bims-mecosi Biomed News
on Membrane contact sites
Issue of 2025–05–25
ten papers selected by
Verena Kohler, Umeå University
  1. ER-plastid contact sites as molecular crossroads for plastid lipid biosynthesis.
  2. Phosphatidic acid drives spatiotemporal distribution of Pex30 at ER-LD contact sites.
  3. Pex30-dependent membrane contact sites maintain ER lipid homeostasis.
  4. Mitochondria-Associated Membranes: A Key Point of Neurodegenerative Diseases.
  5. Co-opted ATG2 lipid transfer protein delivers phospholipids for biogenesis of viral replication organelles.
  6. GRP75 inhibition attenuates arterial calcification.
  7. Metformin improves intestinal ischemia-reperfusion injury by reducing the formation of mitochondrial associated endoplasmic reticulum membranes (MAMs) and inhibiting ferroptosis in intestinal cells.
  8. Controlling lipid droplet dynamics via tether condensates.
  9. Copper-Induced DRP1 Activation Disrupts Mitochondrial-Lipid Droplet Contact to Promote Hepatic Steatosis.
  10. Lipid droplet - organelle crosstalk and its implication in cancer.
  1. BMC Biol. 2025 May 22. 23(1): 139
    ER-plastid contact sites as molecular crossroads for plastid lipid biosynthesis.
    Carolina Huercano, Miriam Moya-Barrientos, Oliver Cuevas, Victoria Sanchez-Vera, Noemi Ruiz-Lopez.
      Membrane contact sites are specialized regions where organelle membranes are in close proximity, enabling lipid transfer while preserving membrane identity. In plants, ER‒chloroplast contact sites are critical for maintaining glycerolipid homeostasis. This review examines the lipid-modifying and lipid-transfer proteins/complexes involved in these processes. Key proteins at these sites, including components of the TGD and VAP27‒ORP2A complexes, as well as Sec14 proteins, facilitate lipid exchange. Additionally, the roles of lipid-modifying proteins at these contact sites are discussed. Despite significant progress, further research is needed to identify additional proteins, investigate ER‒chloroplast dynamics under stress and explore ER contact sites in non-chloroplast plastids.
    Keywords:  Chloroplast; Contact sites; Endoplasmic reticulum; Glycerolipid; Lipid transfer; NTMC2 T5; ORP; Plastid; SFH5; TGD4
    DOI:  https://doi.org/10.1186/s12915-025-02239-2
  2. J Cell Biol. 2025 Jul 07. pii: e202405162. [Epub ahead of print]224(7):
    Phosphatidic acid drives spatiotemporal distribution of Pex30 at ER-LD contact sites.
    Morgan House, Karan Khadayat, Thomas N Trybala, Nikhil Nambiar, Elizabeth Jones, Steven M Abel, Joshua Baccile, Amit S Joshi.
      Lipid droplets (LDs) are ubiquitous neutral lipid storage organelles that form at discrete subdomains in the ER bilayer. The assembly of these ER subdomains and the mechanism by which proteins are recruited to them is poorly understood. Here, we investigate the spatiotemporal distribution of Pex30 at the ER-LD membrane contact sites (MCSs). Pex30, an ER membrane-shaping protein, has a reticulon homology domain, a dysferlin (DysF) domain, and a Duf4196 domain. Deletion of SEI1, which codes for seipin, a highly conserved protein required for LD biogenesis, results in accumulation of Pex30 and phosphatidic acid (PA) at ER-LD contact sites. We show that PA recruits Pex30 at ER subdomains by binding to the DysF domain. The distribution of Pex30 as well as PA is also affected by phosphatidylcholine (PC) levels. We propose that PA regulates the spatiotemporal distribution of Pex30 at ER subdomains that plays a critical role in driving the formation of LDs in the ER membrane.
    DOI:  https://doi.org/10.1083/jcb.202405162
  3. J Cell Biol. 2025 Jul 07. pii: e202409039. [Epub ahead of print]224(7):
    Pex30-dependent membrane contact sites maintain ER lipid homeostasis.
    Joana Veríssimo Ferreira, Yara Ahmed, Tiaan Heunis, Aamna Jain, Errin Johnson, Markus Räschle, Robert Ernst, Stefano Vanni, Pedro Carvalho.
