bims-mecosi Biomed News
on Membrane contact sites
Issue of 2025–07–20
nine papers selected by
Verena Kohler, Umeå University
  1. The role of mitochondria-associated ER membranes in disease pathology: protein complex and therapeutic targets.
  2. The neurological pathology of peroxisomal ACBD5 deficiency - lessons from patients and mouse models.
  3. Structures and functions of the MICOS: Pathogenesis and therapeutic implications in Alzheimer's disease.
  4. Synergistic Control of Mitochondrial Dynamics and Function by ERAD and Autophagy in Brown Adipocytes.
  5. Mechanism of mitofusin 2/mitochondria-associated membrane/mitochondrial pathway in alleviating oxidative stress and cell senescence in bovine mammary epithelial cells.
  6. PACS2 initiates foam cell formation in macrophages through the ROS-PPARγ-CD36 positive feedback loop.
  7. Unraveling the Molecular Mechanisms of ABHD5 Membrane Targeting.
  8. Drug Repurposing Screen Identifies an HRI Activating Compound that Promotes Adaptive Mitochondrial Remodeling in MFN2-deficient Cells.
  9. A bridge-like lipid transport protein controls plasma membrane lipid composition and fluidity.
  1. Front Cell Dev Biol. 2025 ;13 1629568
    The role of mitochondria-associated ER membranes in disease pathology: protein complex and therapeutic targets.
    Jin Zhang, Dan Li, Lingjie Zhou, Yanying Li, Qian Xi, Liuyun Zhang, Juan Zhang.
      The dynamic interactions among organelles play a crucial role in facilitating various intercellular functions, with the interaction between the endoplasmic reticulum (ER) and mitochondria being acknowledged as a prominent example of an interorganellar system. Numerous studies have established that the majority of proteins located at the physically tethered regions between the mitochondria and ER, referred to as mitochondria-associated ER membranes (MAMs), play a crucial role in intracellular physiological processes. MAMs are dynamic membrane coupling regions arising from the interaction between the ER and the outer mitochondrial membrane (OMM). MAMs regulate many biological processes, such as Ca2+ transport, lipid metabolism, and mitochondrial dynamics. A recent study has demonstrated that the proteins associated with MAMs are crucial for both the structural integrity and functional capabilities of the MAMs. Dysregulations in the MAMs proteins are implicated in the onset and progression of various associated diseases, including cancer, neurodegenerative disorders, diabetes mellitus, and cardiovascular diseases. In this review, we provide a comprehensive overview of the protein complex associated with MAMs. We examine its involvement in the pathological mechanisms underlying these diseases, focusing on its functional roles. Additionally, we evaluate and consider the potential of MAMs as therapeutic targets for these diseases.
    Keywords:  cancer; cardiovascular diseases; diabetes mellitus; endoplasmic reticulum; mitochondria; mitochondria-associated ER membranes; neurodegeneration
    DOI:  https://doi.org/10.3389/fcell.2025.1629568
  2. Front Mol Neurosci. 2025 ;18 1602343
    The neurological pathology of peroxisomal ACBD5 deficiency - lessons from patients and mouse models.
    Michael L Dawes, Jim P Haberlander, Markus Islinger, Michael Schrader.
      The absence or dysfunction of the peroxisomal membrane protein Acyl-CoA Binding Domain-Containing Protein 5 (ACBD5) is the cause of the most recently discovered peroxisomal disorder "Retinal Dystrophy with Leukodystrophy" (RDLKD). ACBD5 is a tail-anchored protein, anchored by its C-terminus into the peroxisomal membrane; hence, the bulk of its amino acid sequence faces the cytosol. With respect to ACBD5's molecular functions, RDLKD is unique since it is not only an accessory protein for the import of very-long-chain fatty acids (VLCFAs) into peroxisomes but also the first identified peroxisomal tethering protein facilitating membrane contacts with the endoplasmic reticulum (ER). Consequently, RDLKD is neither a peroxisomal biogenesis disorder nor single enzyme deficiency, since a deficiency in ACBD5 likely affects several aspects of peroxisomal function including VLCFA degradation, ether lipid synthesis, docosahexaenoic acid synthesis but also the transfer of membrane lipids from the ER to peroxisomes. Hence, RDLKD appears to be a multifactorial disorder leading to a mosaic pathology, combining symptoms caused by the disruption of several pathways. In this review, we will highlight recent findings obtained from case reports of RDLKD patients as well as insights from ACBD5-deficient mouse models to better understand its complex retinal and brain pathology. Moreover, we will discuss the possible contribution of the different dysregulated metabolites in the neurological pathogenesis of this latest peroxisomal disorder.
