bims-mecosi 2025-08-03 papers

bims-mecosi

Biomed News

on Membrane contact sites

Issue of 2025–08–03
ten papers selected by
Verena Kohler, Umeå University

Phosphoinositides as regulators of membrane contact sites.
Membrane Contact Sites in Proteostasis and ER Stress Response.
Endoplasmic reticulum-mediated organelle crosstalk in kidney disease.
AI-directed voxel extraction and volume EM identify intrusions as sites of mitochondrial contact.
Mitochondria-associated membranes (MAMs) in age-related heart diseases, role of endoplasmic reticulum stress.
Rab14 promotes Parkin mediated mitophagy.
The impact of ERUPR on mitochondrial integrity mediated by PDK4.
Mitochondrial‑endoplasmic reticulum crosstalk: Molecular mechanisms and implications for cardiovascular disease (Review).
Oxysterol-Binding Protein ORP6 Regulates Lipid Metabolism and Brain Aβ Production.
Endoplasmic reticulum-mitochondria coupling prompts ZBP1-mediated RPE cell PANoptosis in age-related macular degeneration.

Biochim Biophys Acta Mol Cell Biol Lipids. 2025 Jul 26. pii: S1388-1981(25)00081-2. [Epub ahead of print] 159673

Phosphoinositides as regulators of membrane contact sites.

Håvard S Haukaas, Harald Stenmark.

Membrane contact sites (MCSs) between the different compartments of the cell play important roles in lipid, protein and ion transfer. Phosphoinositides are crucial for the functions of many MCSs, either as membrane anchors for MCS proteins, or as part of a countertransport mechanism driven by phosphoinositide dephosphorylation in the endoplasmic reticulum. Here we review the involvement of phosphoinositides in MCSs between the endoplasmic reticulum and other organelles such as the plasma membrane, mitochondria, endosomes, lysosomes, autophagosomes and the Golgi complex. These phosphoinositide-containing MCSs mediate transfer of Ca2+, phospholipids, cholesterol, and a motor protein, and thus are of great importance for cellular physiology.

DOI: https://doi.org/10.1016/j.bbalip.2025.159673
Contact (Thousand Oaks). 2025 Jan-Dec;8:8 25152564251363050

Membrane Contact Sites in Proteostasis and ER Stress Response.

Febe Vermue, Aysegul Sapmaz, Ilana Berlin.

  Execution of all cellular functions depends on a healthy proteome, whose maintenance requires multimodal oversight. Roughly a third of human proteins reside in membranes and thus present unique topological challenges with respect to biogenesis and degradation. To meet these challenges, eukaryotes have evolved organellar pathways of protein folding and quality control. Most transmembrane proteins originate in the endoplasmic reticulum (ER), where they are subject to surveillance and, if necessary, removal through either ER-associated proteasomal degradation (cytosolic pathway) or selective autophagy (ER-phagy; organellar pathway). In the latter case, ER cargoes are shuttled to (endo)lysosomes - the same organelles that degrade cell surface molecules via endocytosis. Here, we provide an overview of dynamic coordination between the ER and endolysosomes, with a focus on their engagement in specialized physical interfaces termed membrane contact sites (MCSs). We cover how cross-compartmental integration through MCSs allows biosynthetic and proteolytic organelles to fine-tune each other's membrane composition, organization, and dynamics and facilitates recovery from proteotoxic stress. Along the way, we highlight recent developments and open questions at the crossroads between organelle biology and protein quality control and cast them against the backdrop of factor-specific diseases associated with perturbed membrane homeostasis.

Keywords:  endolysosome; endoplasmic reticulum; membrane contact sites; proteostasis; proteotoxic stress

DOI:  https://doi.org/10.1177/25152564251363050
Nat Rev Nephrol. 2025 Jul 31.

Endoplasmic reticulum-mediated organelle crosstalk in kidney disease.

Yu Ah Hong, Reiko Inagi.

