated with GRP75-IN-1, a novel small-molecule compound that targets and binds GRP75, was included as a control. MAM morphology, mitochondrial bioenergetic activity, and mitochondrial biogenesis were systematically evaluated. For the in vitro experiments, human KGN ovarian granulosa-like tumor cells were transduced with a GRP75-overexpressing lentiviral construct to clarify how elevated GRP75 expression affects MAM architecture and function and subsequently influences mitochondrial homeostasis. Protein levels of GRP75, voltage-dependent anion channel 1 (VDAC1), mitochondrial calcium uniporter (MCU), sirtuin 1 (SIRT1), peroxisome proliferator-activated receptor γ coactivator 1-α (PGC-1α), and nuclear factor erythroid 2-related factor 2 (Nrf2) were assessed in GCs. Cellular adenosine triphosphate (ATP) production, reactive oxygen species (ROS) levels, mitochondrial Ca2+ loading, and mitochondrial membrane potential (MMP) were determined using fluorescence-based assays. In addition, mitochondrial permeability transition pore (mPTP) opening was evaluated quantitatively by flow cytometric analysis.
RESULTS: Sequential BSTJD treatment attenuated COH-induced aberrant GRP75 overexpression, restored MAM ultrastructural integrity, reduced mitochondrial oxidative stress (OS) and Ca2+ overload, and enhanced mitochondrial energy metabolism and biogenesis. Mechanistically, BSTJD increased the expression of SIRT1, PGC-1α, and Nrf2 while inhibiting activation of the PERK/ATF4 pathway, thereby alleviating endoplasmic reticulum (ER) stress and enhancing mitochondrial energy metabolism and biogenesis. GRP75-IN-1 reproduced the protective effects of BSTJD. Conversely, GRP75 overexpression in KGN cells disrupted MAMs and impaired mitochondrial function, further supporting GRP75 as a key mediator of the protective effects of BSTJD.
CONCLUSION: Sequential BSTJD treatment preserves MAM homeostasis by suppressing aberrant GRP75 overexpression, thereby mitigating OS and mitochondrial Ca2+ overload. It also activates the SIRT1-PGC-1α-Nrf2 pathway to restore mitochondrial energy metabolism and biogenesis, ultimately ameliorating mitochondrial dysfunction in GCs. These findings provide new molecular evidence supporting the Bushen Tiaojing therapeutic approach for infertility.

Keywords:  Bushen tiaojing decoctions; GRP75; Mitochondrial biogenesis; Mitochondrial energy metabolism; Oxidative stress; mitochondria‐associated endoplasmic reticulum membrane

DOI:  https://doi.org/10.1016/j.jep.2026.122502
FASEB J. 2026 Oct 31. 40(20): e72382

Lipid Transporter TMEM24/C2CD2L Plays Essential Roles in Retinal Photoreceptor Survival by Regulating Calcium Signaling and Synaptic Transmission.

Guangyi Chen, Jiajie He, Wenhan Wei, Zhenghao Wang, Xianjun Zhu, Yeming Yang.

Retinal neurotransmission is fundamental to vision, relying on the precise calcium-dependent release of glutamate at photoreceptor ribbon synapses. Disruptions in this pathway underlie multiple visual disorders in humans. TMEM24/C2CD2L, an SMP domain-containing phospholipid transporter enriched at endoplasmic reticulum (ER)-plasma membrane (PM) contact sites, regulates phosphoinositide homeostasis and calcium signaling. However, its role in the retina remains unknown. Here, we show that C2CD2L is predominantly expressed in retinal photoreceptors. Using a rod-specific conditional knockout mouse, we demonstrate that loss of C2CD2L impairs rod-mediated visual function, causes progressive outer retinal degeneration, induces reactive Müller glia activation, and triggers apoptotic photoreceptor death. Transcriptomic profiling of pre-degenerative retinas revealed significant downregulation of genes associated with voltage-gated calcium channel complexes, postsynaptic density membranes, and visual perception. These changes were accompanied by severe synaptic defects, including fewer RIBEYE- and Bassoon-positive puncta, reduced ribbon-bearing terminals, shortened synaptic ribbons, and decreased ribbon-tethered synaptic vesicles. Our findings establish C2CD2L as a critical regulator of rod photoreceptor synaptic integrity, calcium-channel-associated signaling, and retinal homeostasis.

DOI: https://doi.org/10.1096/fj.202602920RR
Plants (Basel). 2026 Sep 30. pii: 2995. [Epub ahead of print]15(19):

A Review of Nuclear-Organellar Communication in Response to Heat Stress.

