bims-mecosi 2025-06-01 papers

bims-mecosi

Biomed News

on Membrane contact sites

Issue of 2025–06–01
nine papers selected by
Verena Kohler, Umeå University

Sphingosine-1-phosphate signalling activates E-Syt1 to facilitate HDL-derived cholesterol transport.
The power of connections: Recent advances in understanding the regulation of mitochondrial dynamics by membrane contact sites.
Endoplasmic reticulum tubule junctions are sites of autophagy.
Ca2+ transfer via enhancing ER-Mito coupling contributed to BDE-47- induced hippocampal neuronal necroptosis and cognitive dysfunction.
Recruitment of the cellular lipid transport protein CERT to C. psittaci inclusions regulates the timing of bacterial egress.
Epimedin C enhances mitochondrial energy supply by regulating the interaction between MIC25 and UBC in rodent model.
The P-type calcium pump Spf1 regulates immune response by maintenance of the endoplasmic reticulum-plasma membrane contacts during Candida albicans systemic infection.
Restoring calcium crosstalk between ER and mitochondria promotes intestinal stem cell rejuvenation through autophagy in aged Drosophila.
Lipid transporters E-Syt3 and ORP5 regulate epithelial ion transport by controlling phosphatidylserine enrichment at ER/PM junctions.

Nat Cell Biol. 2025 May 28.

Sphingosine-1-phosphate signalling activates E-Syt1 to facilitate HDL-derived cholesterol transport.

Zizhen Xu, Ying Meng, Jonathan St-Germain, Arezoo Afshari, Charneal L Dixon, Saskia Heybrock, Qiang Zhao, Xialian Weng, Jishun Chen, Richard Collins, Hu Hu, Quan Zhou, Qiming Sun, Pinglong Xu, Wei Liu, Paul Saftig, Brian Raught, Gregory D Fairn, Dante Neculai.

Cholesterol derived from high-density lipoprotein (HDL) is rapidly redistributed to intracellular compartments in steroidogenic and bile-producing cells, but the molecular mechanisms governing this essential transport process remain poorly understood. Here we uncover a signalling cascade coordinating HDL-derived cholesterol transport through membrane contact sites between the endoplasmic reticulum (ER) and plasma membrane (PM). We find that HDL-resident sphingosine-1-phosphate (S1P) activates S1P receptor 3 and its associated G protein αq, leading to phospholipase-C-β3-mediated hydrolysis of phosphatidylinositol 4,5-bisphosphate and an elevation in cytosolic calcium. This calcium signal triggers the rapid recruitment of Extended-Synaptotagmin 1 to ER-PM membrane contact sites. Genetic or pharmacological disruption of this pathway impairs the non-vesicular transfer of HDL-derived cholesterol to intracellular compartments. Our findings reveal how HDL binding to the cell surface alters ER-PM membrane contact site dynamics through S1P signalling. This ensures efficient offloading and redistribution of HDL cholesterol to support steroid and bile acid synthesis.

DOI: https://doi.org/10.1038/s41556-025-01665-2
Curr Opin Cell Biol. 2025 May 28. pii: S0955-0674(25)00073-0. [Epub ahead of print]95 102535

The power of connections: Recent advances in understanding the regulation of mitochondrial dynamics by membrane contact sites.

Jason C Casler, Laura L Lackner.

The continuous remodeling of the mitochondrial network through fusion, fission, transport, and turnover events, collectively known as mitochondrial dynamics, is essential for the maintenance of mitochondrial metabolic and genomic health. While the primary molecular machines that mediate these processes were discovered decades ago, the regulation of mitochondrial dynamics clearly involves additional factors. A major breakthrough came from the discovery that sites of close apposition between organelles, known as membrane contact sites (MCSs), serve as critical regulators of organelle function. MCSs between mitochondria and the ER are now universally recognized as important regulatory hubs of mitochondrial dynamics. Despite this, there are still many unknowns pertaining to the mechanisms by which MCSs influence mitochondrial dynamics. In this review, we describe recent progress identifying novel protein and lipid components that regulate mitochondrial dynamics and emphasize clear gaps in our understanding of how mitochondrial dynamics are coordinated at MCSs. Finally, we conclude by discussing progress towards defining the highly biomedically relevant, but enigmatic, role of mitochondrial dynamics in the preservation of mitochondrial DNA integrity.

