bims-mecosi 2025-04-13 papers

bims-mecosi

Biomed News

on Membrane contact sites

Issue of 2025–04–13
eleven papers selected by
Verena Kohler, Umeå University

Improving mitochondria-associated endoplasmic reticulum membranes integrity as converging therapeutic strategy for rare neurodegenerative diseases and cancer.
MIRO1 Is Required for Dynamic Increases in Mitochondria-ER Contact Sites and Mitochondrial ATP During the Cell Cycle.
Biophysical characterization of anion channels in Mitochondrion-Endoplasmic-Reticulum Contact sites (MERCs).
CNPY2 Aggravates Renal Tubular Cell Ferroptosis in Diabetic Nephropathy by Regulating PERK/ATF4/CHAC1 Pathway and MAM Integrity.
Decoding ischemic stroke: Perspectives on the endoplasmic reticulum, mitochondria, and their crosstalk.
PERK's novel agonist protects against myocardial ischemia-reperfusion injury by modulating ER-mitochondria contacts and phosphatidic acid transport.
The ACBD3 protein coordinates ER-Golgi contacts to enable productive TBEV infection.
PITPβ promotes COPI vesicle fission through lipid transfer and membrane contact formation.
A novel membrane contact site in vestibular hair cells.
Tumor acidosis supports cancer cell lipid uptake via a rapid, transporter-independent mechanism.
Diallyl Trisulfide From Garlic Regulates RAB18 Phase Separation to Inhibit Lipophagy and Induce Cuproptosis in Hepatic Stellate Cells for Antifibrotic Effects.

Biochim Biophys Acta Mol Cell Res. 2025 Apr 09. pii: S0167-4889(25)00059-X. [Epub ahead of print] 119954

Improving mitochondria-associated endoplasmic reticulum membranes integrity as converging therapeutic strategy for rare neurodegenerative diseases and cancer.

Michal Cagalinec, Mohd Adnan, Silvia Borecka, Geert Bultynck, Vinay Choubey, Shira Yanovsky-Dagan, Shlomit Ezer, Daniela Gasperikova, Tamar Harel, Dana Jurkovicova, Allen Kaasik, Jean-Charles Liévens, Tangui Maurice, Marco Peviani, Elodie Marie Richard, Jan Skoda, Martina Skopkova, Pauline Tarot, Robbe Van Gorp, Liga Zvejniece, Benjamin Delprat.

  Membrane contact sites harbor a distinct set of proteins with varying biological functions, thereby emerging as hubs for localized signaling nanodomains underlying adequate cell function. Here, we will focus on mitochondria-associated endoplasmic reticulum membranes (MAMs), which serve as hotspots for Ca2+ signaling, redox regulation, lipid exchange, mitochondrial quality and unfolded protein response pathway. A network of MAM-resident proteins contributes to the structural integrity and adequate function of MAMs. Beyond endoplasmic reticulum (ER)-mitochondrial tethering proteins, MAMs contain several multi-protein complexes that mediate the transfer of or are influenced by Ca2+, reactive oxygen species and lipids. Particularly, IP3 receptors, intracellular Ca2+-release channels, and Sigma-1 receptors (S1Rs), ligand-operated chaperones, serve as important platforms that recruit different accessory proteins and intersect with these local signaling processes. Furthermore, many of these proteins are directly implicated in pathophysiological conditions, where their dysregulation or mutation is not only causing diseases such as cancer and neurodegeneration, but also rare genetic diseases, for example familial Parkinson's disease (PINK1, Parkin, DJ-1), familial Amyotrophic lateral sclerosis (TDP43), Wolfram syndrome1/2 (WFS1 and CISD2), Harel-Yoon syndrome (ATAD3A). In this review, we will discuss the current state-of-the-art regarding the molecular components, protein platforms and signaling networks underlying MAM integrity and function in cell function and how their dysregulation impacts MAMs, thereby driving pathogenesis and/or impacting disease burden. We will highlight how these insights can generate novel, potentially therapeutically relevant, strategies to tackle disease outcomes by improving the integrity of MAMs and the signaling processes occurring at these membrane contact sites.