      In eukaryotic cells, communication between organelles and the coordination of their activities depend on membrane contact sites (MCS). How MCS are regulated under the dynamic cellular environment remains poorly understood. Here, we investigate how Pex30, a membrane protein localized to the endoplasmic reticulum (ER), regulates multiple MCS in budding yeast. We show that Pex30 is critical for the integrity of ER MCS with peroxisomes and vacuoles. This requires the dysferlin (DysF) domain on the Pex30 cytosolic tail. This domain binds to phosphatidic acid (PA) both in vitro and in silico, and it is important for normal PA metabolism in vivo. The DysF domain is evolutionarily conserved and may play a general role in PA homeostasis across eukaryotes. We further show that the ER-vacuole MCS requires a Pex30 C-terminal domain of unknown function and that its activity is controlled by phosphorylation in response to metabolic cues. These findings provide new insights into the dynamic nature of MCS and their coordination with cellular metabolism.
    DOI:  https://doi.org/10.1083/jcb.202409039
  4. CNS Neurosci Ther. 2025 May;31(5): e70378
    Mitochondria-Associated Membranes: A Key Point of Neurodegenerative Diseases.
    Yiwei Zhang, Xiuqin Rao, Jiayi Wang, Hantian Liu, Qixian Wang, Xifeng Wang, Fuzhou Hua, Xilong Guan, Yue Lin.
       BACKGROUND: Neurodegenerative diseases pose significant health challenges in the 21st century, with increasing morbidity and mortality, particularly among the elderly population. One of the key factors contributing to the pathogenesis of these diseases is the disrupted crosstalk between mitochondria and the endoplasmic reticulum. Mitochondria-associated membranes (MAMs), which are regions where the ER interfaces with mitochondria, serve as crucial platforms facilitating communication between these organelles.
    OBJECTIVES: This review focuses on the structural composition and functions of MAMs and highlights their roles. Additionally, in this review, we summarize the relationship between MAM dysfunction and various neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, and others. The involvement of key proteins such as Sig-1R, IP3R, and VAPB in maintaining ER-mitochondrial communication and their dysfunction in neurodegenerative diseases is emphasized.
    CONCLUSION: Through analyzing the effects of MAM on neurodegenerative diseases, we provide the newest insights and potential therapeutic targets for the treatment of these debilitating conditions.
    Keywords:  Alzheimers' disease; Ca2+ homeostasis; IP3R; Parkinson's disease; Sig‐1R; VAPB; mitochondria‐associated membranes; neurodegenerative disease
    DOI:  https://doi.org/10.1111/cns.70378
  5. Autophagy Rep. 2024 ;3(1): 2426437
    Co-opted ATG2 lipid transfer protein delivers phospholipids for biogenesis of viral replication organelles.
    Yuanrong Kang, Judit Pogany, Peter D Nagy.
      Positive-strand RNA viruses, which are important pathogens of humans, animals and plants, subvert cellular membranes and induce de novo membrane proliferation to generate viral replication organelles (VROs) that support virus replication. Tomato bushy stunt virus (TBSV), an extensively-studied plant virus replicating in yeast model host and plants, hijacks ATG2 (autophagy-related 2), a lipid transfer protein (LTP) that transports lipids between adjacent organelles at membrane contact sites, for the biogenesis of their membranous VROs. Subversion of ATG2 by TBSV is important to enrich VRO membranes with phosphatidylethanolamine (PE), phosphatidylserine (PS) and the phosphoinositide phosphatidylinositol-3-phosphate [PI(3)P], which are all required for viral replication. TBSV replication protein directly interacts with ATG2 leading to recruitment to VRO membranes independently of the autophagy machinery.
    DOI:  https://doi.org/10.1080/27694127.2024.2426437
  6. Atherosclerosis. 2025 May 15. pii: S0021-9150(25)00141-8. [Epub ahead of print] 119243
    GRP75 inhibition attenuates arterial calcification.
    Jonas Heyn, Andrea Gorgels, Nicolas Hense, Alexander Gombert, Eva Miriam Buhl, Lisa Stark, Sonja Vondenhoff, Joel Simon, Heidi Noels, Nikolaus Marx, Claudia Goettsch.
       BACKGROUND AND AIMS: Arterial calcification is a risk factor for cardiovascular mortality. The calcification process is driven by the osteogenic transition of vascular smooth muscle cells (SMCs), which release extracellular vesicles (EVs) that act as mineralization nucleation sites. While mitochondrial dysfunction and endoplasmic reticulum (ER) stress have been implicated in arterial calcification, the role of their contact sites remains unknown. Mitochondria-associated membranes (MAMs) are inter-organelle contacts connecting the outer mitochondrial membrane to the ER membrane through protein-protein interactions. This study investigated the role of Glucose-regulated protein 75 (GRP75), a MAM linker protein, in SMC calcification and EV cargo.
