bims-mecosi 2026-02-22 papers

bims-mecosi

Biomed News

on Membrane contact sites

Issue of 2026–02–22
ten papers selected by
Verena Kohler, Umeå University

DAPL1 restrains RPE PANoptosis in experimental AMD by inhibiting GRP75-mediated mitochondria-associated endoplasmic reticulum membranes.
Spatial Pharmacology: Redefining Organelle Contact Sites as Therapeutic Targets.
Characterizing mitochondrial phenotypes and MERCS in aged human skeletal muscle myoblasts.
Single-cell transcriptomic analysis and machine learning identify ATAD3A as a key gene that stabilizes mitochondrial-endoplasmic reticulum membranes, promoting bladder cancer progression.
Insulin resistance: The central node of convergence between unfolded protein response, diabetes, and cancer.
miR-3099-5p alters cellular lipid levels and induces mitochondrial dysfunction by targeting FACL4 in mouse hepatic cells.
BRD4-mediated ER membrane contact creates functionally distinct mitochondrial subtypes.
Mitochondria-associated membranes and hallucinogenic therapy in Alzheimer's disease.
Mitochondrial double-stranded RNA drives aging-associated cognitive decline.
Spatiotemporal analysis of phosphatidylinositol 4-phosphate dynamics.

Proc Natl Acad Sci U S A. 2026 Feb 24. 123(8): e2511926123

DAPL1 restrains RPE PANoptosis in experimental AMD by inhibiting GRP75-mediated mitochondria-associated endoplasmic reticulum membranes.

Yan Li, Meiyu Jing, Wanxiao Wang, Wanzhen Lin, Yingxin Zhang, Tianyin Nie, Pingping Liu, Wan-Ni Lu, Yu Chen, J Fielding Hejtmancik, Qinxiang Zheng, Ling Hou, Xiaoyin Ma.

  Retinal pigment epithelium (RPE) cell damage is a critical factor of age-related macular degeneration (AMD), the leading cause of blindness among the aged population. This study focuses on the AMD susceptible gene, Death associated protein like 1 (DAPL1), and provides insights with significant therapeutic implications. DAPL1-deficient mice exhibit dry AMD-like pathological features, a phenomenon whose mechanisms have remained largely unknown. Here, we reveal that DAPL1 deficiency promotes the formation of mitochondria-associated endoplasmic reticulum membranes (MAMs) to cause mitochondrial Ca2+ overload and dysfunction, which triggers the activation of inflammasomes, leading RPE cells to RIPK1-mediated PANoptosis, an inflammatory programmed cell death, in an experimental dry AMD (dAMD) mouse model. Knockdown of Ripk1 in the Dapl1-/- mice RPE inhibits RPE cell PANoptosis and ameliorates the severity of dAMD pathological features. Conversely, overexpression of DAPL1 inhibits MAM formation and protects RPE cells from PANoptosis in the model. Mechanistically, DAPL1 suppresses MAM formation by downregulating GRP75 expression. This disrupts the formation of the VDAC-GRP75-IP3R axis, which comprises critical tethering proteins responsible for endoplasmic reticulum to mitochondria coupling and Ca2+ trafficking. Knockdown of Grp75 inhibits the formation of MAM and prevents mitochondrial Ca2+ overload, improving mitochondrial quality and inhibiting PANoptosis in RPE cells, thereby interrupting the progression of experimental dAMD in Dapl1-deficient mice. These results unveil the role of MAMs regulated by DAPL1 in RPE cell PANoptosis and AMD progression, highlighting targeting MAM formation as a potential therapeutic strategy for treating dAMD.

Keywords:  AMD; GRP75; PANoptosis; RPE; mitochondria-associated ER membrane

DOI:  https://doi.org/10.1073/pnas.2511926123
Int J Biol Sci. 2026 ;22(4): 2121-2123

Spatial Pharmacology: Redefining Organelle Contact Sites as Therapeutic Targets.

Minjeong Ko, Jiho You, Eunwoo Cho, Ho Jeong Kwon.

