bims-mecosi 2025-06-29 papers

Issue of 2025–06–29
seven papers selected by
Verena Kohler, Umeå University

Nat Rev Mol Cell Biol. 2025 Jun 23.

Key challenges and recommendations for defining organelle membrane contact sites.

Tito Calì, Emmanuelle M Bayer, Emily R Eden, György Hajnóczky, Benoit Kornmann, Laura Lackner, Jen Liou, Karin Reinisch, Hyun-Woo Rhee, Rosario Rizzuto, Luca Scorrano, Marisa Brini.

Intracellular membrane contact sites (MCSs) between organelles have crucial roles in cellular signalling and homeostasis. These sites, which are often disrupted in pathological conditions, enable the exchange of ions, lipids and metabolites between membrane-bound compartments, helping cells adapt to varying physiological conditions. Specific tether proteins and complexes stabilize these interactions and mediate responses to different intracellular or extracellular stimuli. The study of MCSs has progressed in recent years, owing to the development of new methods such as genetically encoded reporter constructs, advanced imaging techniques, including super-resolution microscopy and electron tomography, and proteomic approaches based on mass spectrometry. These tools have enabled unprecedented visualization and quantification of organelle interactions, as well as identification of the molecular players involved. This Expert Recommendation aims to define and map the 'organelle contactome', describing key proteins involved in contact site formation and the roles of MCSs in cellular function. We also explore contact site dynamics and detail advantages and disadvantages of the methodologies for studying them. Importantly, we consolidate open questions in contact site research and discuss challenges and limitations of the current experimental approaches.

DOI: https://doi.org/10.1038/s41580-025-00864-x

J Biol Chem. 2025 Jun 21. pii: S0021-9258(25)02260-4. [Epub ahead of print] 110410

Maintenance of proper phosphatidylinositol-4-phosphate level by Stt4 and Sac1 contributes to vesicular transport to and from the plasma membrane.

Tomoki Sano, Makoto Nagano, Hiroki Shimamura, Wataru Yamamoto, Tomoyuki Tamada, Junko Y Toshima, Jiro Toshima.

Growing evidence suggests that counter-transport of phosphatidylinositol-4-phosphate (PtdIns(4)P) and phosphatidylserine (PS) at endoplasmic reticulum (ER)-plasma membrane (PM) contact sites is required for intracellular vesicle transport. PtdIns(4)P is metabolized by Stt4 PI 4-kinase residing at the PM and by Sac1 PtdIns(4)P phosphatase at the ER, and ER-PM contact sites are believed to be important for its efficient turnover. Recently, Stt4 has been shown to extensively localize to ER-PM contact sites. However, the precise location of Stt4 and the mechanism of localization to these sites have not been clarified. Additionally, although several studies have suggested a requirement for PS/PtdIns(4)P and sterol/PtdIns(4)P exchange at ER-PM contact sites in endocytosis, it is still unclear whether contact between the ER and PM, turnover of PtdIns(4)P or PS, or maintenance of PtdIns(4)P or PS levels is more important. Here we found that Stt4 localizes to the cER regions where Scs2 and Ist2 are localized abundantly, and that localization of Stt4 is maintained in the Δtether mutant, which has a reduced number of ER-PM contact sites. We also demonstrated that the Δtether and sac1Δ mutants showed defects at different stages of endocytosis, and that inactivation mutation of Stt4 restored the endocytosis defect only in the Δtether mutant. Furthermore, these mutants exhibited defective transport in the secretory and recycling pathways, and inactivation of Stt4 restored the secretory pathway in the Δtether mutant, but not the recycling pathway in either mutant. These results suggest that endocytosis, secretion, and recycling pathways are regulated directly or indirectly by different PtdIns(4)P-mediated mechanisms.

Keywords: endocytosis; endoplasmic reticulum; phosphatidylinositol-4-phosphate; phosphatidylserine; plasma membrane; recycling; secretion

DOI: https://doi.org/10.1016/j.jbc.2025.110410

Curr Biol. 2025 Jun 23. pii: S0960-9822(25)00576-7. [Epub ahead of print]35(12): R595-R597

MICOS.

Karina von der Malsburg, Anastasiia Maitova, Martin van der Laan.

von der Malsburg et al. introduce the mitochondrial contact site and cristae organizing system, a complex that localises to the inner mitochondrial membrane at crista junctions and stabilises these curved membrane domains.

DOI: https://doi.org/10.1016/j.cub.2025.05.001

Sci Adv. 2025 Jun 27. 11(26): eads6132

External strain on the plasma membrane is relayed to the endoplasmic reticulum by membrane contact sites and alters cellular energetics.

Ziming Chen, Peilin Chen, Jiayue Li, Euphemie Landao-Bassonga, John Papadimitriou, Junjie Gao, Delin Liu, Andrew Tai, Jinjin Ma, David Lloyd, Brendan F Kennedy, Ming Hao Zheng.

Mechanotransduction is essential for living cells to adapt to their extracellular environment. However, it is unclear how the biophysical adaptation of intracellular organelles responds to mechanical stress or how these adaptive changes affect cellular homeostasis. Here, using the tendon cell as a mechanosensitive cell type within a bioreactor, we show that the tension of the plasma membrane (PM) and the endoplasmic reticulum (ER) adaptively increases in response to repetitive external stimuli. Depletion of stromal interaction molecule 1 (STIM1), the highest expressed PM-ER tether protein, interfered with mechanotransduction from the PM to the ER, and affected the ER tension. We found that an optimized mechanical strain increased ER tension in a homeostatic manner, but excessive strain resulted in ER expansion, as well as activating ER stress. Last, we showed that changes in ER tension were linked with ER-mitochondria interactions and associated with cellular energetics and function. Together, these findings identify a PM-ER mechanotransduction mechanism that dose-dependently regulates cellular metabolism.