The endoplasmic reticulum (ER) is a key organelle involved in a wide range of intracellular biological processes, including Ca2+ homeostasis; lipid metabolism; proteostasis through protein synthesis, folding and processing of secretory and transmembrane proteins; and signal transduction. The ER forms extensive physical interactions with various intracellular organelles through the membrane contact sites, enabling direct exchange of ions and lipids without vesicular transport. At mitochondria-associated membranes, ER-mitochondria communication governs calcium transfer, lipid synthesis, mitochondrial dynamics, the unfolded protein response and inflammation, all of which are essential for maintaining cellular homeostasis. The ER also interacts with the Golgi apparatus, endosomes and plasma membrane to facilitate transfer of calcium and lipids. Disruption of ER-organelle communication contributes to the development and progression of various kidney diseases, including diabetic kidney disease, acute kidney injury and polycystic kidney disease. Accordingly, ER-organelle communication has emerged as a promising therapeutic target. Pharmacological agents such as SGLT2 inhibitors, AMPK activators, mTOR inhibitors and RAAS blockers have been shown to restore ER-mitochondria communication and alleviate kidney injury in experimental models. Advancing our understanding of ER-organelle crosstalk may offer new mechanistic insights and contribute to the optimization of current treatment strategies for kidney disease.

DOI: https://doi.org/10.1038/s41581-025-00989-4
J Cell Biol. 2025 Oct 06. pii: e202411138. [Epub ahead of print]224(10):

AI-directed voxel extraction and volume EM identify intrusions as sites of mitochondrial contact.

Benjamin S Padman, Runa S J Lindblom, Michael Lazarou.

Membrane contact sites (MCSs) establish organelle interactomes in cells to enable communication and exchange of materials. Volume EM (vEM) is ideally suited for MCS analyses, but semantic segmentation of large vEM datasets remains challenging. Recent adoption of artificial intelligence (AI) for segmentation has greatly enhanced our analysis capabilities. However, we show that organelle boundaries, which are important for defining MCS, are the least confident predictions made by AI. We outline a segmentation strategy termed AI-directed voxel extraction (AIVE), which refines segmentation results and boundary predictions derived from any AI-based method by combining those results with electron signal values. We demonstrate the precision conferred by AIVE by applying it to the quantitative analysis of organelle interactomes from multiple FIB-SEM datasets. Through AIVE, we discover a previously unknown category of mitochondrial contact that we term the mitochondrial intrusion. We hypothesize that intrusions serve as anchors that stabilize MCS and promote organelle communication.

DOI: https://doi.org/10.1083/jcb.202411138
Adv Pharmacol. 2025 ;pii: S1054-3589(25)00028-6. [Epub ahead of print]104 289-312

Mitochondria-associated membranes (MAMs) in age-related heart diseases, role of endoplasmic reticulum stress.

Alejandro Silva-Palacios, Zeltzin Alejandra Ceja-Galicia, Alejandra María Zúñiga-Muñoz, Cecilia Zazueta.

  The study of interoganellar contactology represents a substantial advance in conceiving cells and their organelles. This presents a great challenge in terms of understanding their function and response to aging and in the development of different pathologies. This chapter will address changes in mitochondria-associated membranes (MAMs) in aging-related heart diseases, such as acute myocardial infarction and heart failure, emphasizing the role of endoplasmic reticulum stress (ERS). We also discuss the role of MAMs as possible markers of cardiovascular disease progression in geriatrician clinics, with a view to personalized therapy. Finally, we will contemplate the use of naturally occurring drugs that have been used in the experimental setting for the regulation of mitochondrial-ER communication. (119 words).

Keywords:  Aging; Contactology; ER stress; Heart failure; Mitochondria-associated membranes; Myocardial ischemia; Natural compounds; Senescence

DOI:  https://doi.org/10.1016/bs.apha.2025.01.018
Mol Biol Cell. 2025 Jul 30. mbcE25060271

Rab14 promotes Parkin mediated mitophagy.

Samina Momtaz, Marco Padilla-Rodriguez, Paola Cruz Flores, Natalia Rulli, Nam Yong Lee, Jean M Wilson.

