bims-mecosi Biomed News
on Membrane contact sites
Issue of 2025–07–13
sixteen papers selected by
Verena Kohler, Umeå University
  1. A guide to characterizing the dynamic mitochondria-endoplasmic reticulum contact sites.
  2. Pex3 promotes formation of peroxisome-peroxisome and peroxisome-lipid droplet contact sites.
  3. Nondisruptive inducible labeling of ER-membrane contact sites using the Lamin B receptor.
  4. Organelles share the load.
  5. Ca2+-dependent vesicular and non-vesicular lipid transfer controls hypoosmotic plasma membrane expansion.
  6. Sarcoplasmic Reticulum-Mitochondria Microdomains: Hugging and Kissing in the Heart.
  7. Acid sphingomyelinase promotes diabetic cardiomyopathy via disruption of mitochondrial calcium homeostasis.
  8. ER-endosome contacts generate a local environment promoting phagophore formation.
  9. Photobiomodulation mediates endoplasmic reticulum-mitochondria contact and ameliorates lipotoxicity in MASLD via Mfn2 upregulation.
  10. ROS transfer at peroxisome-mitochondria contact regulates mitochondrial redox.
  11. Peroxisome dynamics and inter-organelle interactions in neuronal health and disease.
  12. Bis(2-Ethylhexyl)-2,3,4,5-Tetrabromophthalate Promotes NASH Progression through Disrupting Endoplasmic Reticulum-Mitochondria Contacts.
  13. Controlling mitochondrial membrane architecture via MIC60 determines viral replication to promote anti-viral immunity.
  14. Mendelian Randomization Analysis of Mitochondria-Related Genes and Screening of Prognostic Genes in Colorectal Cancer.
  15. Increased BNIP3-mediated mitophagy attenuates GDAP1 loss of function - implications for Charcot-Marie-Tooth disease 4A.
  16. Integrated bioinformatics and experimental analysis of mitochondrial-associated membrane function and mechanism in acute respiratory distress syndrome​​.
  1. FEBS J. 2025 Jul 07.
    A guide to characterizing the dynamic mitochondria-endoplasmic reticulum contact sites.
    Antigoni Diokmetzidou, Luca Scorrano.
      Organelles were once regarded as discrete entities, but it is now established that they interact through specialized membrane contacts maintained by protein tethers and lipid interactions. Among these, mitochondria-endoplasmic reticulum contact sites (MERCS) emerged as hubs for calcium signaling, lipid metabolism, and mitochondrial dynamics. Here, we critically appraise current methodologies for MERC visualization and quantification, survey the molecular toolbox for their selective perturbation, and highlight common experimental pitfalls. We also discuss key conceptual issues-defining MERCs on structural and functional grounds, addressing redundancy among tethering factors, and distinguishing primary MERC-mediated effects from secondary cellular responses. Finally, we propose that an integrative strategy combining imaging, precise biochemical isolation, proteomics, and functional assays will be essential to resolve outstanding questions about MERC dynamics in physiology and pathology.
    Keywords:  endoplasmic reticulum; imaging; membrane contact sites; mitochondria; mitochondria–ER contact sites
    DOI:  https://doi.org/10.1111/febs.70184
  2. Sci Rep. 2025 Jul 08. 15(1): 24480
    Pex3 promotes formation of peroxisome-peroxisome and peroxisome-lipid droplet contact sites.
    Lucía Amado, Louis Percifull, Rico Franzkoch, Vico Flatemersch, Eleni Joana Brüggemann, Olympia Ekaterini Psathaki, Maya Schuldiner, Maria Bohnert, Margret H Bülow, Ayelén González Montoro.
