bims-mecosi 2025-03-02 papers

bims-mecosi

Biomed News

on Membrane contact sites

Issue of 2025–03–02
ten papers selected by
Verena Kohler, Umeå University

Hoi1 targets the yeast BLTP2 protein to ER-PM contact sites to regulate lipid homeostasis.
Lysosome-Mitochondrial Crosstalk in Cellular Stress and Disease.
ER-mitochondria contact sites: a refuge for mitochondrial mRNAs under ER stress.
The role of Nir2, a lipid-transfer protein, in regulating endothelial cell functions.
RH3 enhances antiviral defense by facilitating small RNA loading into Argonaute 2 at endoplasmic reticulum-chloroplast membrane contact sites.
"Trafficking Disorders: Phenotypical Similarities and Differences With Other IMDs".
Editorial on Special Collection in Contact: Lipid Transfer Proteins: From Molecular Mechanisms to Functional Validation.
Stbd1 stimulates AMPK signaling and alleviates insulin resistance in an in vitro hepatocyte model.
The HOPS and vCLAMP protein Vam6 connects polyphosphate with mitochondrial function and oxidative stress resistance in Cryptococcus neoformans.
Sigma-1 receptor activation attenuates DOX-induced cardiotoxicity by alleviating endoplasmic reticulum stress and mitochondrial calcium overload via PERK and IP3R-VDAC1-MCU signaling pathways.

bioRxiv. 2025 Feb 19. pii: 2025.02.11.637747. [Epub ahead of print]

Hoi1 targets the yeast BLTP2 protein to ER-PM contact sites to regulate lipid homeostasis.

Samantha K Dziurdzik, Vaishnavi Sridhar, Hailey Eng, Sarah D Neuman, Junran Yan, Michael Davey, Stefan Taubert, Arash Bashirullah, Elizabeth Conibear.

Membrane contact sites between organelles are important for maintaining cellular lipid homeostasis. Members of the recently identified family of bridge-like lipid transfer proteins (BLTPs) span opposing membranes at these contact sites to enable the rapid transfer of bulk lipids between organelles. While the VPS13 and ATG2 family members use organelle-specific adaptors for membrane targeting, the mechanisms that regulate other bridge-like transporters remain unknown. Here, we identify the conserved protein Ybl086c, which we name Hoi1 (Hob interactor 1), as an adaptor that targets the yeast BLTP2-like proteins Fmp27/Hob1 and Hob2 to ER-PM contact sites. Two separate Hoi1 domains interface with alpha-helical projections that decorate the central hydrophobic channel on Fmp27, and loss of these interactions disrupts cellular sterol homeostasis. The mutant phenotypes of BLTP2 and HOI1 orthologs indicate these proteins act in a shared pathway in worms and flies. Together, this suggests that Hoi1-mediated recruitment of BLTP2-like proteins represents an evolutionarily conserved mechanism for regulating lipid transport at membrane contact sites.

DOI: https://doi.org/10.1101/2025.02.11.637747
Antioxidants (Basel). 2025 Jan 22. pii: 125. [Epub ahead of print]14(2):

Lysosome-Mitochondrial Crosstalk in Cellular Stress and Disease.

Szilvia Kiraly, Jack Stanley, Emily R Eden.

  The perception of lysosomes and mitochondria as entirely separate and independent entities that degrade material and produce ATP, respectively, has been challenged in recent years as not only more complex roles for both organelles, but also an unanticipated level of interdependence are being uncovered. Coupled lysosome and mitochondrial function and dysfunction involve complex crosstalk between the two organelles which goes beyond mitochondrial quality control and lysosome-mediated clearance of damaged mitochondria through mitophagy. Our understanding of crosstalk between these two essential metabolic organelles has been transformed by major advances in the field of membrane contact sites biology. We now know that membrane contact sites between lysosomes and mitochondria play central roles in inter-organelle communication. This importance of mitochondria-lysosome contacts (MLCs) in cellular homeostasis, evinced by the growing number of diseases that have been associated with their dysregulation, is starting to be appreciated. How MLCs are regulated and how their coordination with other pathways of lysosome-mitochondria crosstalk is achieved are the subjects of ongoing scrutiny, but this review explores the current understanding of the complex crosstalk governing the function of the two organelles and its impact on cellular stress and disease.

Keywords:  crosstalk; lysosomes; membrane contact sites; mitochondria

DOI:  https://doi.org/10.3390/antiox14020125
Trends Cell Biol. 2025 Feb 25. pii: S0962-8924(25)00036-4. [Epub ahead of print]

ER-mitochondria contact sites: a refuge for mitochondrial mRNAs under ER stress.