Keywords:  ATAD3A related disorders; Amyotrophic lateral sclerosis; Calcium signaling; Endoplasmic reticulum stress; Familial Parkinson's disease; Harel-Yoon syndrome; Metabolomics; Mitochondria quality control; Mitochondria-associated endoplasmic reticulum membranes; Rare neurodegenerative diseases; Wolfram syndrome; cancer

DOI:  https://doi.org/10.1016/j.bbamcr.2025.119954
Cells. 2025 Mar 22. pii: 482. [Epub ahead of print]14(7):

MIRO1 Is Required for Dynamic Increases in Mitochondria-ER Contact Sites and Mitochondrial ATP During the Cell Cycle.

Benney T Endoni, Olha M Koval, Chantal Allamargot, Tara Kortlever, Lan Qian, Riley J Sadoski, Denise Juhr, Isabella M Grumbach.

  Mitochondria-ER contact sites (MERCS) are vital for mitochondrial dynamics, lipid exchange, Ca2+ homeostasis, and energy metabolism. We examined whether mitochondrial metabolism changes during the cell cycle depend on MERCS dynamics and are regulated by the outer mitochondrial protein mitochondrial rho GTPase 1 (MIRO1). Wound healing was assessed in mice with fibroblast-specific deletion of MIRO1. Wild-type and MIRO1-/- fibroblasts and vascular smooth muscle cells were evaluated for proliferation, cell cycle progression, number of MERCS, distance, and protein composition throughout the cell cycle. Restoration of MIRO1 mutants was used to test the role of MIRO1 domains; Ca2+ transients and mitochondrial metabolism were evaluated using biochemical, immunodetection, and fluorescence techniques. MERCS increased in number during G1/S compared with during G0, which was accompanied by a notable rise in protein-protein interactions involving VDAC1 and IP3R as well as GRP75 and MIRO1 by proximity-ligation assays. Split-GFP ER/mitochondrial contacts of 40 nm also increased. Mitochondrial Ca2+ concentration ([Ca2+]), membrane potential, and ATP levels correlated with the formation of MERCS during the cell cycle. MIRO1 deficiency blocked G1/S progression and the cell-cycle-dependent formation of MERCS and altered ER Ca2+ release and mitochondrial Ca2+ uptake. MIRO1 mutants lacking the Ca2+-sensitive EF hands or the transmembrane domain did not rescue cell proliferation or the formation of MERCS. MIRO1 controls an increase in the number of MERCS during cell cycle progression and increases mitochondrial [Ca2+], driving metabolic activity and proliferation through its EF hands.

Keywords:  Ca2+; ER; MAM; MERCS; MIRO1; cell cycle; fibroblasts; mitochondria; vascular smooth muscle cells

DOI:  https://doi.org/10.3390/cells14070482
Biophys J. 2025 Apr 04. pii: S0006-3495(25)00214-0. [Epub ahead of print]

Biophysical characterization of anion channels in Mitochondrion-Endoplasmic-Reticulum Contact sites (MERCs).

Shridhar Kiran Sanghvi, Denis Gabrilovich, Satish K Raut, Ajay Gopalan, Aryan Singh, Harmeet Rireika Bhachu, Mayukha Dyta, Veronica Loyo-Celis, Jenna Thuma, Devasena Ponnalagu, Jonathan Davis, Shubha Gururaja Rao, Harpreet Singh.