      Peroxisomes are ubiquitous organelles that mediate central metabolic functions, such as fatty acid β-oxidation, as well as diverse tissue- and organism-specific processes. Membrane contact sites, regions of close apposition with other organelles for direct communication, are central to several aspects of their life cycle. Pex3 is a conserved multifunctional peroxisomal transmembrane protein that is involved in the insertion of peroxisomal membrane proteins, in pexophagy, and in the formation of membrane contact sites. Here, we show that high Pex3 levels in Saccharomyces cerevisiae induce the formation of peroxisome clusters surrounded by lipid droplets, mediated by peroxisome-peroxisome and peroxisome-lipid droplet contact sites. This clustering occurs independently of Pex3 partners in other processes Pex19, Inp1, and Atg36. The cytosolic domain of Pex3 binds peroxisomes, suggesting a direct role in homotypic contact site formation. Lipid droplet-peroxisome contact sites require the lipid droplet-localized triacylglycerol lipase Tgl4, which is enriched at this interface along with other lipases. Pex3 overexpression in Drosophila melanogaster similarly alters peroxisome and lipid droplet morphology and promotes contact site formation. Together, our results offer novel molecular insights into homotypic peroxisome contact sites and peroxisome-lipid droplet contact sites across species.
    DOI:  https://doi.org/10.1038/s41598-025-07934-2
  3. PLoS Biol. 2025 Jul;23(7): e3003249
    Nondisruptive inducible labeling of ER-membrane contact sites using the Lamin B receptor.
    Laura Downie, Nuria Ferrandiz, Elizabeth Courthold, Megan Jones, Stephen J Royle.
      Membrane contact sites (MCSs) are areas of close proximity between organelles that allow the exchange of material, among other roles. The endoplasmic reticulum (ER) has MCSs with a variety of organelles in the cell. MCSs are dynamic, responding to changes in cell state, and are, therefore, best visualized through inducible labeling methods. However, existing methods typically distort ER-MCSs, by expanding contacts or creating artificial ones. Here, we describe a new method for inducible labeling of ER-MCSs using the Lamin B receptor (LBR) and a generic anchor protein on the partner organelle. Termed LaBeRling, this versatile, one-to-many approach allows labeling of different types of ER-MCSs (mitochondria, plasma membrane, lysosomes, early endosomes, lipid droplets, and Golgi), on-demand, in interphase or mitotic human cells. LaBeRling is nondisruptive and does not change ER-MCSs in terms of the contact number, extent or distance measured; as determined by light microscopy or a deep-learning volume electron microscopy approach. We applied this method to study the changes in ER-MCSs during mitosis and to label novel ER-Golgi contact sites at different mitotic stages in live cells.
    DOI:  https://doi.org/10.1371/journal.pbio.3003249
  4. Science. 2025 Jul 10. 389(6756): 130-131
    Organelles share the load.
    Marc Fransen.
      Peroxisome-mitochondria contact sites manage mitochondrial oxidative stress.
    DOI:  https://doi.org/10.1126/science.adz0109
  5. BMC Biol. 2025 Jul 09. 23(1): 207
    Ca2+-dependent vesicular and non-vesicular lipid transfer controls hypoosmotic plasma membrane expansion.
    Baicong Mu, David M Rutkowski, Gianluca Grenci, Dimitrios Vavylonis, Dan Zhang.
       BACKGROUND: Robust coordination of surface and volume changes is critical for cell integrity. Few studies have elucidated the plasma membrane (PM) remodeling events during drastic cell surface and volume alteration, especially regarding PM sensing and its subsequent rearrangements.
    RESULTS: In this article, using fission yeast protoplasts, we reveal a Ca2+-dependent mechanism for membrane addition that ensures PM integrity and allows its expansion during acute hypoosmotic cell swelling. We show that MscS-like mechanosensitive channels activated by PM tension control extracellular Ca2+ influx, which triggers potential direct lipid transfer at endoplasmic reticulum (ER)-PM contact sites by conserved extended-synaptotagmins and accelerates exocytosis, enabling PM expansion necessary for osmotic equilibrium. Defects in any of these key events result in rapid protoplast rupture upon severe hypotonic shock. Our numerical simulations of such hypoosmotic PM expansion further propose a cellular strategy that combines instantaneous non-vesicular lipid transfer with bulk exocytic membrane delivery to maintain PM integrity for dramatic cell surface/volume adaptation.
    CONCLUSIONS: We propose a cellular strategy that combines instantaneous non-vesicular lipid transfer with bulk exocytic membrane delivery to maintain PM integrity for dramatic cell surface/volume adaptation.
