bims-mecosi 2025-09-28 papers

Issue of 2025–09–28
six papers selected by
Verena Kohler, Umeå University

MedComm (2020). 2025 Oct;6(10): e70379

Mitochondria-Associated Endoplasmic Reticulum Membranes in Health and Diseases.

Hangnan Hong, Zhenyang Guo, Junbo Ge, Hua Li.

Membrane contact sites enable organelles to interact closely, thereby coordinating cellular homeostasis and functional regulation. Among diverse subcellular membrane architectures, mitochondria-associated endoplasmic reticulum membranes (MAMs) assume a crucial role in the physiological and pathological environments. A plethora of cellular processes are intertwined with MAMs, such as Ca2+ translocation, lipid metabolism, endoplasmic reticulum (ER) stress response, mitochondrial dynamics, and mitophagy. In the event of improper modulation of MAMs components, the incidence of diseases would surge remarkably. This review endeavors to expound upon the functions of key MAMs proteins in healthy state and decipher their regulatory mechanisms under physiological and pathological circumstances. In addition, we try to probe into the specific contribution of MAMs within the occurrence and development of diseases, and subsequently collate drug compounds and clinical trials that target MAMs components. Finally, we proffer our insights regarding the contentious perspectives and prospective research directions of MAMs. Understanding the roles and mechanisms of MAMs may potentially offer novel diagnostic biomarkers and treatment targets in clinical practice, paving the way for more precise and effective clinical interventions for common diseases.

Keywords: cancers; cardiovascular diseases; metabolic diseases; mitochondrial‐associated membranes; neurodegenerative diseases

DOI: https://doi.org/10.1002/mco2.70379

Membranes (Basel). 2025 Aug 31. pii: 263. [Epub ahead of print]15(9):

Mitochondria-Associated Membrane Dysfunction in Neurodegeneration and Its Effects on Lipid Metabolism, Calcium Signaling, and Cell Fate.

Thi Thuy Truong, Alka Ashok Singh, Nguyen Van Bang, Nguyen Minh Hung Vu, Sungsoo Na, Jaeyeop Choi, Junghwan Oh, Sudip Mondal.

Mitochondria-associated membranes (MAMs) are essential for cellular homeostasis. MAMs are specialized contact sites located between the endoplasmic reticulum (ER) and mitochondria and control apoptotic pathways, lipid metabolism, autophagy initiation, and calcium signaling, processes critical to the survival and function of neurons. Although this area of membrane biology remains understudied, increasing evidence links MAM dysfunction to the etiology of major neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis (ALS). MAMs consist of a network of protein complexes that mediate molecular exchange and ER-mitochondria tethering. MAMs regulate lipid flow in the brain, including phosphatidylserine and cholesterol; disruption of this process causes membrane instability and impaired synaptic function. Inositol 1,4,5-trisphosphate receptor-voltage-dependent anion channel 1 (IP3R-VDAC1) interactions at MAMs maintain calcium homeostasis, which is required for mitochondria to produce ATP; dysregulation promotes oxidative stress and neuronal death. An effective therapeutic approach for altering neurodegenerative processes is to restore the functional integrity of MAMs. Improving cell-to-cell interactions and modulating MAM-associated proteins may contribute to the restoration of calcium homeostasis and lipid metabolism, both of which are key for neuronal protection. MAMs significantly contribute to the progression of neurodegenerative diseases, making them promising targets for future therapeutic research. This review emphasizes the increasing importance of MAMs in the study of neurodegeneration and their potential as novel targets for membrane-based therapeutic interventions.

Keywords: apoptosis; autophagy; calcium homeostasis; endoplasmic reticulum–mitochondria tethering; lipid metabolism; mitochondria-associated membranes (MAMs); neurodegeneration

DOI: https://doi.org/10.3390/membranes15090263

bioRxiv. 2025 Sep 16. pii: 2025.09.11.675705. [Epub ahead of print]

TRPML1 signaling at lysosomes-mitochondria nexus drives triple-negative breast cancer mitophagy, metabolic reprogramming and chemoresistance.

Alia K Syeda, Shekoufeh Almasi, J Cory Benson, Barry E Kennedy, Ryan M Yoast, Scott M Emrich, Logan Slade, Shanmugasundaram Pakkiriswami, Vishnu V Vijayan, Shashi Gujar, Thomas Pulinilkunnil, Mohamed Trebak, Yassine El Hiani.

Inter-organelle signaling mechanisms, particularly those at the lysosomes-mitochondria interface, are critical for cancer cell metabolism, mitophagy and survival. However, the incomplete understanding of these mechanisms has limited the development of effective therapies, especially for triple-negative breast cancers (TNBC). Here, we demonstrate the lysosomal Ca²⁺-release channel TRPML1 as a master regulator of mitochondrial bioenergetics in TNBC cells. TRPML1 knockdown (ML1-KD) in TNBC cells selectively compromises mitochondrial respiration, reprograms cell metabolism, and induces mitochondrial fragmentation without impacting non-cancerous cells. Mitochondria of ML1-KD TNBC cells sequester around the endoplasmic reticulum (ER), increasing mitochondria-ER contact sites at the expense of mitochondria-lysosomes contacts. Mechanistically, ML1-KD reduces lysosomal acidification, thus hindering autophagic flux and completion of autophagy. ML1-KD inhibits TFEB-mediated mitophagy and oxidative defense mechanisms while causing mitochondrial Ca 2+ overload, further impairing mitochondrial function. These alterations render ML1-KD TNBC cells highly sensitive to doxorubicin and paclitaxel at low doses that are typically ineffective on their own. Together, our findings establish TRPML1 as a critical inter-organelle regulator and highlight its potential as a therapeutic target to exploit the metabolic vulnerabilities of TNBC cells.