  The mitochondrion-endoplasmic reticulum (ER) contact sites (MERCs, also known as mitochondrial-associated membranes (MAMs)) are specialized regions of the endoplasmic reticulum that are in close proximity to the mitochondrion. These organelle structures play essential roles in a variety of processes, such as calcium signaling, lipid metabolism, renin-angiotensin-aldosterone system control, the unfolded protein response, and autophagy. MERCs are known to actively participate in ion transport between the ER and mitochondria. Although active calcium channels in MERCs have been detected, limited studies have been carried out to identify or characterize functional anion channels. Here, we tested whether functional anion channels are present in MERCs. We isolated MERCs from mouse organs (heart and brain) and reconstituted them in planar bilayers. The single-channel properties were recorded in the presence of various anion channel blockers or antagonists (IAA-94, DIDS, A9C, and NPPB). We corroborated the presence of anion channels targeted by these drugs using immunoblotting and immunocytochemistry. Biochemical analysis and immunocytochemistry corroborate that CLIC4, CLIC3, and VDACs are present in MERCs. Our results indicate that anion channels are active in MERCs, which could play a pertinent role in intracellular organelle communication.

Keywords:  Mitochondria-Endoplasmic-Reticulum (ER) Contact sites (MERCs); anion channels; cardiomyocytes; electrophysiology; mitochondrial-associated membranes

DOI:  https://doi.org/10.1016/j.bpj.2025.04.002
Adv Sci (Weinh). 2025 Apr 11. e2416441

CNPY2 Aggravates Renal Tubular Cell Ferroptosis in Diabetic Nephropathy by Regulating PERK/ATF4/CHAC1 Pathway and MAM Integrity.

Jingfang Chen, Dongwei Liu, Lei Lei, Ting Liu, Shaokang Pan, Hui Wang, Yong Liu, Yingjin Qiao, Zhangsuo Liu, Qi Feng.

  Ferroptosis is emerging as a novel mechanism for understanding renal tubular injury in diabetic nephropathy (DN). The mitochondria-associated endoplasmic reticulum membrane (MAM) plays a crucial role in the regulation of numerous cellular processes, including mitochondrial dysfunction and endoplasmic reticulum (ER) stress (ERS). However, the exact mechanism underlying ferroptosis and MAM in DN remains unclear. In this study, we identified that canopy FGF signaling regulator 2 (CNPY2) is upregulated in the renal tubules of DN. Downregulation of CNPY2 alleviated ferroptosis and improved MAM integrity in the renal tubular epithelial cells of db/db mice. Conversely, CNPY2 overexpression aggravated tubular injury in DN by accelerating ferroptosis and disrupting MAM formation. Mechanistically, CNPY2 activated the PERK/ATF4/CHAC1 signaling pathway to facilitate ferroptosis, thus contributing to tubular injury in DN. These findings highlight the critical role of CNPY2 in modulating ferroptosis and MAM formation in DN progression, and suggest that CNPY2 is a feasible therapeutic target for DN.

Keywords:  canopy FGF signaling regulator 2 (CNPY2); diabetic nephropathy; endoplasmic reticulum (ER) stress; ferroptosis; mitochondria‐associated endoplasmic reticulum membrane (MAM)

DOI:  https://doi.org/10.1002/advs.202416441
Redox Biol. 2025 Mar 27. pii: S2213-2317(25)00135-1. [Epub ahead of print]82 103622

Decoding ischemic stroke: Perspectives on the endoplasmic reticulum, mitochondria, and their crosstalk.

Chuxin Zhang, Xin Lan, Qingguo Wang, Yuxiao Zheng, Jialin Cheng, Jinhua Han, Changxiang Li, Fafeng Cheng, Xueqian Wang.