DOI: https://doi.org/10.1016/j.ceb.2025.102535
Autophagy. 2025 May 25.

Endoplasmic reticulum tubule junctions are sites of autophagy.

Susan Ferro-Novick.

  Selective endoplasmic reticulum (ER) macroautophagy/autophagy, also called reticulophagy, is a disposal pathway that degrades ER domains. A major role of reticulophagy is the removal of ER domains that contain misfolded proteins resistant to ER-associated degradation (ERAD). Our studies have shown that RTN3L, the SEC24C-SEC23 COPII coat subcomplex, and the CUL3KLHL12 E3 ligase that ubiquitinates RTN3L targets ERAD-resistant misfolded protein condensates for degradation at ER-reticulophagy sites (ERPHS), autophagic sites that form at tubule junctions. Unexpectedly, we found that the Parkinson disease protein PINK1 regulates ER tubulation. Loss of PINK1 disrupts the formation of peripheral tubule junctions, and, as a consequence, reticulophagy is blocked and misfolded proteins accumulate in the ER. Overexpression of the ER tubulating domain of DNM1L/DRP1, a multifunctional PINK1 kinase substrate that localizes to ER-mitochondria contact sites, increases junctions and restores reticulophagy. Our findings show that PINK1 shapes the ER to target misfolded proteins for RTN3L-SEC24C-mediated macroreticulophagy at defined ER sites, peripheral tubule junctions.

Keywords:  ER junctions; ER quality control; Reticulophagy

DOI:  https://doi.org/10.1080/15548627.2025.2508934
Ecotoxicol Environ Saf. 2025 May 23. pii: S0147-6513(25)00732-8. [Epub ahead of print]299 118396

Ca2+ transfer via enhancing ER-Mito coupling contributed to BDE-47- induced hippocampal neuronal necroptosis and cognitive dysfunction.

Junhong Geng, Quan Yuan, Chaofang Ni, Yarong Zhang, Xiaoli Liu, Xiaoying Zhu, Xueqin Hao, Gaofeng Liang, Dongmei Wang, Hua Fan.

  2,2,4,4-Tetrabromodiphenyl ether (BDE-47), a ubiquitous environmental pollutant, has gained increasing attention due to its high level in biological samples and potential neurotoxicity. Recent studies have indicated that the receptor interacting protein kinase 1 (RIPK1)-mediated necroptosis is implicated in BDE-47 cytotoxicity. However, little is known about the underlying mechanism and whether the necroptosis participates in BDE-47-induced neuronal injury and cognitive impairment. Our results indicated that exposure to BDE-47 triggered RIPK1-dependent neuronal necroptosis in mice hippocampi and HT-22 mouse hippocampal neurons. Necrostain-1 (Nec-1), a specific RIPK1 inhibitor, suppressed the RIPK1/RIPK3/mixed lineage kinase-like domain protein (MLKL) signaling and rescued neuronal survival in BDE-47-treated HT-22 neurons. Mechanically, increased mitochondrial Ca2+ influx precipitated the opening of the mitochondrial permeability transition pore (mPTP), leading to occurrence of hippocampal neuronal necroptosis under BDE-47 stress. BDE-47 exposure induced excessive mitochondria-associated endoplasmic reticulum membranes (MAMs) formation and promoted ER-to-mitochondria Ca2+ transfer, while diminishing ER-mitochondrial contacts by Glucose-regulated protein 75 (Grp75)-deficiency remarkably prevented mitochondria Ca2+ overload and opening of mPTP as well as neuronal necroptosis. Notably, Nec-1 pre-treatment could substantially mitigate neuronal/synaptic damage and cognitive impairment in BDE-47-exposed mice. Collectively, these data suggest that BDE-47 exposure intensified endoplasmic reticulum (ER)-mitochondrial (Mito) contact and facilitated Ca2+ transfer from ER towards mitochondria, resulting in mPTP opening-mediated hippocampal neuronal necroptosis and subsequent cognitive dysfunction. Our study shed new light on the mechanisms underlying BDE-47 neurotoxicity and provided a novel therapeutic strategy through targeting RIPK1 kinase activity.