    Keywords:  Ca2+ signaling; ER-PM contacts; Exocytosis; Extended-synaptotagmins; Fission yeast; Hypoosmotic shock; MscS-like mechanosensitive channels; Non-vesicular lipid transfer; PM expansion; PM integrity
    DOI:  https://doi.org/10.1186/s12915-025-02309-5
  6. Am J Physiol Cell Physiol. 2025 Jul 11.
    Sarcoplasmic Reticulum-Mitochondria Microdomains: Hugging and Kissing in the Heart.
    Bong Sook Jhun, Jin O-Uchi, Brian Rhee, Ameneh Ahrari, Nathan DeMichaelis, Kye-Im Jeon, David M Booth, Shey-Shing Sheu.
      Endoplasmic reticulum (ER)-mitochondrial (ER-Mito) interface, termed mitochondrial-ER contacts (MERCs), plays significant roles in the maintenance of bioenergetics and basal cell functions via the exchange of lipids, Ca2+, and reactive oxygen species (ROS) in various cell-types/tissues. Genetic deletion of mitofusin 2 (Mfn2), one of the key components of ER-Mito tethering, in cardiomyocytes (CMs) in vivo revealed the importance of the microdomains between mitochondria and sarcoplasmic reticulum (SR), a differentiated form of ER in muscle cells, for maintaining normal mitochondrial Ca2+ (mtCa2+) handling and bioenergetics in the adult heart. However, key questions remain to be answered: 1) What tethering proteins sustain SR-Mito contact site structure in SR-Mito contact sites in the adult ventricular CMs (AVCMs), the predominant cell type in adult heart; 2) Which MERC proteins operate in AVCMs to mediate specific microdomain functions under physiological conditions; 3) How is the MERC protein expression profile and function altered in cardiac pathophysiology. In this review, we summarize current knowledge regarding the structure, function, and regulation of SR-Mito microdomains in the heart, with particular focus on AVCMs, which display unique membrane organization and Ca2+ handling compared to other cell types. We further explore molecular mechanisms underpinning microdomain dysfunction in cardiac diseases and highlight the emerging roles of MERC proteins in the development and progression of cardiac pathology.
    Keywords:  IP3 receptor; calcium; cardiac myocyte; mitochondria-associated membrane; ryanodine receptor
    DOI:  https://doi.org/10.1152/ajpcell.00435.2025
  7. Cardiovasc Diabetol. 2025 Jul 10. 24(1): 272
    Acid sphingomyelinase promotes diabetic cardiomyopathy via disruption of mitochondrial calcium homeostasis.
    Yu Wei, Yang Ji, Jiahui Meng, Li Yu, Yongzhong Tang, Wei-Jin Fang.
       BACKGROUND: Impaired Ca2+ handling is involved in diabetic cardiomyopathy (DCM) progression. The activation of acid sphingomyelinase (ASMase) stimulated cardiomyocytes apoptosis and caused DCM. Here, we aimed to investigate whether ASMase regulates mitochondrial Ca2+ homeostasis by acting on mitochondrial calcium uptake 1 (MICU1) and mitochondria-associated endoplasmic reticulum membranes (MAMs) formation to induce apoptosis during DCM.
    METHODS AND RESULTS: We established a type 2 diabetes model by combining high-fat diet (HFD) with streptozotocin (STZ) injection in wild-type and cardiomyocyte-specific ASMase deletion (ASMaseMyh6KO) mice. ASMase deletion restored HFD/STZ-induced cardiac dysfunction, remodeling, myocardial lipid accumulation and apoptosis. Single cell sequencing and Gene ontology (GO) enrichment analysis pointed to "cardiac muscle contraction" and "positive regulation of mitochondrial calcium ion concentration", which were confirmed by high glucose (HG, 30 mM) and palmitic acid (PA, 200 μM) induced mitochondrial Ca2+ overload in H9c2 cell lines at time dependence, accompanied by the upregulation of ASMase and MICU1 protein expressions. The similar effects were noted in ASMase overexpressed cardiomyocytes. Interestingly, endoplasmic reticulum (ER) Ca2+ level was decreased at the corresponding time, suggesting that increased mitochondrial Ca2+ level may be derived from ER. Notably, enhanced MAMs formation was found in HG + PA treated H9c2 cells, accompanied by blocked autophagy, similar results were obtained in ASMase overexpressing cells or HFD/STZ hearts. Loss of ASMase prevented HFD/STZ or HG + PA incubation induced cardiac hypertrophy, mitochondrialCa2+ overload, ROS production, autophagy blockage and MICU1 upregulation.