DOI: https://doi.org/10.7150/ijbs.129515
PLoS One. 2026 ;21(2): e0343604

Characterizing mitochondrial phenotypes and MERCS in aged human skeletal muscle myoblasts.

Yufu Unten, Kazuaki Takafuji, Yumiko Masukagami, Isshin Shiiba, Keigo Horiuchi, Filip Husnik, Shigeru Yanagi, Norifumi Tateishi, Toshihide Suzuki.

Age-associated declines in skeletal muscle function are linked to cellular senescence and mitochondrial alterations, yet mitochondrial phenotypes in aged human myoblasts remain insufficiently characterized. Here, we examined primary skeletal muscle myoblasts from young and elderly donors to assess mitochondrial function, morphology, and mitochondria-endoplasmic reticulum (ER) contact sites (MERCS). Myoblasts from older donors exhibited senescence features, including elevated SA-β-gal activity and reduced Lamin B1 expression, accompanied by increased mitochondrial oxidative stress. Despite marked mitochondrial hyperfusion and increased mitochondrial DNA content, mitochondrial oxygen consumption rate and membrane potential per mitochondrial area were comparable between young and old cells. MERCS were significantly elevated in aged myoblasts and were reduced by scavenging mitochondrial reactive oxygen species (mtROS), indicating an association between oxidative stress and MERCS formation. These findings suggest that mitochondrial hyperfusion and enhanced MERCS accompany cellular aging in human myoblasts and may contribute to maintaining mitochondrial function under elevated oxidative stress.

DOI: https://doi.org/10.1371/journal.pone.0343604
J Transl Med. 2026 Feb 20.

Single-cell transcriptomic analysis and machine learning identify ATAD3A as a key gene that stabilizes mitochondrial-endoplasmic reticulum membranes, promoting bladder cancer progression.

Henghui Zhang, Sisi Han, Zhengming Su, Zaosong Zheng, Dejun Ru, Bihong Xu, Xianhan Jiang, Fengjin Zhao.

   BACKGROUND: Mitochondria-associated endoplasmic reticulum membranes (MAM) play a critical regulatory role in cancer, yet their function in bladder cancer (BCa) remains unclear.
METHODS: This study conducted a comprehensive analysis of extensive RNA sequencing and single-cell transcriptomic data. A MAM risk feature model was constructed and evaluated using LASSO-Cox regression, Kaplan-Meier survival curves, and receiver operating characteristic (ROC) analysis. Cell communication networks were decoded using CellChat, and tumor-infiltrating immune cells were quantified through CIBERSORT. Machine learning, OncoPredict, Scissor algorithm, and spatial transcriptomics were employed to analyze chemical reactions. The tumor-promoting functions and molecular mechanisms of ATAD3A were validated through cell and animal models, as well as transmission electron microscopy and fluorescence confocal microscopy.
RESULTS: This study systematically delineates the gene expression profile of MAM in BCa and constructs a robust MAM prognostic signature that effectively predicts poor patient outcomes. A high MAM score is significantly associated with an immunosuppressive microenvironment and chemotherapy resistance. Using machine learning, we developed a random forest model that successfully identified ATAD3A as a key gene predicting cisplatin resistance, which is significantly correlated with platinum resistance at both single-cell and spatial transcriptomic levels. Further validation shows that ATAD3A is highly expressed in BCa tissue, and its knockdown significantly suppresses tumor growth. Mechanistically, ATAD3A maintains MAM structural integrity, regulates mitochondrial calcium homeostasis and membrane potential, thereby promoting cellular homeostasis and enhancing chemotherapy resistance.
CONCLUSION: This study connects MAM to BCa chemotherapy resistance through machine learning and multi-omics analysis, establishing ATAD3A as a prognostic biomarker and potential therapeutic target in BCa.

Keywords:  ATAD3A; Bladder cancer; Machine learning; Mitochondria-associated endoplasmic reticulum membranes; Single cell

DOI:  https://doi.org/10.1186/s12967-026-07857-0
Mol Aspects Med. 2026 Feb 13. pii: S0098-2997(26)00014-2. [Epub ahead of print]108 101458

Insulin resistance: The central node of convergence between unfolded protein response, diabetes, and cancer.