Mitochondrial degradation by mitophagy is essential to maintain cell metabolism; dysregulation can result in the accumulation of damaged mitochondria. While the Rab family of small GTPase proteins are involved with vesicular trafficking in the endocytic and biosynthetic pathways, Rab-GTPases also have a role in mitochondrial integrity. However, a role for Rab14, a trans-Golgi network (TGN)-endosomal Rab-GTPase in mitophagy has not been described. In cells knocked down for Rab14, mitochondria acquire an elongated morphology and increased levels of mitochondrial proteins, whereas overexpression of Rab14 decreased these proteins. Furthermore, mito-Keima assays show increased mitophagy upon Rab14 overexpression. Rab14-induced mitophagy is dependent on Parkin expression, as well as TBK1 and PI3K activity, placing it in the Parkin-dependent mitophagy pathway. 3D-reconstruction shows contact site formation between Rab14 and mitochondria, and inhibition of the TGN kinase PI(4)KIIIβ decreases Rab14-mitochondria contact sites and prevents Rab14-mediated mitophagy, suggesting that TGN-derived Rab14 vesicles mediate mitophagy. These results suggest that Rab14 promotes mitophagy and plays an essential role in modulating cellular metabolism. [Media: see text].

DOI: https://doi.org/10.1091/mbc.E25-06-0271
Cell Death Dis. 2025 Jul 29. 16(1): 573

The impact of ERUPR on mitochondrial integrity mediated by PDK4.

Priyanka Mallick, Sebabrata Maity, Rupsha Mondal, Trina Roy, Puyam Milan Meitei, Shashank Saxena, Bhavani Shankar Sahu, Oishee Chakrabarti, Saikat Chakrabarti.

ER and mitochondrial stress are often interconnected and considered major contributors to aging as well as neurodegeneration. Coordinated induction of ERUPR and mitoUPR has been observed in diabetes and pulmonary disorders. However, in the context of aging and neurodegeneration, regulation of this intra-organellar crosstalk has remained relatively elusive. Here, we demonstrate that pyruvate dehydrogenase kinase 4 (PDK4), a mitochondrial protein, accumulates at the ER-mitochondrial contact sites (MAMs) during ER stress. Classically, PDK4 is known to phosphorylate PDHA1 (pyruvate dehydrogenase E1 subunit alpha 1) and plays a significant role in regulating the oxidative phosphorylation-driven ATP production. In this study, we propose a non-canonical kinase-independent function of PDK4; we show that it acts as a connecting link between ERUPR and mitoUPR, with significance in aging and Alzheimer's disease (AD) associated neurodegeneration. Transcriptomics analyses show increased PDK4 levels upon drug-induced ER stress. We detect elevated PDK4 levels in lysates from human AD patient and mouse models as well as in ex vivo AD models. Additionally, exogenous expression of PDK4 was found to refine ER-mitochondria communication, significantly altering mitochondrial morphology and function. Further, we also observe defective autophagic clearance of mitochondria under such conditions. It is prudent to suggest that elevated PDK4 levels could be one of the key factors connecting ERUPR with mitoUPR, a phenotypic contributor in aging and in AD-like neurodegenerative disorders.

DOI: https://doi.org/10.1038/s41419-025-07743-5
Mol Med Rep. 2025 Oct;pii: 275. [Epub ahead of print]32(4):

Mitochondrial‑endoplasmic reticulum crosstalk: Molecular mechanisms and implications for cardiovascular disease (Review).

Yue Liu, Xuejia Gong, Shasha Xing.

  Cardiovascular disease (CVD), which includes conditions such as coronary heart disease, hypertension, heart failure and diabetes cardiomyopathy, is a major cause of mortality among middle‑aged and elderly populations worldwide; however, there is a concerning trend of individuals of increasingly younger ages being affected. Despite extensive research and numerous treatments available, CVD remains a major health threat for middle‑aged and elderly individuals due to its complex causes and the effect of environmental and lifestyle factors. In recent years, the structural and functional abnormalities of mitochondria and endoplasmic reticulum (ER) organelles have been associated with CVD. In addition to the intrinsic role of organelles, the interaction between organelles, particularly the homeostasis imbalance between the mitochondria and the ER through the interaction of the mitochondria‑associated ER membrane (MAM), serves a key role in CVD, such as ischemia‑reperfusion, diabetic cardiomyopathy and heart failure. The main mechanism involves regulating lipid transport, calcium homeostasis, mitochondrial function, cell survival and death, as well as signal transduction. The present review summarized recent advancements in MAM research, elucidated key mechanisms that influence MAM homeostasis, highlighted its significance in cardiovascular health and disease and explored its potential as a therapeutic target for CVD, thereby providing a theoretical foundation for future research.