    METHODS: Human coronary artery SMCs were cultured in osteogenic medium to induce calcification. MAMs were isolated from SMCs and human carotid artery by subcellular fractionation and visualized using transmission electron microscopy. SMC-derived EVs were isolated from the conditioned culture medium by ultracentrifugation. GRP75 inhibition was achieved using silencing RNA or the inhibitor MKT-077. Mitochondrial respiration and ER stress were analyzed using Seahorse analysis and Western blotting.
    RESULTS: Calcifying SMCs expressed higher GRP75 mRNA (2.2-fold ± 0.7, p = 0.043) and protein (1.3-fold ± 0.2, p = 0.008) levels compared to control SMCs. GRP75 was enriched at MAMs, and electron microscopy imaging demonstrated closer mitochondria-ER contacts in both calcifying SMCs in vitro and human calcified carotid artery specimens. GRP75 inhibition by silencing RNA (-35 % ± 13 %, p < 0.001) or MKT-077 (-57 % ± 3 %, p < 0.001) attenuated matrix mineralization and reduced close mitochondria-ER contacts along with attenuating mitochondrial respiration capacity. Additionally, GRP75 was enriched in EVs released by calcifying SMCs (1.3-fold ± 0.1, p = 0.040).
    CONCLUSIONS: Our findings demonstrate that MAMs are altered in calcifying SMCs. GRP75 inhibition disrupted close mitochondria-ER contact formation, decreased mitochondrial respiration, modulated the osteogenic transition of SMCs, and reduced vascular calcification. Therefore, GRP75 could serve as a potential target for preventing arterial calcification.
    Keywords:  Arterial calcification; Extracellular vesicles; Mitochondria-ER contacts; Mitochondria-associated membranes; Vascular smooth muscle cells
    DOI:  https://doi.org/10.1016/j.atherosclerosis.2025.119243
  7. Front Pharmacol. 2025 ;16 1581085
    Metformin improves intestinal ischemia-reperfusion injury by reducing the formation of mitochondrial associated endoplasmic reticulum membranes (MAMs) and inhibiting ferroptosis in intestinal cells.
    Xu Zhao, Likun Yan, Lifei Tian, Xiaolong Zhang, Ruiting Liu, Zeyu Li.
       Introduction: Intestinal ischemia-reperfusion (I/R) injury represents an inevitable and formidable postoperative challenge for all clinical surgeons. Ferroptosis has emerged as a crucial factor in the pathogenesis of intestinal I/R injury. Metformin, which is known to exhibit antiferroptotic properties, has elicited significant attention from both researchers and clinicians. This study was designed to comprehensively examine the protective effects of metformin against intestinal I/R injury and to elucidate the underlying potential mechanisms.
    Methods: To achieve this goal, both in vivo and in vitro models of I/R injury were established. For the in vivo experiments, metformin was administered via intraperitoneal injection at the onset of reperfusion.
    Results: The results from HE staining in the in vivo model, along with IF staining of tight junction proteins in the in vitro model, clearly demonstrated that metformin effectively mitigated the damage to the intestinal barrier following I/R injury. Additionally, metformin was shown to improve ROS levels and mitochondrial function in the context of I/R injury. Moreover, metfornin was observed to reduce the formation of mitochondria-associated membranes (MAMs), which is a process that is intricately linked to the onset of ferroptosis. Significantly, Western blot analysis of key ferroptosis-related proteins, including GPX4, FTH1 and SLC7A11, indicated that metformin inhibited ferroptosis.
    Discussion: In conclusion, this study suggests that metformin exerts beneficial effects on intestinal I/R injury by suppressing MAM formation and ferroptosis, thereby highlighting its potential as a therapeutic agent for this challenging clinical condition.
    Keywords:  ROS; ferroptosis; intestinal I/R injury; metformin; mitochondria-associated membranes; reactive oxygen species
    DOI:  https://doi.org/10.3389/fphar.2025.1581085
  8. Nat Chem Biol. 2025 May 21.
    Controlling lipid droplet dynamics via tether condensates.