  Stroke is known for its high disability and mortality rates. Ischemic stroke (IS), the most prevalent form, imposes a considerable burden on affected individuals. Nevertheless, existing treatment modalities are hindered by limitations, including narrow therapeutic windows, substantial adverse effects, and suboptimal neurological recovery. Clarifying the pathological mechanism of IS is a prerequisite for developing new therapeutic strategies. In this context, the functional disruption of mitochondria, the endoplasmic reticulum (ER), and the crosstalk mechanisms between them have garnered increasing attention for their contributory roles in the progression of IS. Therefore, this review provides a comprehensive summary of the current pathomechanisms associated with the involvement of the ER and mitochondria in IS, emphasising Ca2+ destabilization homeostasis, ER stress, oxidative stress, disordered mitochondrial quality control, and mitochondrial transfer. Additionally, this article highlights the functional interaction between the ER and mitochondria, as well as the mitochondrial-ER contacts (MERCs) that structurally connect mitochondria and the ER, aiming to provide ideas and references for the research and treatment of IS.

Keywords:  Endoplasmic reticulum; Ischemic stroke; Mitochondria; Mitochondria and endoplasmic reticulum contacts; Oxidative stress

DOI:  https://doi.org/10.1016/j.redox.2025.103622
Int J Cardiol. 2025 Apr 04. pii: S0167-5273(25)00265-7. [Epub ahead of print] 133222

PERK's novel agonist protects against myocardial ischemia-reperfusion injury by modulating ER-mitochondria contacts and phosphatidic acid transport.

Zeyu Li, Suiqing Huang, Huayang Li, Quan Liu, Jing Lu, Peiqing Liu, Zhongkai Wu.

  The role of PERK in maintaining the homeostasis of MAM is believed to exert a significant impact on mitochondrial energy metabolism and structural morphology. However, there exists controversy regarding the therapeutic effect of PERK activation on ischemia-reperfusion injury. We have discovered a novel agonist for PERK named ZY341. ZY341 interacts with the active pocket of PERK through π-π stacking interactions, and surface plasmon resonance experiments have confirmed its exceptional potency as an agonist with a Kd value of 17.5 μM. This study provides initial evidence that ZY341 exhibits potent activity as a PERK agonist, effectively activating the PERK/eIF2α pathway in a mouse model of ischemia-reperfusion and demonstrating significant anti-apoptotic effects on cardiomyocytes. Ischemia-reperfusion not only induces cardiomyocyte apoptosis but also leads to substantial increases in MAM-mediated mitochondrial calcium overload, resulting in severe damage to mitochondrial structure and function. ZY341 significantly protects cardiac myocytes' respiratory capacity and improves heart function. Mechanistically, through PERK activation, ZY341 inhibits abnormal binding between VAPB-PTPIP51 complex in OGD/R models, regulates MAM-mediated calcium ion and phosphatidic acid transport homeostasis, suppresses mitochondrial fragmentation thereby significantly enhancing cardiac function. In conclusion, this study unveils new avenues for targeting PERK as a therapeutic strategy for myocardial ischemia-reperfusion treatment.

Keywords:  ER stress; Mitochondria; Mitochondria-associated membranes; Myocardial ischemia/reperfusion; PERK

DOI:  https://doi.org/10.1016/j.ijcard.2025.133222
J Virol. 2025 Apr 10. e0222424

The ACBD3 protein coordinates ER-Golgi contacts to enable productive TBEV infection.

Wai-Lok Yau, Marie B A Peters, Sebastian Rönfeldt, Marie N Sorin, Richard Lindqvist, Lauri I A Pulkkinen, Lars-Anders Carlson, Anna K Överby, Richard Lundmark.