Philippe Pihán, Lisa M Ellerby, Claudio Hetz.

  Tight mitochondria-endoplasmic reticulum (ER) contacts (MERCS) play essential roles in cellular homeostasis. Brar et al. reveal a novel mechanism where mitochondrial mRNAs escape global translational repression at novel context-specific MERCS during ER stress, uncovering spatially regulated translation as a critical adaptive strategy to cope with cellular stress.

Keywords:  ATAD3A; PERK; endoplasmic reticulum stress; mitochondria–ER contact sites (MERCS); spatial translation regulation

DOI:  https://doi.org/10.1016/j.tcb.2025.02.002
Biochim Biophys Acta Mol Cell Res. 2025 Feb 25. pii: S0167-4889(25)00031-X. [Epub ahead of print]1872(3): 119926

The role of Nir2, a lipid-transfer protein, in regulating endothelial cell functions.

Zydrune Polianskyte-Prause, Amita Arora, Juuso H Taskinen, Vaishali Chaurasiya, Salla Keskitalo, Antti Tuhkala, Ida Hilska, Markku Varjosalo, Vesa M Olkkonen.

  Lipid transfer proteins regulate the metabolism of phosphoinositides with key roles in cell signaling, membrane and actin dynamics, intracellular trafficking, and diseases. Nir2/PITPNM1 acts as a cellular phosphatidylinositol/phosphatidic acid (PI/PA) exchanger that maintains phosphoinositide signaling at the plasma membrane (PM) and endoplasmic reticulum (ER) membrane contact sites. Here, we assessed the function of Nir2 in human umbilical vein endothelial cells (HUVECs), by analyzing the impacts of Nir2 knockdown (KD) on angiogenesis in vitro, cell viability, proliferation, migration, actin cytoskeletal regulation and vascular endothelial growth factor (VEGF)-mediated downstream cellular signaling pathways. We show that Nir2 KD inhibits angiogenic tube formation in HUVECs, reduces cell viability, proliferation and migration, as well as diminishes actin stress fibers, while Nir2 overexpression increases cell viability and overexpression of an shRNA-resistant Nir2 construct rescues it. Nir2 KD results in decreased activity of AKT and ERK signaling pathways upon VEGF stimulus, plausibly underlying the observed defects in proliferation, migration and angiogenesis. In addition, our interactome analysis confirmed an interaction of Nir2 with the membrane contact site organizer VAPA (vesicle-associated membrane protein-associated protein A), validated by co-immunoprecipitation and co-localization analyses. VAPA KD inhibited angiogenesis similar to that of Nir2, and double KD of the two tended to have even stronger inhibitory effect. A number of other tentative partners of Nir2 were detected; according to STRING analysis, these likely represent indirect interactions driven by a complex with VAPA. The present findings unravel new avenues to understanding the molecular mechanisms by which Nir2 regulates key endothelial functions such as angiogenesis.

Keywords:  AKT/ERK signaling; Angiogenesis; Endothelial cell proliferation; Interactome; Migration; Nir2

DOI:  https://doi.org/10.1016/j.bbamcr.2025.119926
Nat Commun. 2025 Feb 25. 16(1): 1953

RH3 enhances antiviral defense by facilitating small RNA loading into Argonaute 2 at endoplasmic reticulum-chloroplast membrane contact sites.

Juan Huang, Juan Du, Yan Liu, Lu Lu, Yanzhuo Xu, Jianfei Shi, Qing Liu, Qi Li, Yang Liu, Yaqiu Chen, Meng Du, Yiming Zhao, Liangxiao Huo, Weiran Wang, Chenxi Ding, Liya Wei, Jianguo Wu, Yao-Wu Yuan, Jinfeng Chen, Ruixi Li, Feng Cui, Xiaoming Zhang.

While RNA silencing is crucial for plant resistance against viruses, the cellular connections between RNA silencing and antiviral responses in plants remain poorly understood. In this study, we aim to investigate this relationship by examining the subcellular localization of small RNA loading and viral replication in Arabidopsis. Our findings reveal that Argonaute 2 (AGO2), a key component of RNA silencing, loads small RNAs at the endoplasmic reticulum (ER)-chloroplast membrane contact sites (MCSs). We identify a chloroplast-localized protein, RNA helicase 3 (RH3), which interacts with AGO2 and facilitates the loading of small RNAs into AGO2 at these MCSs. Furthermore, we discover that MCSs serve as replication sites for certain plant viruses. RH3 also promotes the loading of viral-derived small RNAs into AGO2, thereby enhancing plant antiviral resistance. Overall, our study sheds light on the roles of RH3 in RNA silencing and plant antiviral defenses, providing valuable insights into the cytobiological connections between RNA silencing, viral replication, and antiviral immunity.

