bims-mecosi 2025-10-26 papers

Issue of 2025–10–26
six papers selected by
Verena Kohler, Umeå University

Proc Natl Acad Sci U S A. 2025 Oct 28. 122(43): e2516849122

Nir2 crystal structures reveal a phosphatidic acid-sensing mechanism at ER-PM contact sites.

Dongyoung Kim, Seowhang Lee, Youngsoo Jun, Changwook Lee.

Agonist-induced activation of phosphoinositide-specific phospholipase C (PLC) converts phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2] to diacylglycerol (DAG) at the inner leaflet of the plasma membrane (PM). DAG can be enzymatically transformed into phosphatidic acid (PA) and accumulated at the PM. PYK2 N-terminal domain-interacting receptor 2 (Nir2) mediates the formation of ER-PM membrane contact sites (MCSs) by specifically recognizing PA at the PM and directly interacting with ER membrane protein vesicle-associated membrane protein-associated proteins (VAPs). The N-terminal phosphatidylinositol transfer protein domain of Nir2 facilitates PI/PA exchange at ER-PM MCSs to maintain PI and PA levels. Here, we reveal the mechanisms by which Nir2 senses phosphatidic acid (PA) and associates with membranes, based on three crystal structures of its C-terminal Lipin/Ned1/Smp2 (LNS2) domain bound to PA, the diphenylalanine [FF]-containing acidic tract (FFAT) motif complexed with vesicle-associated membrane protein-associated protein B/C (VAPB), and the Asp-Asp-His-Asp (DDHD) domain. The C-terminal LNS2 domain of Nir2 directly interacts with the phosphate in the headgroup of PA via hydrogen bonds involving S1025, T1065, K1103, and K1126. Formation of a salt bridge between E355 in Nir2 and R55 in VAPB is essential for Nir2 FFAT-VAPB interaction. The central DDHD domain of Nir2 forms a twofold symmetric dimer, and this self-association contributes to stable and tight membrane association. These findings reveal how Nir2-mediated ER-PM MCS formation maintains continued PI(4,5)P2-dependent PLC signaling.

Keywords: Nir2; PLC signaling; crystal structure; lipid transfer protein; membrane contact site

DOI: https://doi.org/10.1073/pnas.2516849122

Acta Biomater. 2025 Oct 17. pii: S1742-7061(25)00775-5. [Epub ahead of print]

Subcellular two-pronged targeting therapeutics: disrupting mitochondria-endoplasmic reticulum communication in inflammatory disorders.

Jianheng Ren, Yuanyi Hua, Zhumei Liao, Xin Wen, Qin Wang.

Researchers have made significant efforts to develop mitochondria or endoplasmic reticulum (ER)-targeting strategies to regulate cellular signaling cascades in inflammatory diseases. Although ER and mitochondria function relatively independently, these organelles can form extensive physical interactions, known as mitochondria-associated ER membranes (MAMs). Emerging evidence suggests that the development of inflammatory diseases depends largely on the pathological crosstalk between mitochondria and ER through MAMs, whereby ER stress and mitochondrial dysfunction collectively activate inflammatory signaling. Due to the presence of MAMs, single-organelle (ER or mitochondria)-specific therapies may not adequately suppress inflammatory signaling activation, highlighting the need for two-pronged strategies to thoroughly interfere with the pathological crosstalk between ER and mitochondria. This review highlights how the interaction between mitochondria and ER contributes to the progression of inflammatory diseases, and systematically summarizes the current advances in delivery strategies for ER and mitochondria targeting. Furthermore, we emphasize the therapeutic potential of simultaneously regulating mitochondrial and ER function to achieve precise control of inflammatory disorders. Our review aims to establish a framework for two-pronged targeting strategies that can restore ER and mitochondrial homeostasis, thereby facilitating the treatment of inflammatory diseases. STATEMENT OF SIGNIFICANCE: Due to the extensively formed mitochondria-associated endoplasmic reticulum (ER) membranes (MAMs) under inflammatory conditions, previous studies focusing on modulating the dysfunction of either mitochondria or ER have demonstrated limited efficacy in inflammatory disorders. MAM-mediated pathological inter-organelles crosstalk can drive the vicious cycle between mitochondria dysfunction and ER stress in inflammatory diseases, underscoring the need for two-pronged approaches that precisely disrupting mitochondria-ER communication. This review highlighted the key role of MAMs in inflammation and summarized recent advances in ER/mitochondria targeted delivery strategies. Furthermore, we underscored the potential therapeutic targets within MAMs for inflammatory intervention, and discussed therapeutic potential of two-pronged approaches in restoring organelle homeostasis and mitigating inflammatory diseases.

Keywords: Drug delivery systems; Inflammatory diseases; Mitochondrial-associated endoplasmic reticulum membranes (MAMs); Organelle targeting

DOI: https://doi.org/10.1016/j.actbio.2025.10.029

Aging Dis. 2025 Oct 16.

The Role of Mitochondria-Associated Endoplasmic Reticulum Membranes in Fibrotic Diseases.

Fei Wang, Han Wang, Yun Chao Zhang, Cao Dan, Yi Ming Qin, Mei Juan Xie, Xiao Yan Lyu.