    Keywords:  ACBD5; RDLKD; VAP; fatty acid metabolism; membrane contact sites; peroxisomes
    DOI:  https://doi.org/10.3389/fnmol.2025.1602343
  3. Acta Pharm Sin B. 2025 Jun;15(6): 2966-2984
    Structures and functions of the MICOS: Pathogenesis and therapeutic implications in Alzheimer's disease.
    Zihan Wang, Kaige Zhang, Minghao Huang, Dehao Shang, Xiaomin He, Zhou Wu, Xu Yan, Xinwen Zhang.
      Mitochondrial dysfunction is a critical factor in the pathogenesis of Alzheimer's disease (AD). The mitochondrial contact site and cristae organizing system (MICOS) plays a pivotal role in shaping the inner mitochondrial membrane, forming cristae junctions and establishing interaction sites between the inner and outer mitochondrial membranes and thereby serving as a cornerstone of mitochondrial structure and function. In the past decade, MICOS abnormalities have been extensively linked to AD pathogenesis. In particular, dysregulated expression of MICOS subunits and mutations in MICOS-related genes have been identified in AD, often in association with hallmark pathological features such as amyloid-β plaque accumulation, neurofibrillary tangle formation, and neuronal apoptosis. Furthermore, MICOS subunits interact with several etiologically relevant proteins, significantly influencing AD progression. The intricate crosstalk between these proteins and MICOS subunits underscores the relevance of MICOS dysfunction in AD. Therapeutic strategies targeting MICOS subunits or their interacting proteins may offer novel approaches for AD treatment. In the present review, we introduce current understanding of MICOS structures and functions, highlight MICOS pathogenesis in AD, and summarize the available MICOS-targeting drugs potentially useful for AD.
    Keywords:  Alzheimer's disease; CHCHD10; CHCHD2; Cristae junctions; MIC10; MIC60; MICOS complex; Mitochondria
    DOI:  https://doi.org/10.1016/j.apsb.2025.04.019
  4. bioRxiv. 2025 Jun 15. pii: 2025.06.14.659625. [Epub ahead of print]
    Synergistic Control of Mitochondrial Dynamics and Function by ERAD and Autophagy in Brown Adipocytes.
    Xinxin Chen, Siwen Wang, Mauricio Torres, Sijie Hao, Shengyi Sun, Ling Qi.
      Mitochondrial quality control is essential for maintaining cellular energy homeostasis, particularly in brown adipocytes where dynamic mitochondrial remodeling supports thermogenesis. Although the SEL1L-HRD1 endoplasmic reticulum (ER)-associated degradation (ERAD) pathway and autophagy are two major proteostatic systems, how these pathways intersect to regulate mitochondrial integrity in metabolically active tissues remains poorly understood. Here, using adipocyte-specific genetic mouse models combined with high-resolution 2D and 3D ultrastructural imaging technologies, we reveal an unexpected synergy between SEL1L-HRD1 ERAD and autophagy in maintaining mitochondrial structure and function in brown adipocytes. Loss of ERAD alone triggers compensatory autophagy, whereas combined deletion of both pathways (double knockout, DKO) results in severe mitochondrial abnormalities, including the accumulation of hyperfused megamitochondria penetrated by ER tubules, even under basal room temperature conditions. These phenotypes are absent in mice lacking either pathway individually or in SEL1L-IRE1α DKO, highlighting the pathway-specific coordination between ERAD and autophagy. Mechanistically, dual loss of ERAD and autophagy induces ER expansion, excessive ER-mitochondria contact, upregulation of mitochondria-associated membrane (MAM) tethering proteins, impaired calcium transfer, and defective mitochondrial turnover. As a result, DKO adipocytes accumulate dysfunctional mitochondria, exhibit respiratory deficits, and fail to sustain thermogenesis. Collectively, our study uncovers a cooperative and previously unrecognized mechanism of mitochondrial surveillance, emphasizing the critical role of ERAD-autophagy crosstalk in preserving mitochondrial integrity and thermogenic capacity in brown fat.
    One-sentence summary: Our study uncovers a previously unrecognized synergy between SEL1L-HRD1 ERAD and autophagy that is essential for preserving mitochondrial integrity and thermogenic capacity in brown adipocytes, revealing new opportunities for targeting mitochondrial dysfunction in metabolic disease.