    CONCLUSIONS: HFD/STZ-induced ASMase upregulation enhances MAMs formation, promoting mitochondrial Ca2+ overload through MICU1 activation, leading to ROS generation, autophagy blockage and apoptosis in DCM. Therefore, targeting ASMase-MICU1 pathway emerges as a potential therapeutic approach for managing DCM.
    Keywords:  ASMase; Diabetic cardiomyopathy; MICU1; Mitochondrial calcium homeostasis
    DOI:  https://doi.org/10.1186/s12933-025-02801-w
  8. Cell Rep. 2025 Jul 09. pii: S2211-1247(25)00764-8. [Epub ahead of print]44(7): 115993
    ER-endosome contacts generate a local environment promoting phagophore formation.
    Juliane Da Graça, Charlotte Thiola, Myckaëla Rouabah, Ida Chiara Guerrera, Naïma El Khallouki, Maryse Romao, Carla Alemany, Dobrawa Amiri, Sarah Dubois, Ashvini Srimoorthy, Francesca Giordano, Graça Raposo, Etienne Morel.
      Autophagy starts with the formation of a double-membrane vacuole called the autophagosome, initiated by a transient structure known as the phagophore. Previous studies reported that phagophore biogenesis primarily occurs at endoplasmic reticulum (ER) omegasome subdomains, but other evidence suggests that the phagophore derives from recycling endosomes. Our study demonstrates the importance of ER-endosome interactions, revealing the dynamic mobilization of endosome-ER contact sites (EERCSs) in response to starvation. We characterize a sequential tethering of Rab5 and Rab11 endosomes to omegasomes, facilitating phagophore biogenesis. Detailed analyses reveal that EERCS-associated molecular machinery creates a confined environment that promotes local Ca2+ accumulation and liquid-liquid phase separation at ER exit sites. This environment primes de novo phagophore formation through a Rab3a-RAB3GAP1/2-mediated nano-vesicle fusion. We propose that EERCS mobilization generates transient cytoplasmic confinement, fostering localized accumulation of components for phagophore biogenesis. Our study reveals a novel role for the ER-endosome interface in the nutrient deprivation response, emphasizing organelle coordination during autophagy initiation.
    Keywords:  CP: Cell biology; ER; autophagy; calcium; endoplasmic reticulum; endosomes; membrane contact sites; phagophore; phase transition; starvation
    DOI:  https://doi.org/10.1016/j.celrep.2025.115993
  9. J Photochem Photobiol B. 2025 Jul 02. pii: S1011-1344(25)00112-5. [Epub ahead of print]270 113209
    Photobiomodulation mediates endoplasmic reticulum-mitochondria contact and ameliorates lipotoxicity in MASLD via Mfn2 upregulation.
    Zhixuan Jiang, Shan Wu, Shengzhe Zhou, Hongjie Zheng, Yubing Bai, Yiqiu Zhang, Min Yao.
      The disruption of mitochondria associated membranes (MAMs) is involved in the pathogenesis of metabolic dysfunction-associated steatotic liver disease (MASLD) by modulating endoplasmic reticulum stress (ERS) and mitochondrial malfunction induced by lipotoxicity. Photobiomodulation (PBM), as a non-invasive physical therapy, has been demonstrated to improve cellular metabolism in various diseases. Here we found that PBM with 650 nm ameliorated lipid accumulation and liver injury in high-fat-diet-fed mice. Moreover, MAMs integrity was restored in liver tissues of MASLD after PBM. Correspondingly, PBM enhanced mitochondria-ER colocalization and improved mitochondrial homeostasis in fatty-acid-treated HepG2 cells. Mechanically, Mfn2 expression was selectively elevated by PBM, accompanied by downregulation of PERK, p-PERK, and CHOP. The beneficial effects of PBM were diminished by Mfn2 knockdown, while PERK activity regulated oxidative stress without altering MAMs formation. Thus, PBM relieves lipotoxicity in MASLD by enhancing MAMs integrity via the Mfn2/PERK/CHOP pathway. Our findings may provide evidence for noninvasive physical light therapeutics for lifestyle-related metabolic diseases.
