bims-mecosi 2025-10-12 papers

Issue of 2025–10–12
five papers selected by
Verena Kohler, Umeå University

Autophagy. 2025 Oct 08. 1-3

Atg2/TRAPPIII-Ypt1 axis: deciphering the phagophore-ERES connection.

Rubén Gómez-Sánchez, J Christopher Fromme, Christian Ungermann, Fulvio Reggiori.

De novo generation of membrane contact sites (MCSs) between the nascent phagophore and the endoplasmic reticulum (ER), particularly the ER exit sites (ERES), are crucial for autophagy as they provide the lipids necessary for the phagophore expansion into an autophagosome. Our recent study provides insights into the mechanism involved in the formation of phagophore-ERES MCSs and uncovers how this event synchronizes the factors involved in phagophore expansion. We revealed that the TRAPPIII complex, the guanine nucleotide exchange factor of the Rab GTPase Ypt1, and the lipid transfer protein Atg2 participate in the phagophore-ERES association. We also show that establishment of phagophore-ERES MCSs leads to TRAPPIII activation and subsequent Ypt1 recruitment onto the phagophore. The presence of active Ypt1 on the growing phagophore enhances local biosynthesis of phosphatidylinositol-3-phosphate (PtdIns3P), triggering the recruitment of the PtdIns3P-effectors Atg18 and Atg21, which play a central role in phagophore expansion. These findings suggest that generation of phagophore-ERES MCSs is one of the signals initiating phagophore expansion.Abbreviations: Atg, autophagy related; ER, endoplasmic reticulum; ERES, ER exit sites; GEF, guanine nucleotide exchange factor; MCS, membrane contact site; PAS, phagophore assembly site; PtdIns3P, phosphatidylinositol-3-phosphate; PtdIns3K, phosphatidylinositol 3-kinase; SNARE, soluble NSF attachment protein receptor; TOR, Target of Rapamycin; WIPI, WD-repeat domain, phosphoinositide interacting.

Keywords: Atg2; Atg9; TRAPPIII; Ypt1; autophagy; membrane contact sites; phagophore

DOI: https://doi.org/10.1080/15548627.2025.2571682

FEBS Open Bio. 2025 Oct 10.

Mitochondria-associated membranes (MAMs): molecular organization, cellular functions, and their role in health and disease.

Viet Bui, Maryline Santerre, Natalia Shcherbik, Bassel E Sawaya.

Mitochondria-associated membranes (MAMs) are specialized contact sites between the endoplasmic reticulum (ER) and mitochondria that maintain cellular homeostasis through precisely orchestrated molecular mechanisms. These dynamic interfaces are maintained at 10-50 nm distances by complex tethering proteins, including the core IP3R-GRP7 5-VDAC1 complex and regulatory proteins, such as the sigma-1 receptor. MAMs coordinate multiple essential cellular processes: lipid synthesis and transfer, calcium signaling, metabolic regulation, and quality control through autophagy and mitophagy. Recent advances in super-resolution microscopy and proteomics have revealed that MAM dysfunction drives pathogenesis across various diseases. In Alzheimer's disease, disrupted MAM spacing directly affects Aβ production and mitochondrial function, while in Parkinson's disease, α-synuclein accumulation at MAMs impairs phosphatidylserine metabolism and mitochondrial dynamics. Beyond neurodegeneration, MAMs play crucial roles in metabolic disorders, cancer progression, and viral infections. This review provides mechanistic insights into MAM biology, from molecular organization to disease pathogenesis, integrating structural analyses with dynamic visualization approaches. We examine emerging therapeutic strategies targeting MAM-associated pathways and highlight their potential in treating complex diseases.

Keywords: ER–mitochondria contact sites; calcium signaling; cellular stress responses; lipid metabolism; mitochondria‐associated membranes; neurodegeneration

DOI: https://doi.org/10.1002/2211-5463.70121

Nat Microbiol. 2025 Oct 10.

Toxoplasma gondii VIP1 mediates parasitophorous vacuole-host endoplasmic reticulum interactions to facilitate parasite development.

Julia D Romano, Ruth Buh, Tanner Grudda, Julia R Box, John Beltran, Shahbaz M Khan, Isabelle Coppens.

Membrane contact sites (MCS) are areas of close apposition between organelles without membrane fusion, allowing for exchange of biomolecules. The endoplasmic reticulum (ER) forms many MCS via two proteins, vesicle-associated membrane protein-associated proteins A and B (VAPA and VAPB). The obligate intracellular parasite Toxoplasma gondii resides within mammalian cells in a parasitophorous vacuole (PV), which closely contacts the host ER at distances compatible with MCS. However, the proteins mediating this interaction remain largely unknown. Here, using molecular and microscopy approaches, we show that VAPA and VAPB localize at the PV membrane and, with motile sperm domain-containing protein 2 (MOSPD2), mediate ER-PV interactions. Cells deficient in VAPA, VAPB and MOSPD2 do not recruit host ER at the PV, and parasites show growth defects. We identify a parasite protein that localizes at the PV membrane, called TgVIP1, which harbours an FFAT-like motif that binds VAPA and VAPB. These findings lay the basis for understanding how and why Toxoplasma exploits ER-PV interactions and may uncover new drug targets.