Fibrotic diseases are characterized by high incidence and mortality rates, posing substantial challenges to global public health due to their considerable disease burden. Mitochondrial damage is a common feature in all fibrotic diseases. Mitochondria do not function in isolation; rather, they are often influenced by stress signals from adjacent organelles. Mitochondria and the endoplasmic reticulum are frequently studied as a subfunctional unit. Mitochondria-associated endoplasmic reticulum membranes (MAM) serve as physical connectors between mitochondria and the endoplasmic reticulum. MAM plays a pivotal role in multiple pathological and physiological processes, including lipid metabolism, inflammation, mitochondrial function, cell death, and cellular senescence. These pathological processes are also implicated in the progression of fibrotic diseases. In this review, we examine the relationship between MAM and key pathological mechanisms in fibrotic diseases, such as cell death, cellular senescence, and inflammation. We further explore the potential of MAM as diagnostic biomarkers and therapeutic targets for fibrotic diseases, thereby offering novel research directions and treatment strategies aimed at improving outcomes for patients with fibrotic diseases.

DOI: https://doi.org/10.14336/AD.2025.1087

Front Pharmacol. 2025 ;16 1549060

Rheumatoid arthritis-associated depression: focusing on the interactions between mitochondria and endoplasmic reticulum.

Mingqin Shi, Xinyao Li, Haimei Zhou, Zhenmin Li, Yuanyuan Wei, Zihui Wang, Yuqing She, Xuelian Zou, Xiangdian Xiao, Jiashun Zeng, Dongdong Qin.

The interplay between mitochondria and endoplasmic reticulum (ER) is essential for cellular viability. The structures known as mitochondria-associated endoplasmic reticulum membranes (MAM) provide complicated connections between these organelles, which house a variety of proteins, each serving distinct roles across different cellular environments. Growing evidence indicates that disruptions in mitochondrial-ER interactions are linked to immune and inflammatory responses. The concurrent presence of rheumatoid arthritis (RA), an immune-mediated inflammatory condition, and depression has been well-documented. Alterations in proteins that mediate mitochondrial-ER interactions and MAM functionality are increasingly correlated with immune and inflammatory pathways. This suggests that a comprehensive understanding of disease mechanisms can be enhanced by examining the alterations in their intercommunication rather than viewing the organelles in isolation. In this review, we explore the pathophysiological mechanisms underlying RA in conjunction with depression, the relationships among mitochondria, the endoplasmic reticulum, mitochondrial-ER interactions, and their association with RA-associated depression, and propose that targeting MAM could offer a novel therapeutic approach for managing RA-associated depression.

Keywords: depression; endoplasmic reticulum; mitochondria; mitochondria-associated endoplasmic reticulum membranes; rheumatoid arthritis

DOI: https://doi.org/10.3389/fphar.2025.1549060

Neurobiol Dis. 2025 Oct 22. pii: S0969-9961(25)00369-9. [Epub ahead of print] 107152

Endoplasmic reticulum in the axon: Insights into structural dynamics and implications in neurodegeneration.

Trang Dai Vu, Hyun Sung.

The endoplasmic reticulum (ER) is an interconnected and highly dynamic organelle essential for multiple cellular functions. In neurons, the ER extends into axons, where it plays a pivotal role in maintaining neuronal polarity. The unique structural and dynamic adaptations of the axonal ER enable it to meet the specialized demands of neurons, ranging from compartmentalized physiological regulation to long-distance intracellular communication. Recent studies have shown that axonal ER supports the regulation of organelle remodeling and trafficking in a spatiotemporal manner, processes that become compromised in aged neurons. Moreover, disruptions in the structure and dynamics of the axonal ER have increasingly become associated with neurodegenerative diseases, including hereditary spastic paraplegia, amyotrophic lateral sclerosis, and peripheral neuropathies. This review synthesizes current knowledge of axonal ER biology, highlighting its structural and dynamic characteristics, its impact on organelle arrangement and distribution, and its pathological implications in neurodegeneration. By consolidating recent advances, this review outlines emerging questions and future directions in axonal ER research, a field gaining recognition for its contribution to neuronal dysfunction and neurodegenerative pathomechanisms.

Keywords: Axon; Axonal transport; ER-shaping proteins; Endoplasmic reticulum; Membrane contact sites; Neurodegenerative diseases; Organelle dynamics

DOI: https://doi.org/10.1016/j.nbd.2025.107152

J Cell Sci. 2025 Oct 24. pii: jcs.264171. [Epub ahead of print]

Role of Pex31 in metabolic adaptation of the nucleus vacuole junction NVJ.

Marie Hugenroth, Pascal Höhne, Xue-Tong Zhao, Mike Wälte, Duy Trong Vien Diep, Rebecca Martina Fausten, Maria Bohnert.

The nucleus vacuole junction NVJ in yeast is a multifunctional contact site between the nuclear ER membrane and the vacuole with diverse roles in lipid metabolism, transfer and storage. Adaptation of NVJ functions to metabolic cues is mediated by a striking remodeling of the size and the proteome of the contact site, but the extent and the molecular determinants of this plasticity are not fully understood. Using microscopy-based screens, we monitored NVJ remodeling in response to glucose availability. We identified Pex31, Nsg1, Nsg2, Shr5, and Tcb1 as NVJ residents. Glucose starvation typically results in an expansion of the NVJ size and proteome. Pex31 shows an atypical behavior, being specifically enriched at the NVJ at high glucose conditions. Loss of Pex31 uncouples NVJ remodeling from glucose availability, resulting in recruitment of glucose starvation-specific residents and NVJ expansion at glucose replete conditions. Moreover, PEX31 deletion results in alterations of sterol ester storage and a remodeling of vacuolar membranes that phenocopy glucose starvation responses. We conclude that Pex31 has a role in metabolic adaptation of the NVJ.

Keywords: Nsg1; Nsg2; Pex30; Pex31; Shr5; Tcb1

DOI: https://doi.org/10.1242/jcs.264171