    Keywords:  MAMs; MASLD; Mfn2; Mitochondria; PERK; Photobiomodulation
    DOI:  https://doi.org/10.1016/j.jphotobiol.2025.113209
  10. Science. 2025 Jul 10. 389(6756): 157-162
    ROS transfer at peroxisome-mitochondria contact regulates mitochondrial redox.
    Laura F DiGiovanni, Prabhsimran K Khroud, Ruth E Carmichael, Tina A Schrader, Shivneet K Gill, Kyla Germain, Robert Y Jomphe, Christoph Wiesinger, Maxime Boutry, Maki Kamoshita, Daniel Snider, Garret Stubbings, Rong Hua, Noel Garber, Christian Hacker, Andrew D Rutenberg, Roman A Melnyk, Johannes Berger, Michael Schrader, Brian Raught, Peter K Kim.
      Maintenance of mitochondrial redox homeostasis is of fundamental importance to cellular health. Mitochondria harbor a host of intrinsic antioxidant defenses, but the contribution of extrinsic, nonmitochondrial antioxidant mechanisms is less well understood. We found a direct role for peroxisomes in maintaining mitochondrial redox homeostasis through contact-mediated reactive oxygen species (ROS) transfer. We found that ACBD5 and PTPIP51 form a contact between peroxisomes and mitochondria. The percentage of these contacts increased during mitochondrial oxidative stress and helped to maintain mitochondrial health through the transfer of mitochondrial ROS to the peroxisome lumen. Our findings reveal a multiorganelle layer of mitochondrial antioxidant defense-suggesting a direct mechanism by which peroxisomes contribute to mitochondrial health-and broaden the scope of known membrane contact site functions.
    DOI:  https://doi.org/10.1126/science.adn2804
  11. Front Mol Neurosci. 2025 ;18 1603632
    Peroxisome dynamics and inter-organelle interactions in neuronal health and disease.
    Ruth E Carmichael.
      Peroxisomes are essential organelles, present in all nucleated cells, with key roles in lipid and redox homeostasis. They are important for maintaining healthy cell function, with defects in peroxisome biogenesis and/or metabolism leading to disease. Notably, patients with peroxisomal diseases exhibit predominantly neurological phenotypes, and peroxisomes are observed to be altered in a range of neurodegenerative conditions, highlighting the crucial roles they play in the brain. While most studies so far have focused on the contribution of peroxisomal metabolism, it is becoming apparent that many different aspects of peroxisome biology are necessary for healthy neural function. Peroxisomes are highly dynamic, responding to cellular needs with changes in number, shape and distribution. Furthermore, they do not act in isolation but instead interact and cooperate with a range of organelles to carry out their roles. This review summarizes our current knowledge on the importance of peroxisome dynamics and inter-organelle interactions in neuronal function and dysfunction. It considers their impact on neuronal physiology, and discusses the evidence that defects in these processes are associated with neurological pathophysiology and may thus represent a novel therapeutic target for treating diseases affecting the nervous system. Finally, the review outlines the current knowledge gaps relating to the mechanisms by which peroxisome dynamics and inter-organelle interactions influence neuronal (dys)function, proposing potential new research directions to address these and further our understanding of the multi-faceted roles peroxisomes play in brain health and disease.
    Keywords:  MFF; PEX11β; membrane contact sites; membrane dynamics; neurodegeneration; neuron; peroxisome
    DOI:  https://doi.org/10.3389/fnmol.2025.1603632
  12. Environ Sci Technol. 2025 Jul 10.
    Bis(2-Ethylhexyl)-2,3,4,5-Tetrabromophthalate Promotes NASH Progression through Disrupting Endoplasmic Reticulum-Mitochondria Contacts.
    Yuxi Zhou, Bingjie Li, Jiadi Zhao, Xinxin Ren, Yongyong Guo, Lihua Yang, Jian Han, Lijun Wu, Bingsheng Zhou.