K M Abdullah, Gunjan Sharma, Baby Anjum, Mohammad Fazle Alam, Sudhanshu Yadav, Yashi Singh, Rohit Anthony Sinha, Vimala Venkatesh, Jawed Akhtar Siddiqui, Bandana Chakravarti.

  Modern lifestyle patterns, characterized by high-calorie diets and sedentary behaviour, have driven a global surge in obesity, which is a primary driver of insulin resistance (IR) and type 2 diabetes mellitus (T2D). Initially, pancreatic β-cells adapt to IR by increasing proliferation, neogenesis, and insulin secretion to maintain normoglycemia. Also, a prolonged exposure to genetic and environmental stress compromises the β-cell functioning and survival, leading to chronic hyperglycaemia. Beyond its central role in T2D, IR and its metabolic hallmarks, such as hyperinsulinemia, hyperglycaemia, dyslipidaemia, and chronic inflammation, are increasingly linked to heightened cancer risk and adverse outcomes in breast, colon, pancreatic, liver, bladder, and endometrial cancers. Aberrant insulin/IGF signalling, enhanced oxidative stress, inflammatory cytokines, and metabolic reprogramming are key molecular mediators of cancer progression. At the organelle level, both endoplasmic reticulum (ER) and mitochondria, and their functional crosstalk via mitochondria-associated membranes (MAMs), are critical in IR. However, a disruption in ER homeostasis might trigger ER stress and activate the unfolded protein response (UPR), culminating in a cellular adaptive mechanism. A dysregulation in this response contributes to lipid accumulation, inflammation, impaired insulin biosynthesis, and β-cell apoptosis. Simultaneously, altered MAM integrity disrupts calcium signalling, mitochondrial metabolism, and ER-mitochondria crosstalk, further aggravating IR across tissues, including liver, muscle, β-cells, and brain. Thus, UPR dysregulation and MAM perturbations represent a mechanistic nexus linking IR, T2D, and cancer. Understanding how these processes intersect might help in uncovering promising therapeutic avenues targeting ER stress, restoring MAM integrity, modulating UPR signalling, and thereby improving insulin sensitivity, mitigating metabolic disease and oncogenic risk.

Keywords:  Cancer; Diabetes; Endoplasmic reticulum stress; Insulin resistance; Mitochondria-associated membranes; Unfolded protein response

DOI:  https://doi.org/10.1016/j.mam.2026.101458
Biochim Biophys Acta Mol Basis Dis. 2026 Feb 15. pii: S0925-4439(26)00043-8. [Epub ahead of print]1872(4): 168195

miR-3099-5p alters cellular lipid levels and induces mitochondrial dysfunction by targeting FACL4 in mouse hepatic cells.

Shalu Rathore, Ashima Rizvi, Radhika Kansal, Rajat Ujjainiya, Malabika Datta.

  Aberrant endoplasmic reticulum (ER) and mitochondria function mediated by deregulated levels of tethering proteins at the mitochondria-associated ER membranes (MAM) sites is a hallmark of several diseases, yet very little is known of the regulatory mechanisms of these tethering proteins. Here, using mouse hepatic cells, we present data to show that miR-3099-5p binds to the 3'UTR of one such MAM protein, FACL4 and regulates its levels within the cell. Hepatic levels of miR-3099-5p are up-regulated during diabetes with a concomitant down-regulation of FACL4 levels. Overexpressing miR-3099-5p levels in mouse Hepa1-6 cells effectively down-regulates FACL4 levels, the effect being prevented by the miR-3099-5p inhibitor. miR-3099-5p-FACL4 interaction leads to accumulation of arachidonic acid and its reduced incorporation into phospholipids. Further, while this interaction did not impact mitochondrial ROS or calcium levels, it altered mitochondrial membrane potential and mitochondrial permeability transition pore opening together with increased apoptosis. FACL4 inhibition alone exerted effects similar to miR-3099-5p overexpression including accumulation of arachidonic acid, altering mitochondrial membrane potential and mitochondrial permeability transition pore opening and induction of apoptosis. Interestingly, arachidonic acid overloading in Hepa1-6 cells was sufficient to induce apoptosis and impair mitochondrial membrane potential; such arachidonic acid supplementation also significantly reversed the effects of miR-3099-5p inhibition on apoptosis and mitochondrial membrane potential. These findings suggest that FACL4 mediates the deleterious effects of miR-3099-5p in mouse hepatic cells and interrogating such miRNA mediated changes in hepatic FACL4 levels might be explored to address aberrant hepatic metabolism during diabetes.