Keywords:  BDE-47; Cognitive deficits; ER-Mito coupling; MPTP; Necroptosis

DOI:  https://doi.org/10.1016/j.ecoenv.2025.118396
Sci Rep. 2025 May 25. 15(1): 18241

Recruitment of the cellular lipid transport protein CERT to C. psittaci inclusions regulates the timing of bacterial egress.

Jana Scholz, Gudrun Holland, Michael Laue, Sebastian Banhart, Dagmar Heuer.

  Egress of intracellular pathogens is highly regulated and carefully timed. For the zoonotic bacterium C. psittaci, the predominant egress pathway is Chlamydia-containing sphere (CCS) formation, a calcium-dependent sequential mechanism including protease activity, inclusion membrane destabilization, intracellular calcium increase, and plasma membrane blebbing. How egress is regulated to ensure that it takes place only after productive C. psittaci intracellular development is thus far unknown. Here, we show that C. psittaci recruits the cellular ceramide transporter CERT to its inclusion during intracellular development, but this recruitment is reduced at late time points prior to egress. In addition, an early loss of CERT at the inclusion membrane induced by CERT-KO induces premature egress by CCS formation. Complementation of the CERT-KO with different CERT-GFP variants prevents premature egress, except of complementation with a variant lacking the inclusion targeting PH domain, showing that specific localization of CERT is critical for CCS formation. The CERT-KO induced premature CCS are formed by the sequential process described for mature CCS, but they contain mostly RBs and are predominantly non-infectious. Thus, our findings suggest that the timing of C. psittaci egress by CCS formation is regulated by the recruitment of CERT to the inclusion. We propose that CERT stabilizes the chlamydial inclusion by the formation of ER-inclusion membrane contact sites during intracellular development, and the loss of CERT recruitment facilitates inclusion membrane destabilization and CCS formation.

Keywords:   Chlamydia ; Chlamydia psittaci ; CERT; Egress; Membrane contact sites; Obligate intracellular pathogens

DOI:  https://doi.org/10.1038/s41598-025-02077-w
PLoS One. 2025 ;20(5): e0325031

Epimedin C enhances mitochondrial energy supply by regulating the interaction between MIC25 and UBC in rodent model.

Mi Huang, Lei Yu, Zhong Li, Ying Wang, Chunlin Yang.

The study investigates the molecular mechanisms underlying the skeletal muscle-enhancing effects of Epimedin C, a natural flavonoid, focusing on its interaction with the mitochondrial cristae structural protein MIC25. Using C57BL/6 mice, we demonstrate that Epimedin C enhances exercise performance through preservation of mitochondrial function. Proteomic analysis identified MIC25 as a key protein modulated by Epimedin C, whose stability is regulated via ubiquitin-dependent degradation. Functional experiments revealed that Epimedin C disrupts the interaction between MIC25 and ubiquitin-conjugating enzyme C (UBC), preventing MIC25 degradation and maintaining the integrity of the mitochondrial contact site and cristae organizing system (MICOS). This stabilization preserves mitochondrial cristae structure, improves ATP production, and delays muscle fatigue. Notably, MIC25 overexpression mimicked Epimedin C's effects, while its knockdown abolished these benefits. Our findings establish MIC25 as a critical effector of Epimedin C, elucidating a novel pathway through which flavonoids maintain mitochondrial homeostasis to enhance muscle function. These insights hold promise for developing therapies targeting muscle atrophy and metabolic disorders.

DOI: https://doi.org/10.1371/journal.pone.0325031
Mycology. 2025 ;16(2): 856-875

The P-type calcium pump Spf1 regulates immune response by maintenance of the endoplasmic reticulum-plasma membrane contacts during Candida albicans systemic infection.

Yuchao Ji, Dou Chen, Menglin Shao, Zhuo Liu, Mingchun Li, Qilin Yu.