  Flavivirus infection involves extensive remodeling of the endoplasmic reticulum (ER), which is key to both the replication of the viral RNA genome as well as the assembly and release of new virions. However, little is known about how viral proteins and host factors cooperatively facilitate such a vast transformation of the ER, and how this influences the different steps of the viral life cycle. In this study, we screened for host proteins that were enriched in close proximity to the tick-borne encephalitis virus (TBEV) protein NS4B and found that the top candidates were coupled to trafficking between ER exit sites (ERES) and the Golgi. We characterized the role of ACBD3, one of the identified proteins, and showed that it promotes TBEV infection. Depletion of ACBD3 inhibited virus replication and resulted in abnormal transformation of the ER, leading to reduced virion release. ACBD3's proviral mechanism did not involve the recruitment of PI4PK as previously described for enteroviruses. Instead, productive TBEV infection required the full-length ACBD3, which localizes to ER-Golgi contact sites together with NS4B. We propose that NS4B and ACBD3 promote replication by coordinating the transformation of the ER, which is required for RNA replication and particle release. The transformation involves direct coupling to the Golgi which facilitates efficient virion transport.
IMPORTANCE: Flaviviruses like tick-borne encephalitis have significant effects on human health. During flavivirus infection, the viral particles enter the host cells and transform the endoplasmic reticulum (ER), which is a membranous organelle and the main site of cellular protein synthesis. Although this is critical for successful infection, the details of the process are unknown. Here, we found that the viral protein NS4B and the host protein ACBD facilitate this transformation by ensuring that the ER is coupled to the Golgi apparatus, the organelle responsible for transporting material out of the cell. TBEV uses ACBD3 to guarantee that the connection sites between the transformed ER and the Golgi remain functional so that RNA is replicated and the produced viral particles are exported from the cell and can infect further cells. Our work sheds light both on the basic biology of flavivirus infection, and virus-induced remodeling of membranous organelles.

Keywords:  ACBD3; ER exit sites; ERES-Golgi contact; NS4B; Orthoflavivirus; flavivirus; host-pathogen interaction; replication organelles

DOI:  https://doi.org/10.1128/jvi.02224-24
J Cell Biol. 2025 May 05. pii: e202407166. [Epub ahead of print]224(5):

PITPβ promotes COPI vesicle fission through lipid transfer and membrane contact formation.

Kunyou Park, Sungeun Ju, Hyewon Choi, Peng Gao, Geul Bang, Jung Hoon Choi, Jiwon Jang, Andrew J Morris, Byung-Ho Kang, Victor W Hsu, Seung-Yeol Park.

Intracellular transport among organellar compartments occurs in two general ways: by membrane-bound carriers and membrane contacts. Specific circumstances that involve the coordination of these two modes of transport remain to be defined. By studying coat protein I (COPI) transport, we find that phosphatidylcholine with short acyl chains (sPC) is delivered through membrane contact from the endoplasmic reticulum (ER) to sites of COPI vesicle formation at the Golgi to support the fission stage. Phosphatidylinositol transfer protein beta (PITPβ) plays a key role in this process, with the elucidation of this role shedding new insights into how PITPβ acts, providing a mechanistic understanding of a specific circumstance when vesicular transport requires membrane contact and contributing to the general understanding of how intracellular transport carriers are formed.

DOI: https://doi.org/10.1083/jcb.202407166
bioRxiv. 2025 Mar 24. pii: 2025.03.21.644540. [Epub ahead of print]

A novel membrane contact site in vestibular hair cells.

Nicolas Brouilly, Nathalie Pujol, Fabrice Richard, Chantal Cazevieille, Jennifer Stone, Ruth Anne Eatock, Rémy Pujol.

The mammalian vestibular system has two types of sensory receptor hair cells (HCs), each with different neurotransmission mechanisms. Type II HCs use ribbon synapses to transmit neurotransmitters like glutamate to afferent neurons. On the other hand, type I HCs are nearly engulfed by a calyceal afferent ending and also form ribbon synapses. These HCs regulate afferent activity through non-quantal transmission (NQT), which is faster than classic neurotransmitter release and may play a key role in stabilizing vision and balance during rapid head movements. Here, we describe a novel striated contact, present between the mouse type I HC and its calyceal afferent ending, and intimately associated with atypical plasma membrane-apposed (PMA) mitochondria. This distinctive arrangement has the potential to serve or modulate NQT.

DOI: https://doi.org/10.1101/2025.03.21.644540
J Cell Sci. 2025 Apr 07. pii: jcs.263688. [Epub ahead of print]

Tumor acidosis supports cancer cell lipid uptake via a rapid, transporter-independent mechanism.