Linlin Zhang, Xiaofei Li, Ankun Pan, Xueming Su, Long Chen, Tianxiao Chen, Baohua Feng, Shen Ni.

  Plants coordinate their growth and developmental programs through dynamic communication in the core of the nucleus, enabling them to adapt to persistently high-temperature environments. Upon heat stress, plants primarily perceive and transduce thermal signals between the nucleus and other organelles, a process defined as nuclear-organellar communication. The published research on plants in response to heat environments mainly focuses on sensing heat physical signals from the plasma membrane (PM)/cytosol to the nucleus, eliciting nuclear transcriptional reprogramming and decoding organelle-derived retrograde signals to the nucleus. Consequently, plants have evolved sophisticated systems to decode adverse temperature signals relying on efficient nuclear-organellar coordination. This review summarizes how plants maintain cellular homeostasis via nuclear crosstalk. Heat signals are initially perceived, which triggers the production of secondary messengers including phosphatidic acid (PA), calcium ions (Ca2+) and reactive oxygen species (ROS). In addition, proteins also deliver thermal signals to the nucleus. As the central signaling hub, the nucleus orchestrates global transcriptional reprogramming predominantly through the Heat Shock Transcriptional Factors (HSFs)-heat shock proteins (HSPs) regulatory module, and sends instructions to the endoplasmic reticulum (ER), chloroplasts and mitochondria. Conversely, organelle-derived retrograde signals coordinate stress adaptation: the unfolded protein response relieves ER stress, and heat stress activates ROS-mediated chloroplast-to-nucleus and mitochondria-to-nucleus feedback pathways. We further outline candidate thermosensing proteins residing in different organelles, and highlight major unsolved issues. Critical knowledge gaps include the intrinsic thermosensing capacity of chloroplasts and mitochondria, inter-organellar coordination of second-messenger dynamics, specific organelle functions, and the biological roles of membrane contact sites. Further mechanistic insights will facilitate the application of genome editing, synthetic biology and artificial-intelligence-aided design to breed heat-tolerant crops without yield penalties.

Keywords:  chloroplasts; endoplasmic reticulum; heat stress; mitochondria; nuclear-organellar communication; nucleus; plasma membrane

DOI:  https://doi.org/10.3390/plants15192995
bioRxiv. 2026 Oct 04. pii: 2026.09.28.754991. [Epub ahead of print]

A Novel NO Donor 3A72 Activates Mitochondrial-Associated Endoplasmic Reticulum Membrane Structures to Induce Ferroptosis in Triple-Negative Breast Cancer.

Yunke Long, Yuxin Jiang, La Li, Xiufan Wu, Jiachen Weng, Ying Chen, Hongrui Liu.

Triple-negative breast cancer (TNBC) remains a major clinical challenge due to a lack of effective interventions and severe drug resistance. Disrupting tumor metabolism using nitric oxide (NO) donors to drive ferroptosis represents a promising therapeutic strategy. Here, we developed 3A72, a novel furan-coumarin-based NO donor with potent anti-TNBC efficacy. In vitro and in vivo studies demonstrated that 3A72 significantly suppresses TNBC cell proliferation and restricts xenograft tumor growth. Notably, its efficacy matches the first-line drug paclitaxel but with enhanced safety and reduced systemic toxicity. Mechanistically, 3A72 induces ferroptosis in triple negative breast cancer (TNBC) cells via a synergistic dual-pathway mechanism. Initially, 3A72 releases intracellular NO to trigger cytoplasmic calcium overload, followed by high-affinity binding to both inositol 1,4,5-trisphosphate receptor (IP R) and acyl-CoA synthetase long-chain family member 4 (ACSL4). Binding to IP 3 R provokes mitochondrial calcium overload and a massive burst of reactive oxygen species (ROS), while concurrent ACSL4 activation drives essential membrane phospholipid remodeling. Crucially, our transcriptomic and structural predictions reveal that while ACSL4 exhibits a broader distribution across organelle membranes, its functional association with IP 3 R spatially converges at the endoplasmic reticulum membranes associated with mitochondria (MAMs). This subcellular niche closely couples IP R-mediated ROS generation with ACSL4-driven lipid remodeling, accelerating lethal malondialdehyde (MDA) accumulation and triggering irreversible ferroptosis. Overall, these findings highlight the MAMs calcium-lipid metabolic hub as a promising structural scaffold for antitumor drug development.

DOI: https://doi.org/10.64898/2026.09.28.754991