    DOI:  https://doi.org/10.1101/2025.06.14.659625
  5. J Dairy Sci. 2025 Jul 09. pii: S0022-0302(25)00517-X. [Epub ahead of print]
    Mechanism of mitofusin 2/mitochondria-associated membrane/mitochondrial pathway in alleviating oxidative stress and cell senescence in bovine mammary epithelial cells.
    Huijie Hu, Juxiong Liu, Junxi Yin, Guiqiu Hu, Bingxu Huang, Liqun Tu, Xuanting Liu, Bin Xu, Yu Cao, Wenjin Guo, Shoupeng Fu.
      Bovine mastitis is a major challenge in the dairy industry, leading to persistent oxidative stress and mammary epithelial cell senescence, which impairs mammary gland function and hinders milk yield recovery. The mitochondria-associated membrane (MAM), a critical interface between mitochondria and the endoplasmic reticulum, plays an important role in redox balance and mitochondrial homeostasis. This study aimed to investigate the role of MAM in oxidative stress-induced cellular senescence in lactating Holstein dairy cows. We first examined oxidative stress markers and key proteins related to the MAM pathway in mammary tissues using Western blotting and commercial assay kits, and found that MAM pathway alterations were negatively correlated with oxidative stress. Transcriptome analysis further confirmed this association, with differentially expressed genes enriched in the mitochondria-endoplasmic reticulum network. Subsequently, an H2O2-induced oxidative stress model was established in bovine mammary epithelial cells. The results showed that oxidative stress inhibited MAM formation, promoted mitochondrial fission, and induced cellular senescence. In our previous experiments, we identified mitofusin 2 (MFN2) as a critical regulator in this process. Adenoviral overexpression of MFN2 enhanced MAM formation, alleviated oxidative stress, and delayed senescence. Further investigations revealed that MFN2 undergoes proteasomal degradation under oxidative stress. When the MAM structure was disrupted, MFN2 lost its antioxidative and antisenescence functions, indicating that MAM is essential for its activity. Based on this mechanism, we identified Gracilaria lemaneiformis polysaccharide (GLP) as a potential MFN2 activator. The GLP was found to upregulate MFN2 transcription, inhibit its ubiquitination, and enhance its protein stability. When combined with antibiotic therapy, GLP effectively reduced oxidative stress in mastitic cows, restored mammary gland function, and downregulated the expression of senescence-related markers. These findings suggest that oxidative stress-induced degradation of MFN2 impairs MAM formation, resulting in excessive mitochondrial fission and cellular senescence. Mitofusin 2 overexpression restores MAM integrity and mitigates oxidative stress. Activation of MFN2 by GLP offers a promising therapeutic strategy for mastitis, with potential to reduce recurrence and improve mammary gland health in dairy cows.
    Keywords:  MAM; MFN2; cell senescence; mastitis; oxidative stress
    DOI:  https://doi.org/10.3168/jds.2025-26746
  6. Biochem Pharmacol. 2025 Jul 11. pii: S0006-2952(25)00429-0. [Epub ahead of print]241 117164
    PACS2 initiates foam cell formation in macrophages through the ROS-PPARγ-CD36 positive feedback loop.
    Jie Ouyang, Shuhua Chen, Hong Xiang, Baiyi Tang, Haijiao Long, Quanjun Liu, Shiying Qin, Xinru Zheng, Alex F Chen, Hongwei Lu.
      Disrupted mitochondria-associated endoplasmic reticulum membrane (MAM) homeostasis is closely linked to obesity-related diseases and insulin resistance pathogenesis. The formation of foam cells with classically activated lipid uptake by macrophages is an important mechanism in the progression of atherosclerosis. This study investigated the effects of the MAM interface anchor protein, phosphofurin acidic cluster sorting protein 2 (PACS2), on atherosclerosis. MAM expansion, accompanied by elevated PACS2 expression, was observed in the plaques of atherosclerotic mice and oxidized low-density lipoprotein (Ox-LDL)-treated macrophages. Furthermore, PACS2 knockout in mice significantly reduced atherosclerotic plaque formation and improved the lipid profiles. PACS2 activated the ROS-PPARγ-CD36 signaling pathway, which drove lipid uptake in macrophages. Notably, the activation of this signaling pathway also increased PACS2 production. PACS2 knockout or silencing disrupted the positive feedback loop between PACS2 and ROS-PPARγ-CD36, preventing the proatherogenic phenotypic changes in macrophages. These findings establish the causal role of PACS2 in atherosclerosis related to modulating the macrophage phenotype and highlight its potential as a therapeutic target in atherosclerosis-driven cardiovascular diseases.