  Spf1 is an important P-type ATPase in Candida albicans, which functions as an endoplasmic reticulum calcium pump to maintain calcium homoeostasis. The deficiency of Spf1 attenuates the virulence of C. albicans. However, its impact on immune response remains to be investigated. This study discovered that deletion of SPF1 resulted in a reduction of endoplasmic reticulum-plasma membrane contacts, an important structure mediating material and information exchange. This effect was attributed to the reduced plasma membrane localisation of the crucial endoplasmic reticulum-plasma membrane tethering proteins Ist2 and Tcb1/3. The reduction of the contacts led to a decrease in secretion of the virulence factors phospholipase, secreted aspartyl protease (SAP), candidalysin, and the cell wall-anchored protein Hwp1 during infection. Immunofluorescence staining and quantitative PCR assays further showed that the SPF1 deletion led to a remarkable decrease in the levels of pro-inflammatory cytokines, suggesting the alleviation of the fungus-induced inflammatory response. Ultimately, the regulatory role of Spf1 in immune response significantly weakened the infectivity of C. albicans, and increased the survival rate of the hosts. This finding elucidated the role of fungal calcium pump-governed endoplasmic reticulum-plasma membrane contacts in regulation of immune response. It also makes it possible to regulate the host's immune response via control of SPF1 expression and functions, providing a theoretical basis for treating fungal infections.

Keywords:  Candida albicans; P-type ATPase; endoplasmic reticulum-plasma membrane contact; immune response; virulence factor

DOI:  https://doi.org/10.1080/21501203.2024.2409299
Nat Commun. 2025 May 27. 16(1): 4909

Restoring calcium crosstalk between ER and mitochondria promotes intestinal stem cell rejuvenation through autophagy in aged Drosophila.

Yao Zhang, Peng Ma, Saifei Wang, Shuxin Chen, Hansong Deng.

Breakdown of calcium network is closely associated with cellular aging. Previously, we found that cytosolic calcium (CytoCa2+) levels were elevated while mitochondrial calcium (MitoCa2+) levels were decreased and associated with metabolic shift in aged intestinal stem cells (ISCs) of Drosophila. How MitoCa2+ was decoupled from the intracellular calcium network and whether the reduction of MitoCa2+ drives ISC aging, however, remains unresolved. Here, we show that genetically restoring MitoCa2+ can reverse ISC functional decline and promote intestinal homeostasis by activating autophagy in aged flies. Further studies indicate that MitoCa2+ and Mitochondria-ER contacts (MERCs) form a positive feedback loop via IP3R to regulate autophagy independent of AMPK. Breakdown of this loop is responsible for MitoCa2+ reduction and ISC dysfunction in aged flies. Our results identify a regulatory module for autophagy initiation involving calcium crosstalk between the ER and mitochondria, providing a strategy to treat aging and age-related diseases.

DOI: https://doi.org/10.1038/s41467-025-60196-4
EMBO J. 2025 May 27.

Lipid transporters E-Syt3 and ORP5 regulate epithelial ion transport by controlling phosphatidylserine enrichment at ER/PM junctions.

Paramita Sarkar, Benjamin P Lüscher, Zengyou Ye, Woo Young Chung, Ava Movahed Abtahi, Changyu Zheng, Min Goo Lee, Árpád Varga, Petra Pallagi, József Maléth, Malini Ahuja, Shmuel Muallem.

  Endoplasmic reticulum/plasma membrane (ER/PM) junctions are a major site of cellular signal transduction including in epithelia; however, whether their lipid membrane environment affects junctional ion transporters function remains unclear. Here, we show that epithelial secretion is governed by phosphatidylserine (PtdSer) levels in ER/PM nanodomains, specified by the antagonistic action of the lipid transfer proteins E-Syt3 and ORP5, which transduce cAMP signals to the chloride channel CFTR and activate the sodium-bicarbonate cotransporter NBCe1-B by IRBIT. Lipid transfer by E-Syt3, along with restricted plasma membrane localization by the E-Syt3 C2C domain, are essential for E-Syt3 function, as removal of PtdSer from junctions by E-Syt3 dissociated the cAMP signaling pathway complex, preventing CFTR activation, and prevented NBCe1-B activation by IRBIT. CFTR and NBCe1-B PtdSer sensor domains responded to PtdSer reduction by E-Syt3; which was reversed by exogenous PtdSer or by PtdSer supplied by ORP5. In mice, E-Syt3 depletion improved chloride flux and fluid secretion in salivary glands and isolated pancreatic ducts. These findings provide a framework for understanding the role of junctional lipids in the assembly of functional ion protein complexes and cellular communication at epithelial signaling hubs.

Keywords:  CFTR/NBCe1-B; E-Syt3/ORP5; Junctional Phosphatidylserine; Regulation

DOI:  https://doi.org/10.1038/s44318-025-00470-9