Marc Severin, Rikke K Hansen, Michala G Rolver, Tove Hels, Kenji Maeda, Luis A Pardo, Stine F Pedersen.

  Tumor acidosis alters cancer cell metabolism and favors aggressive disease progression. Cancer cells in acidic environments increase lipid droplet (LD) accumulation and oxidative phosphorylation, characteristics of aggressive cancers. Here, we use live imaging, shotgun lipidomics, and immunofluorescence analyses of mammary and pancreatic cancer cells to demonstrate that both acute acidosis and adaptation to acidic growth drive rapid uptake of fatty acids (FA), which are converted to triacylglycerols (TAG) and stored in LDs. Consistent with its independence of de novo synthesis, TAG- and LD accumulation in acid-adapted cells is unaffected by FA-synthetase inhibitors. Macropinocytosis, which is upregulated in acid-adapted cells, partially contributes to FA uptake, which is independent of other protein-facilitated lipid uptake mechanisms, including CD36, FATP2, and caveolin- and clathrin-dependent endocytosis. We propose that a major mechanism by which tumor acidosis drives FA uptake is through neutralizing protonation of negatively charged FAs allowing their diffusive, transporter-independent uptake. We suggest that this could be a major factor triggering acidosis-driven metabolic rewiring.

Keywords:  CD36; FASN; Lipid diffusion; Macropinocytosis; Membrane contact sites; Protonation

DOI:  https://doi.org/10.1242/jcs.263688
Adv Sci (Weinh). 2025 Apr 11. e2415325

Diallyl Trisulfide From Garlic Regulates RAB18 Phase Separation to Inhibit Lipophagy and Induce Cuproptosis in Hepatic Stellate Cells for Antifibrotic Effects.

Haoyuan Tian, Shujiang Sun, Xinran Qiu, Junrui Wang, Yuanyuan Gao, Jianmei Chen, Xiang Han, Zhengyang Bao, Xiaohan Guo, Yuqi Sun, Yuxin Lin, Mengru Hu, Feng Zhang, Zili Zhang, Feixia Wang, Shizhong Zheng, Jiangjuan Shao.

  Liver fibrosis, a common pathological process, severely impacts human health, yet effective treatments are lacking. Cuproptosis, a newly discovered form of cell death induced by copper ions, triggers cytotoxic stress through sulfenylated protein oligomerization and may offer a novel therapeutic strategy for liver fibrosis. However, the mechanisms underlying cuproptosis in liver fibrosis are not well understood. During liver fibrosis progression, hepatic stellate cells (HSCs) activate, proliferate, and secrete extracellular matrix components, contributing to fibrosis. Activated HSCs also undergo lipophagy, the degradation of lipid droplets. The study shows that Ras-related protein Rab-18 (RAB18), a protein involved in lipid metabolism, inhibits lipophagy, upregulates Carnitine palmitoyltransferase 1A (CPT1A), and promotes succinylation of dihydrolipoamide dehydrogenase (DLD) at site K320, triggering cuproptosis in HSCs. Diallyl trisulfides (DATs), a garlic-derived compound, induces phase separation of RAB18 and promotes mitochondrial-associated membrane structures (MAMs) formation, further accelerating RAB18 phase separation. DATs selectively protects hepatocytes while activating cuproptosis in HSCs. Interfering with RAB18 expression reverses the DATs-induced inhibition of lipophagy and cuproptosis. These findings, confirmed in primary cells, human liver stellate cells (LX2), rodent models and clinical samples, suggest that DATs, by targeting RAB18 and inducing its phase separation, subsequently inhibit lipophagy and promote cuproptosis, making it a promising therapeutic approach for liver fibrosis.

Keywords:  RAB18; cuproptosis; diallyl trisulfide; hepatic stellate cells (HSCs); lipophagy; phase separation

DOI:  https://doi.org/10.1002/advs.202415325