    Keywords:  Atherosclerosis; Foam cell; Lipid uptake; Macrophage; PACS2
    DOI:  https://doi.org/10.1016/j.bcp.2025.117164
  7. bioRxiv. 2025 May 11. pii: 2025.05.06.652485. [Epub ahead of print]
    Unraveling the Molecular Mechanisms of ABHD5 Membrane Targeting.
    Amit Kumar, Matthew Sanders, Huamei Zhang, Li Zhou, Shahnaz Parveen, Christopher V Kelly, James G Granneman, Yu-Ming Huang.
      ABHD5 plays a critical role in lipid metabolism, regulating fatty acid mobilization, skin barrier formation, and phospholipid remodeling. ABHD5 lacks catalytic activity and instead functions as an essential co-regulator of PNPLA enzymes. Understanding how ABHD5 interacts with lipid droplet (LD) and endoplasmic reticulum (ER) membranes is crucial for unraveling its regulatory role in lipid metabolism and identifying potential therapeutic targets for metabolic diseases. While previous studies have modeled ABHD5 structure in solution, its function relies on membrane interactions, requiring a detailed investigation of its binding mechanisms. In this study, we employed multiscale simulations with experimental validation to reveal how ABHD5 interacts with ER and LD. Our findings show that ABHD5 binds membranes through its N-terminus and insertion segment, which subsequently triggers structural changes in the pseudosubstrate pocket and alters lipid distribution. This study also identifies key residues essential for membrane binding, providing potential targets for developing lipid metabolism modulators. These results uncover a previously unrecognized mechanism by which ABHD5 interacts with membranes, offering new insights into lipolysis regulation and potential therapeutic strategies for metabolic diseases.
    DOI:  https://doi.org/10.1101/2025.05.06.652485
  8. bioRxiv. 2025 Jun 26. pii: 2025.06.23.660251. [Epub ahead of print]
    Drug Repurposing Screen Identifies an HRI Activating Compound that Promotes Adaptive Mitochondrial Remodeling in MFN2-deficient Cells.
    Prerona Bora, Mashiat Zaman, Samantha Oviedo, Sergei Kutseikin, Nicole Madrazo, Prakhyat Mathur, Meera Pannikkat, Sophia Krasny, Alan Chu, Kristen A Johnson, Danielle A Grotjahn, Timothy E Shutt, R Luke Wiseman.
      Pathogenic variants in the mitochondrial outer membrane GTPase MFN2 cause the peripheral neuropathy Charcot-Marie-Tooth Type 2A (CMT2A). These mutations disrupt MFN2-dependent regulation of diverse aspects of mitochondrial biology including organelle morphology, motility, mitochondrial-endoplasmic reticulum (ER) contacts (MERCs), and respiratory chain activity. However, no therapies currently exist to mitigate the mitochondrial dysfunction linked to genetic deficiencies in MFN2. Herein, we performed a drug repurposing screen to identify compounds that selectively activate the integrated stress response (ISR) - the predominant stress-responsive signaling pathway responsible for regulating mitochondrial morphology and function. This screen identified the compounds parogrelil and MBX-2982 as potent and selective activators of the ISR through the OMA1-DELE1-HRI signaling axis. We show that treatment with these compounds promotes adaptive, ISR-dependent remodeling of mitochondrial morphology and protects mitochondria against genetic and chemical insults. Moreover, we show that pharmacologic ISR activation afforded by parogrelil restores mitochondrial tubular morphology, promotes mitochondrial motility, rescues MERCs, and enhances mitochondrial respiration in MFN2 -deficient cells. These results demonstrate the potential for pharmacologic HRI activation as a viable strategy to mitigate mitochondrial dysfunction in CMT2A and other pathologies associated with MFN2 deficiency.
    DOI:  https://doi.org/10.1101/2025.06.23.660251
  9. Nat Cell Biol. 2025 Jul;27(7): 1059-1060
    A bridge-like lipid transport protein controls plasma membrane lipid composition and fluidity.
      
    DOI:  https://doi.org/10.1038/s41556-025-01680-3
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