Keywords:  Apoptosis; ER-mitochondria function; FACL4; Mitochondrial dysfunction; miRNA

DOI:  https://doi.org/10.1016/j.bbadis.2026.168195
Mol Cell. 2026 Feb 13. pii: S1097-2765(26)00032-8. [Epub ahead of print]

BRD4-mediated ER membrane contact creates functionally distinct mitochondrial subtypes.

Brandon Chen, Drew C Stark, Pankaj V Jadhav, Theophilus M Lynn-Nguyen, Benjamin S Halligan, Nicholas J Rossiter, Nicole Sindoni, Myungsun Shin, Joao A Paulo, Matthew Chang, Imhoi Koo, Sergei Koshkin, Sanjana Eyunni, Paolo Ronchi, Michelle T Paulsen, Harrison S Greenbaum, Mariana T Ruckert, Pietro Morlacchi, David A Hanna, Jason Lin, Rachel M Guerra, Tao Liu, David J Pagliarini, Ruma Banerjee, Abhijit Parolia, Mats E Ljungman, Andrew D Patterson, Joseph D Mancias, Shyamal Mosalaganti, Jonathan Z Sexton, Tito Calì, Costas A Lyssiotis, Yatrik M Shah.

  Inter-organellar communication is critical for cellular metabolism. One of the most abundant inter-organellar interactions occurs at the endoplasmic reticulum and mitochondria contact sites (ERMCSs). However, an understanding of the mechanisms governing ERMCS regulation and their roles in cellular metabolism is limited by a lack of tools that permit temporal induction and reversal. Through screening approaches, we identified fedratinib, an FDA-approved drug that dramatically increases ERMCS abundance by inhibiting the epigenetic modifier BRD4. Fedratinib rapidly and reversibly modulates mitochondrial and ER morphology, induces a distinct ER-mitochondria envelopment structure, and alters metabolic homeostasis. Moreover, ERMCS modulation depends on mitochondrial electron transport chain complex III function. Comparison of fedratinib activity to other reported inducers of ERMCSs revealed common mechanisms of induction and function, providing clarity to a growing body of experimental observations. In total, our results uncovered a novel epigenetic signaling pathway and an endogenous metabolic regulator that connects ERMCSs and cellular metabolism.

Keywords:  bromodomain protein; endoplasmic reticulum-mitochondria contact sites; high-throughput screening; mitochondrial electron transport chain

DOI:  https://doi.org/10.1016/j.molcel.2026.01.012
Neuroscience. 2026 Feb 16. pii: S0306-4522(26)00125-9. [Epub ahead of print]

Mitochondria-associated membranes and hallucinogenic therapy in Alzheimer's disease.

Fernando Minauro-Sanmiguel, Hector Vargas-Perez.