Keywords:  cardiovascular disease; endoplasmic reticulum; mitochondria; mitochondria‑associated endoplasmic reticulum membrane

DOI:  https://doi.org/10.3892/mmr.2025.13640
J Lipid Res. 2025 Jul 25. pii: S0022-2275(25)00130-0. [Epub ahead of print] 100868

Oxysterol-Binding Protein ORP6 Regulates Lipid Metabolism and Brain Aβ Production.

Arlette A Kasongo, Viyashini Vijithakumar, Khaled S Abd-Elrahman, Radhika Prabhune, Lara Gharibeh, Rachel Nadeau, Isabelle Robillard, Shoshana Spring, Sabrina Robichaud, Shaza Asif, Derrick Gibbings, Kathryn J Moore, John G Sled, Mathieu Ruiz, Mathieu Lavallée-Adam, Stephen S G Ferguson, Baptiste Lacoste, Diane C Lagace, Mireille Ouimet.

  The mammalian brain is the most cholesterol-rich organ of the body, relying on in situ de novo cholesterol synthesis. Maintaining cholesterol homeostasis is crucial for normal brain function. Oxysterol-binding protein (OSBP)-related proteins (ORPs) are highly conserved cytosolic proteins that coordinate lipid homeostasis by regulating cell signaling, inter-organelle membrane contact sites, and non-vesicular transport of cholesterol. Here, we show that ORP6 is highly enriched in the mammalian brain, particularly within neurons and astrocytes, with widespread expression across distinct brain regions, including the hippocampus, which is essential for learning and memory. Whole-body ablation of ORP6 (Osbpl6-/-) in mice resulted in dysregulation of systemic and brain lipid homeostasis, with elevated levels of brain desmosterol and amyloid-beta oligomers (AβOs). Mechanistically, ORP6 knockdown in astrocytes altered the expression of cholesterol metabolism genes, promoting the accumulation of esterified cholesterol in lipid droplets, reducing cholesterol efflux and plasma membrane cholesterol content, and increasing amyloid-beta precursor protein (APP) processing. Our findings underscore the role of ORP6 in systemic and brain lipid homeostasis, highlighting its importance in maintaining overall brain health.

Keywords:  amyloid beta; astrocyte; cholesterol efflux; high-density lipoprotein; lipid droplet; lipid metabolism; oxysterol-binding protein-like 6

DOI:  https://doi.org/10.1016/j.jlr.2025.100868
Commun Biol. 2025 Jul 29. 8(1): 1118

Endoplasmic reticulum-mitochondria coupling prompts ZBP1-mediated RPE cell PANoptosis in age-related macular degeneration.

Ao Zhang, Ting-Ting Wei, Honglin Yin, Cheng-Ye Tan, Cheng Han, Yong Yao, Lingpeng Zhu.

Age-related macular degeneration (AMD) is the leading cause of central vision impairment among the elderly. Geographic atrophy is a defining characteristic of AMD, but the detailed mechanism for massive loss of retinal pigment epithelium (RPE) cells is not fully understood. In this study, we found that Z-DNA binding protein 1 (ZBP1), a sensor for dsDNA, is able to induce RPE cell PANoptosis. Silencing ZBP1 efficiently alleviates RPE degeneration and AMD symptoms. Mechanistically, mitochondrial permeability transition pore (mPTP) opening stimulated by Ca2+ overload can trigger the releasing of mtDNA, which leads to ZBP1 activation and PANoptosis. Importantly, our findings reveal a significant role of aberrant formation of mitochondria-associated ER membranes (MAMs) in AMD. MAMs act as conduits for transferring Ca2+ from the ER to mitochondria through the VDAC1/GRP75/IP3R1 complex. Furthermore, our results indicate that GRP75 O-GlcNAcylation is involved in MAM formation. Genetic suppression of GRP75 attenuates PANoptosis and AMD progression. In summary, our study sheds light on the intricate organelle interplay underlying AMD and presents insights into potential avenues for AMD intervention.

DOI: https://doi.org/10.1038/s42003-025-08565-z