    Chems Amari, Damien Simon, Emma Pasquier, Theodore Bellon, Marie-Aude Plamont, Sylvie Souquere, Gérard Pierron, Juliette Salvaing, Abdou Rachid Thiam, Zoher Gueroui.
      Lipid droplets (LDs) are dynamic cellular organelles that regulate lipid metabolism and various cellular processes. Their functionality relies on a dynamic proteome and precise spatiotemporal interactions with other organelles, making LD biology highly complex. Tools that enable the sequestration and release of LDs within their intracellular environment could synchronize their behavior, providing deeper insights into their functions. To address this need, we developed Controlled Trapping of LDs (ControLD), a new method for manipulating LD dynamics. This approach uses engineered condensates to reversibly sequester LDs, temporarily halting their activity. Upon release, the LDs resume their normal functions. ControLD effectively disrupts LD remobilization during metabolic demands and prevents the formation of LD-mitochondria contact sites, which are re-established upon condensate dissociation. ControLD represents a powerful tool for advancing the study of LD biology and opens avenues for investigating and manipulating other cellular organelles.
    DOI:  https://doi.org/10.1038/s41589-025-01915-2
  9. J Agric Food Chem. 2025 May 19.
    Copper-Induced DRP1 Activation Disrupts Mitochondrial-Lipid Droplet Contact to Promote Hepatic Steatosis.
    Quanwei Li, Luna Su, Pan Guo, Jianzhao Liao, Zhaoxin Tang.
      Copper (Cu) is a vital dietary element for both humans and animals and is widely supplemented in food. However, excessive consumption of this trace element can adversely affect the overall well-being. Previous studies have demonstrated that long-term Cu intake can lead to severe hepatotoxicity. The underlying mechanism by which Cu induces disturbances in hepatic energy metabolism through modulation of mitochondria-lipid droplet (LD) contacts, however, is not known. In this study, we found that Cu exposure significantly disrupted the interaction between mitochondria and LDs, leading to the downregulation of perilipin 2 (PLIN2), perilipin 5 (PLIN5), synaptosomal-associated protein 23 (SNAP23), diacylglycerol acyltransferase 2 (DGAT2), and caveolin-1 (Cav-1) proteins in chicken livers. Mechanistically, we demonstrated that Cu exposure-induced dynamin-related protein 1 (DRP1) protein activation disrupted mitochondria-LD contacts by regulating PLIN2. DRP1 knockdown and PLIN2 overexpression efficiently promoted the mitochondria-LD contacts, alleviating Cu-induced LD accumulation in chicken primary hepatocytes. However, PLIN2 knockdown significantly exacerbated the mitochondria-LD contact disorder induced by Cu exposure. Moreover, PLIN2 knockdown dramatically reversed the ability of DRP1 knockdown to promote mitochondria-LD contacts, while overexpression of PLIN2 had the opposite effect. Overall, our study revealed that the DRP1-PLIN2 axis regulates the connections between mitochondria and LDs under Cu exposure, which may provide a new perspective on Cu exposure-induced lipid metabolism disorders in hepatocytes.
    Keywords:  DRP1; PLIN2; copper; hepatocytes; mitochondria-LD contacts
    DOI:  https://doi.org/10.1021/acs.jafc.5c02147
  10. Prog Biophys Mol Biol. 2025 May 15. pii: S0079-6107(25)00023-9. [Epub ahead of print]197 11-20
    Lipid droplet - organelle crosstalk and its implication in cancer.
    Jing Quan, Chunhong Zhang, Xue Chen, Xinfei Cai, Xiangjian Luo.
      Lipid droplets (LDs) store lipids in cells, provide phospholipids for membrane synthesis, and maintain the intracellular balance of energy and lipid metabolism. Undoubtedly, the crosstalk between LDs and other organelles is the foundation for performing functions. Many studies indicate that LDs promote tumor progression. LD accumulation has been observed in a variety of cancers, and high LD content is associated with malignant phenotype and poor prognosis of cancers. In this paper, we summarized the intimate crosstalk between LDs and intracellular organelles, including endoplasmic reticulum (ER), mitochondria, lysosomes and peroxisomes, and addressed the effects of LD-organelle crosstalk on cancer initiation and progression. We also integrated the changes of LD-organelle interactions in cancers to provide an insightful knowledge for cancer therapeutics.
    Keywords:  Cancer therapy; Lipid droplet; Organelles crosstalk
    DOI:  https://doi.org/10.1016/j.pbiomolbio.2025.05.002
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