DOI: https://doi.org/10.1101/2025.09.11.675705

Front Physiol. 2025 ;16 1647275

Integrated bioinformatic analysis reveals the underlying mitochondria-associated endoplasmic reticulum membranes-related biomarkers for atrial fibrillation.

Youcheng Wang, Mengyang Song, Huanting Liu, Sini Fang, Yumeng Lei, Jiulin Liu, Jiayuan Zhang, Ke Zhang, Ying Mao, Liqiu Yan.

Purpose: To provide novel insights into the diagnosis of atrial fibrillation (AF), we aimed to identify mitochondria-associated endoplasmic reticulum membranes (MAMs)-related biomarkers for AF.
Methods: The training and validation datasets of AF were sourced from the Gene Expression Omnibus (GEO) database. A comprehensive analysis was conducted to identify MAM-related biomarkers, including support vector machine-recursive feature elimination (SVM-RFE) and differentially expressed analysis. Moreover, causal effects of biomarkers on AF were assessed through the two-sample Mendelian randomization (MR) analysis. Functional enrichment, immune infiltration, and single-cell analyses were conducted to investigate the possible mechanisms of biomarkers regulating AF. Finally, the expression of biomarkers was validated at the mRNA and protein levels by developing an in-vivo canine AF model.
Results: Through the comprehensive analysis, TP53, HLA-G, and MAPKAPK5 were identified, which were highly expressed in atrial tissues of AF samples. Notably, MAPKAPK5 was a risk factor for occurrence of AF (P = 0.022, OR = 1.065, 95%CI = 1.009-1.125). Enrichment analysis revealed that three biomarkers were associated with immune-related pathways. Immune infiltration further demonstrated that a total of infiltration abundance of 18 immune cells was significantly different between AF and controls, and all biomarkers had marked positive associations with these immune cells. Moreover, at the cellular level, the expression of TP53 and MAPKAPK5 was markedly different in lymphoid cells and neutrophils between AF and controls. At the experimental levels, the expression of three biomarkers was significantly higher in the AF model than that in the control model, consistent with the bioinformatics results.
Conclusion: We identified three potential MAMs-related biomarkers (TP53, HLA-G, and MAPKAPK5) for AF, thereby providing novel insights for the prevention and treatment of AF.

Keywords: atrial fibrillation; bioinformactics analysis; biomarker; immune infiltration; mitochondria-associated endoplasmic reticulum membranes

DOI: https://doi.org/10.3389/fphys.2025.1647275

Poult Sci. 2025 Sep 11. pii: S0032-5791(25)01059-4. [Epub ahead of print]104(11): 105818

Baicalin alleviates oxidative stress in DF-1 cell line via the Mfn2/MAMs/Ca (2+) pathway.

Zhaoyan Lin, Jiao Wang, Junxin Li, Yu Zheng, Bohan Zheng, Qinjin Li, Xiaohong Huang.

Oxidative stress is intricately associated with a variety of chicken diseases, and represents a significant challenge within the poultry industry. Baicalin (BA), a compound extracted from the plant Scutellaria Baicalensis, possesses potent antioxidant properties, however, the effects and mechanisms underlying the antioxidant activity of BA in chickens remain to be fully elucidated. This study aimed to demonstrate the antioxidant effects of BA in vitro, and to explore the underlying antioxidant mechanism. In this study, hydrogen peroxide (H2O2) was used to construct a model of oxidative stress in DF-1 cell line, and the antioxidant effect of BA in DF-1 cells was detected. The results indicated that BA significantly ameliorated the decline in total antioxidant capacity of DF-1 cells induced by H2O2, and preserved the mitochondrial function of DF-1 cells. Concurrently, H2O2 induced abnormal enrichment of mitochondria⁃associated membranes (MAMs) in DF-1 cells, leading to mitochondrial Ca2+ overload, and BA significantly mitigated this effect. Furthermore, transcriptomic sequencing and western blot analysis suggested that the Mitofusin-2 (Mfn2) gene is involved in the antioxidant process of BA. Moreover, following the siRNA-mediated interference of the Mfn2 gene, the antioxidant efficacy of BA was observed to be significantly diminished. In conclusion, BA alleviates H2O2-induced oxidative stress in DF-1 cells via the Mfn2/MAMs/Ca2+ pathway.

Keywords: Baicalin; Ca(2+); MAM; Mfn2; Oxidative stress

DOI: https://doi.org/10.1016/j.psj.2025.105818