DOI: https://doi.org/10.1038/s41467-025-57296-6
J Inherit Metab Dis. 2025 Mar;48(2): e70004

"Trafficking Disorders: Phenotypical Similarities and Differences With Other IMDs".

Ángeles García-Cazorla, Eva Morava, Jean-Marie Saudubray.

  Cell trafficking disorders (CTD) are genetic defects in complex molecules and correspond to the largest category of IEM with mutations in more than 370 genes described. They are still poorly recognized as a global entity but rather seen as isolated rare diseases by non-metabolic specialists. Complex lipid metabolism (mostly phospholipids, sphingolipids, and non-mitochondrial fatty acids) is tightly associated with cell trafficking and interactions between organelles at the membrane contact sites. Accordingly, from a clinical point of view CTD presents with multisystem manifestations that may overlap and mimic mitochondrial and other complex molecule disorders such as peroxisomal, lysosomal defects, CDG, or autophagy disorders. The nervous system is especially vulnerable and neurological presentations are prominent, but CTD targets any organ at any age. Interestingly the involvement of the immune system is particularly characteristic of CTD and rarely (or at least little described so far) in other categories of IEM. Most CTD are progressive disorders, except for CDG. They may have "metabolic crises" mimicking disorders of intermediary and energy metabolism for which emergency protocols have been developed. They are generally diagnosed by exome sequencing. Relatively few biomarkers are available.

Keywords:  cell trafficking disorders; haematological symptoms; immune symptoms; lipid metabolism; multisystem symptoms; neurodegeneration; neurodevelopment

DOI:  https://doi.org/10.1002/jimd.70004
Contact (Thousand Oaks). 2025 Jan-Dec;8:8 25152564251322628

Editorial on Special Collection in Contact: Lipid Transfer Proteins: From Molecular Mechanisms to Functional Validation.

Bruno Mesmin.

DOI: https://doi.org/10.1177/25152564251322628
FEBS J. 2025 Feb 25.

Stbd1 stimulates AMPK signaling and alleviates insulin resistance in an in vitro hepatocyte model.

Andria Theodoulou, Thilo Speckmann, Louiza Potamiti, Otto Baba, Tsuyoshi Morita, Anthi Drousiotou, Mihalis I Panayiotidis, Annette Schürmann, Petros P Petrou.

  Starch-binding domain-containing protein 1 (Stbd1) is a glycogen-binding protein which localizes to the endoplasmic reticulum (ER) membrane and ER-mitochondria contact sites (ERMCs). The protein undergoes N-myristoylation, which is a major determinant of its subcellular targeting. Stbd1 has been implicated in the control of glucose homeostasis, as evidenced by the finding that mice with targeted inactivation of Stbd1 display insulin resistance associated with increased ERMCs in the liver. In the present study, we addressed the effects of increased Stbd1 expression levels on insulin signaling. We show that Stbd1 overexpression enhances cellular sensitivity to insulin and improves insulin resistance in an in vitro hepatocyte cell model. We further demonstrate that increased Stbd1 expression levels are associated with enhanced activation of the AMP-activated protein kinase (AMPK), which is a central regulator of metabolism and an attractive therapeutic target for metabolic disorders related to insulin resistance, such as type 2 diabetes (T2D). The activation of AMPK signaling and the improved cellular response to insulin induced by Stbd1 overexpression occurred independently of N-myristoylation and associated changes in the number of ERMCs, glycogen levels, mitochondrial calcium, mitochondrial morphology, and respiratory function. Collectively, our findings uncover a new level of interaction between Stbd1 and AMPK, with Stbd1 acting as an upstream activator of AMPK signaling. Given that first-line drug treatments for insulin resistance and T2D are known activators of the AMPK pathway, these findings may provide a new perspective for the development of more effective therapeutic strategies.

Keywords:  AMPK; N‐myristoylation; Stbd1; glycogen; insulin resistance

DOI:  https://doi.org/10.1111/febs.70040
mBio. 2025 Feb 25. e0032825

The HOPS and vCLAMP protein Vam6 connects polyphosphate with mitochondrial function and oxidative stress resistance in Cryptococcus neoformans.

Eddy Sánchez-León, Kabir Bhalla, Guanggan Hu, Christopher W J Lee, Melissa Lagace, Won Hee Jung, James W Kronstad.