DOI: https://doi.org/10.1038/s41564-025-02144-y

J Am Soc Nephrol. 2025 Oct 06.

Illuminating Renal Proximal Tubule Architecture through High-Resolution Volume EM and Machine Learning Analysis.

Raj D Pandya, Emily M Lackner, C Shan Xu, Christopher Zugates, Mariia Burdyniuk, Andrea Reyna-Neyra, Vraj D Pandya, Wei-Ping Li, Song Pang, Ora A Weisz, Michael J Caplan.

BACKGROUND: Kidney epithelial cells perform complex vectorial fluid and solute transport at high volumes and rapid rates. Their structural organization both reflects and enables these sophisticated physiological functions. However, our understanding of the nanoscale spatial organization and intracellular ultrastructure that underlies these crucial cellular functions remains limited.
METHODS: To address this knowledge gap, we generated and reconstructed an extensive electron microscopic dataset of renal proximal tubule (PT) epithelial cells at isotropic resolutions down to 4nm. We employed artificial intelligence-based segmentation tools to identify, trace, and measure all major subcellular components. We complemented this analysis with immunofluorescence microscopy to connect subcellular architecture to biochemical function.
RESULTS: Our ultrastructural analysis revealed complex organization of membrane-bound compartments in proximal tubule cells. The apical endocytic system featured deep invaginations connected to an anastomosing meshwork of dense apical tubules, rather than discrete structures. The endoplasmic reticulum displayed distinct structural domains: fenestrated sheets in the basolateral region and smaller, disconnected clusters in the subapical region. We identified, quantified, and visualized membrane contact sites between endoplasmic reticulum, plasma membrane, mitochondria, and apical endocytic compartments. Immunofluorescence microscopy demonstrated distinct localization patterns for endoplasmic reticulum resident proteins at mitochondrial and plasma membrane interfaces.
CONCLUSIONS: This study provides novel insights into proximal tubule cell organization, revealing specialized compartmentalization and unexpected connections between membrane-bound organelles. We identified previously uncharacterized structures, including mitochondria-plasma membrane bridges and an interconnected endocytic meshwork, suggesting mechanisms for efficient energy distribution, cargo processing and structural support. Morphological differences between 4nm and 8nm datasets indicate subsegment-specific specializations within the proximal tubule. This comprehensive open-source dataset provides a foundation for understanding how subcellular architecture supports specialized epithelial function in health and disease.

DOI: https://doi.org/10.1681/ASN.0000000884

J Integr Neurosci. 2025 Sep 18. 24(9): 40105

Electroacupuncture Regulates Mitochondria-Endoplasmic Reticulum interactions via Fn1 in a Parkinson's Disease Model: Transcriptomic Evidence.

Peilin Lyu, Feng Wen, Zhiyi Fu, Junying Li, Qiyan Li, Xiaowen Cai, Shengtao Huang, Xiaoke Qiu, Zhinan Zhang, Yong Huang, Jiping Zhang.

AIMS: Parkinson's disease (PD) is characterized by dopaminergic neuron degeneration and disruption to mitochondria-associated endoplasmic reticulum membranes (MAMs). This study explores whether electroacupuncture (EA) can alleviate 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) induced PD symptoms and investigates the underlying mechanisms using RNA sequencing (RNA-seq).
METHODS: A PD mouse model was established using MPTP, followed by EA treatment at governing vessel 20 (GV20) and gallbladder meridian 34 (GB34) acupoints, with sham EA treatments as a control. Behavioral assays, immunohistochemistry, and Western blotting assessed neuroprotective effects. MAM integrity was assessed using Western blot, immunofluorescence staining, and transmission electron microscopy. RNA-seq and protein-protein interaction (PPI) analysis identified differentially expressed genes which were validated by real-time fluorescence quantitative polymerase chain reaction (qRT-PCR).
RESULTS: EA treatment improved motor performance, increased substantia nigra (SN) and striatum tyrosine hydroxylase expression, reduced SN alpha-synuclein, and improved SN dopamine neuron MAM structure. Transcriptomic analysis identified 32 MAM-associated genes, of which fibronectin-1 (Fn1) was identified as a key regulator. EA was found to upregulate Fn1 expression, suggesting its involvement in MAM stabilization and neuroprotection.
CONCLUSION: EA at GV20 and GB34 alleviated motor and neural impairments in a PD mouse model potentially through modulation of Fn1 and its role in MAM-associated pathways.

Keywords: Fn1; Parkinson’s disease; RNA sequence analysis; electroacupuncture; mitochondria-associated membranes

DOI: https://doi.org/10.31083/JIN40105