DOI: https://doi.org/10.1126/sciadv.ads6132

Annu Rev Virol. 2025 Jun 24.

Shaping Viral Infection Outcomes via Organelle Remodeling.

William A Hofstadter, Ileana M Cristea.

Subcellular organelles are dynamic structures that tune their functions in conjunction with changes to their shapes and compositions. Each organelle has distinct structure-function relationships that change in response to diverse stimuli. Such remodeling events further affect organelle-organelle interaction networks facilitated by membrane contact sites, thereby activating rapid intra- and intercellular communication cascades. As viruses rely on repurposing the host cell machinery during infections, organelle remodeling is a fundamental facet and outcome of all viral infections. Some organelle remodeling events are unique to particular viruses, while others are shared by an array of viruses. Here, we review knowledge derived from this expanding yet still underexplored research area of infection-induced organelle remodeling. We focus on the molecular mechanisms used by viruses to temporally control organelle structure-function relationships. We highlight how organelle remodeling can inhibit host defenses or facilitate specific stages of a virus replication cycle, i.e., entry, replication, assembly, and spread.

DOI: https://doi.org/10.1146/annurev-virology-092623-094221

Nat Cell Biol. 2025 Jun 27.

The Vps13-like protein BLTP2 regulates phosphatidylethanolamine levels to maintain plasma membrane fluidity and breast cancer aggressiveness.

Subhrajit Banerjee, Stephan Daetwyler, Xiaofei Bai, Morgane Michaud, Juliette Jouhet, Derk Binns, Shruthi Madhugiri, Emma Johnson, Chao-Wen Wang, Reto Fiolka, Alexandre Toulmay, William A Prinz.

Lipid transport proteins (LTPs) facilitate non-vesicular lipid exchange between cellular compartments and have critical roles in lipid homeostasis. A recently identified family of bridge-like LTPs (BLTPs) is thought to form lipid-transporting conduits between organelles. One of these, BLTP2, is conserved across species but its function is not known. Here we show that BLTP2 regulates plasma membrane (PM) fluidity by increasing phosphatidylethanolamine (PE) levels in the PM. BLTP2 localizes to endoplasmic reticulum (ER)-PM contact sites, and transports PE in vivo, suggesting it drives PE movement from ER to PM. We find that BLTP2 works in parallel with another pathway that regulates intracellular PE distribution and PM fluidity. BLTP2 expression correlates with breast cancer aggressiveness. We found that BLTP2 facilitates growth of a triple negative breast cancer cell line and sustains its aggressiveness in an in vivo model of metastasis, suggesting maintenance of PM fluidity by BLTP2 may be critical for tumorigenesis in humans.

DOI: https://doi.org/10.1038/s41556-025-01672-3

Int J Mol Sci. 2025 Jun 14. pii: 5709. [Epub ahead of print]26(12):

From Gene to Pathways: Understanding Novel Vps51 Variant and Its Cellular Consequences.

Damla Aygun, Didem Yücel Yılmaz.

Disorders of vesicular trafficking and genetic defects in autophagy play a critical role in the development of metabolic and neurometabolic diseases. These processes govern intracellular transport and lysosomal degradation, thereby maintaining cellular homeostasis. In this article, we present two siblings with a novel homozygous variant in VPS51 (Vacuolar protein sorting 51) gene (c.1511C>T; p.Thr504Met), exhibiting developmental delay, a thin corpus callosum, severe intellectual disability, epilepsy, microcephaly, hearing loss, and dysphagia. This study aimed to investigate the effects of the novel VPS51 gene variation at the RNA and protein level in fibroblasts derived from patients. A comparative proteomic analysis, which has not been previously elucidated, was performed to identify uncharacterized proteins associated with vesicular trafficking. Furthermore, the impact of disrupted pathways on mitochondria-lysosome contact sites was assessed, offering a thorough pathophysiological evaluation of GARP/EARP (Golgi Associated Retrograde Protein / Endosome Associated Retrograde Protein) complex dysfunction. An analysis of mRNA expression indicated decreased levels of the VPS51 gene, alongside modifications in the expression of autophagy-related genes (LC3B, p62, RAB7A, TBC1D15). Western blotting demonstrated a reduction in VPS51 and autophagy-related protein levels. Proteomic profiling revealed 585 differentially expressed proteins, indicating disruptions in vesicular trafficking, lysosomal function, and mitochondrial metabolism. Proteins involved in mitochondrial β-oxidation and oxidative phosphorylation exhibited downregulation, whereas pathways related to glycolysis and lipid synthesis showed upregulation. Live-cell confocal microscopy revealed a notable increase in mitochondria-lysosome contact sites in patient fibroblasts, suggesting that VPS51 protein dysfunction contributes to impaired organelle communication. The findings indicate that the novel VPS51 gene variation influences intracellular transport, autophagy, and metabolic pathways, offering new insights into its involvement in neurometabolic disorders.

Keywords: EARP; GARP; autophagy; mitochondria–lysosome contact; proteomics; vesicular traffic

DOI: https://doi.org/10.3390/ijms26125709