  Cryptococcus neoformans is considered one of the most dangerous fungal threats to human health, and the World Health Organization recently ranked it in the critical priority group for perceived public health importance. Proliferation of C. neoformans within mammalian hosts is supported by its ability to overcome nutritional limitations and endure stress conditions induced by the host immune response. Previously, we reported that the Vam6/Vps39/TRAP1-domain protein Vam6 was crucial for vacuolar morphology, iron acquisition, and virulence. However, the molecular mechanisms underlying the pleiotropic phenotypes resulting from loss of Vam6 remain poorly understood. In this study, we determined that Vam6 has roles in the HOPS complex for endomembrane trafficking to the vacuole and in the vCLAMP membrane contact site between the vacuole and mitochondria. Importantly, both of these roles regulate polyphosphate (polyP) metabolism, as demonstrated by a defect in trafficking of the VTC complex subunit Vtc2 for polyphosphate synthesis and by an influence on mitochondrial functions. In the latter case, Vam6 was required for polyP accumulation in response to electron transport chain inhibition and for overcoming oxidative stress. Overall, this work establishes connections between endomembrane trafficking, mitochondrial functions, and polyP homeostasis in C. neoformans.IMPORTANCEA detailed understanding of stress resistance by fungal pathogens of humans may provide new opportunities to improve antifungal therapy and combat life-threatening diseases. Here, we used a vam6 deletion mutant to investigate the role of the homotypic fusion and vacuole protein sorting (HOPS) complex in mitochondrial functions and polyphosphate homeostasis in Cryptococcus neoformans, an important fungal pathogen of immunocompromised people including those suffering from HIV/AIDS. Specifically, we made use of mutants defective in late endocytic trafficking steps to establish connections to oxidative stress and membrane trafficking with mitochondria. In particular, we found that mutants lacking the Vam6 protein had altered mitochondrial function, and that the mutants were perturbed for additional mitochondria and vacuole-related phenotypes (e.g., membrane composition, polyphosphate accumulation, and drug sensitivity). Overall, our study establishes connections between endomembrane trafficking components, mitochondrial functions, and polyphosphate homeostasis in an important fungal pathogen of humans.

Keywords:  Vam6; Vtc2; mitochondria; oxidative stress; polyphosphate; vacuole

DOI:  https://doi.org/10.1128/mbio.00328-25
Biol Direct. 2025 Feb 25. 20(1): 23

Sigma-1 receptor activation attenuates DOX-induced cardiotoxicity by alleviating endoplasmic reticulum stress and mitochondrial calcium overload via PERK and IP3R-VDAC1-MCU signaling pathways.

Zixuan Li, Qian Ran, Chuan Qu, Shan Hu, Shengyu Cui, You Zhou, Bo Shen, Bo Yang.

   BACKGROUND: Doxorubicin (DOX) is an anthracycline with potent antitumor properties and rare yet serious cardiotoxic side effects that limit its clinical application. The sigma-1 receptor is a stress-triggered chaperone often dysregulated in diseases and has known cardioprotective effects. Although its anti-oxidative stress and anti-apoptotic effects have been demonstrated, its effectiveness in DOX-induced cardiotoxicity has never been explored. This study investigated the potential role of the activated sigma-1 receptor in a DOX-induced murine cardiotoxicity model to elucidate the receptor's mechanism of action.
METHODS: We established the model in C57BL/6 mice by daily intraperitoneal injections of fluvoxamine (Flv) for 4 consecutive weeks to activate the receptor and by weekly intraperitoneal injections of DOX at 5 mg/kg for 3 weeks. We performed in vitro experiments using cardiomyocytes of neonatal Sprague-Dawley rats to verify the protective effect of the sigma-1 receptor.
RESULTS: We found that sigma-1 expression in the heart decreased in the DOX-treated mice, and activating the receptor with Flv improved cardiac function. Moreover, Flv pretreatment inhibited cardiomyocyte apoptosis and endoplasmic reticulum stress and increased the expression of the Bcl2 apoptosis regulator (Bcl2), effectively alleviating the pathophysiological manifestations in mice. In addition, activating the receptor exerted cardioprotective effects by modulating endoplasmic reticulum stress through the PRKR-like endoplasmic reticulum kinase (PERK) signaling pathway. It also reduced mitochondrial and endoplasmic reticulum contact and alleviated mitochondrial calcium overload through the IP3R-VDAC1-MCU signaling pathway.
CONCLUSION: In conclusion, our study emphasizes the therapeutic potential of activating sigma-1 receptors against DOX-induced cardiotoxicity, suggesting sigma-1 receptors as potential therapeutic targets for this disease.

Keywords:  Ca2+ overload; DOX-induced cardiotoxicity; ER stress; IP3R-VDAC1-MCU signaling pathway; MAM; PERK signaling pathway; Sigma-1 receptor

DOI:  https://doi.org/10.1186/s13062-025-00617-y