  Mitochondrial dysfunction is increasingly recognized as a central driver of Alzheimer's disease (AD), contributing to neuroinflammation, synaptic failure, and energy collapse.Emerging preclinical evidence suggests that classic hallucinogens, such as psilocybin, lysergic acid diethylamide (LSD), N,N-dimethyltryptamine (DMT), mescaline, may restore mitochondrial integrity by activating Serotonin 2A (5-HT2A) and sigma-1(Sig-1R) receptors. In experimental models, these pathways are associated with enhanced mitochondrial biogenesis, reduced oxidative stress, and preservation of ER-mitochondrial coupling. DMT and 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) specifically engage Sig-1R at mitochondria-associated membranes, improving calcium homeostasis and cellular resilience. While these mechanisms are mechanistically compelling, evidence for clinical efficacy in AD remains limited and largely preclinical. Accordingly, this framework is presented as a hypothesis-generating model suggesting that mitochondrial-centered psychedelic mechanisms warrant further investigation,provided that neuropsychiatric safety, patient selection, and translational feasibility are carefully addressed.

Keywords:  5-HT2A receptor; Alzheimer’s disease; Mitochondria; Neuroinflammation; Psychedelics; Sigma-1 receptor; Synaptic plasticity

DOI:  https://doi.org/10.1016/j.neuroscience.2026.02.028
Cell Res. 2026 Feb 16.

Mitochondrial double-stranded RNA drives aging-associated cognitive decline.

Lixiao Zhang, Xiang Li, Hongdi Luo, Yujia Huo, Guangkeng Zhou, Pengcheng Wang, Sipeng Wu, Xinyong Lin, Kai Dai, Jiahao Shi, Zebao Wang, Jiaxin Xu, Renjian Li, Siyi Chen, Zhe Sun, Chunlin Zhao, Zizhuo Zhou, Zhenhong Wang, Chensi Liang, Jun Zhu, Xingjun Chen, Jintao Luo, Yong Yu, Zhirong Zhang, Geng Wang.

Aging is the primary cause of cognitive decline. Despite extensive study, the molecular mechanisms driving aging-associated cognitive decline remain unclear. Here, we describe a proteostasis-independent function of SEC61A1 and its involvement in aging-associated cognitive decline. SEC61A1 regulates ER-mitochondria contact sites, affecting mitochondrial DNA and RNA synthesis and subsequently leading to changes in innate immune signaling mediated by mitochondrial double-stranded RNA (mt-dsRNA). This pathway is activated in aged wild-type mice, Alzheimer's disease patients, and 5×FAD mice. Tissue-specific overexpression of Sec61a1 in the mouse cortex (Sec61a1Tg) is sufficient to induce cognitive decline without affecting motor activity. Knockdown of Sec61a1 or Mavs ablates mt-dsRNA-mediated innate immune signaling and alleviates cognitive decline in naturally aging wild-type mice. These results reveal a molecular mechanism of aging- and disease-associated cognitive decline and provide a potential therapeutic tool for intervention.

DOI: https://doi.org/10.1038/s41422-026-01224-w
Methods Enzymol. 2026 ;pii: S0076-6879(25)00493-8. [Epub ahead of print]726 143-155

Spatiotemporal analysis of phosphatidylinositol 4-phosphate dynamics.

Asami Kawasaki, Shinya Tsukiji, Fubito Nakatsu.

  Phosphatidylinositol 4-phosphate (PI4P) is a fundamental phosphoinositide that controls a variety of cellular processes, including signaling, membrane trafficking and intracellular lipid transport. Given the importance of PI4P, tools and methods for monitoring its dynamics are in high demand. We recently identified the pleckstrin homology (PH) domain of oxysterol-binding protein-related protein 9 (ORP9) as a novel genetically encoded probe that enables high-contrast visualization of PI4P across multiple cellular membranes, including the plasma membrane (PM), Golgi, endosomes and lysosomes. Here, we describe methods for imaging and quantifying PI4P dynamics using ORP9-PH with standard confocal microscopy. These approaches include monitoring PI4P distribution at distinct cellular membranes, quantifying PI4P dynamics at the PM in response to pharmacological inhibition of PI 4-kinase and physiological activation of Gq-coupled G protein-coupled receptors. These methods offer a reliable approach for examining the spatial and temporal dynamics of PI4P in situ.

Keywords:  Imaging; Membrane contact site; Oxysterol-binding protein–related protein; Phosphatidylinositol 4-phosphate

DOI:  https://doi.org/10.1016/bs.mie.2025.11.012