      Growing evidence has established potential associations between environmental pollutants and the progression of chronic liver diseases. Bis(2-ethylhexyl)-2,3,4,5-tetrabromophthalate (TBPH), a widely used novel brominated flame retardant, has raised concerns due to its widespread detection in human tissues. However, its role in chronic liver diseases remains poorly understood. In this study, we established both mouse and liver organoid (LO) models to investigate the impact of TBPH exposure on the progression of nonalcoholic steatohepatitis (NASH) and the underlying mechanisms. In a diet-induced NASH mouse model, TBPH exposure significantly enhanced hepatic steatosis, inflammation, and fibrosis. Lipidomic analysis revealed that TBPH induced dysregulation of phospholipid metabolism, particularly reduced levels of cardiolipin (CL) and phosphatidylserine (PS). Mechanistically, TBPH decreased Mitofusin2 (MFN2) expression, leading to impaired endoplasmic reticulum-mitochondria (ER-Mito) contacts, disrupted phospholipid transfer, and subsequent mitochondrial dysfunction. These alterations triggered both mitochondrial unfolded protein response (UPRmt) and ER stress. Importantly, the activation of MFN2 with the agonist M1 in LOs alleviated TBPH-induced NASH phenotypes by restoring ER-Mito contacts and cellular bioenergetics. Our findings identify TBPH as an environmental risk factor for NASH progression, providing novel insights into the MFN2-mediated ER-Mito contacts in lipid metabolic homeostasis and new perspectives for the health risk evaluation of brominated flame retardants.
    Keywords:  ER-Mito contacts; bis(2-ethylhexyl)-2,3,4,5-tetrabromophthalate; liver organoid; mitochondria-associated membranes; nonalcoholic steatohepatitis
    DOI:  https://doi.org/10.1021/acs.est.5c03965
  13. Cell Rep. 2025 Jul 01. pii: S2211-1247(25)00693-X. [Epub ahead of print] 115922
    Controlling mitochondrial membrane architecture via MIC60 determines viral replication to promote anti-viral immunity.
    Ichiro Katahira, Nina Liebrand, Michal Gorzkiewicz, Niklas Paul Klahm, Džiuljeta Abromavičiūtė, Julia Werner, Karina Stephanie Krings, Sarah Orywol, Tobias Lautwein, Karl Köhrer, Diran Herebian, Ertan Mayatepek, Max Anstötz, Ann Kathrin Bergmann, Arun Kumar Kondadi, Haifeng C Xu, Aleksandra A Pandyra, Takumi Kobayashi, Dirk Brenner, Thomas Floss, Ulrich Kalinke, Andreas S Reichert, Philipp A Lang.
      Virus-infected cells often exhibit dramatic cellular changes accompanied by altered mitochondrial function. The contribution of factors shaping the inner mitochondrial membrane (IMM) and cristae architecture to viral replication is insufficiently understood. Single-cell transcriptomics applying vesicular stomatitis virus infection suggests involvement of factors determining IMM architecture following infection. Consistently, inhibition of the F1FO adenosine triphosphate (ATP) synthase reduces viral replication, which is associated with oligomerization of this complex and altered IMM structure. Moreover, deletion of mitochondrial contact site and cristae organizing system (MICOS) complex by targeting MIC60 results in reduced viral replication. Generation of Mic60inv/invCD11c-Cre+ mice uncovers reduced crista junctions and viral replication in bone marrow-derived dendritic cells. Consequently, reduced viral replication in CD11c-expressing cells limits prolonged immune activation. Altogether, by linking the F1FO ATP synthase and the MICOS complex to viral replication and immune activation, we describe links between the mitochondrial structure-metabolism and the immune response against viral infection.
    Keywords:  BMDC; CP: Cell biology; CP: Microbiology; MIC60; MICOS; immunometabolism; innate immunity; inner mitochondrial membrane; itaconate; mitochondria; viral infection
    DOI:  https://doi.org/10.1016/j.celrep.2025.115922
  14. Cancer Med. 2025 Jul;14(13): e71012
    Mendelian Randomization Analysis of Mitochondria-Related Genes and Screening of Prognostic Genes in Colorectal Cancer.
    Limin Zhu, Xiaowei Huang, Fan Zhang, Jinzu Yang, Zhenye Xu.
       BACKGROUND: Mitochondria have been linked with inflammatory colorectal cancer (CRC) development; however, the association between mitochondria-related genes (MRGs) and CRC remains unknown.
    AIMS: To explore the causal relationship between MRGs and CRC, screen prognostic genes, conduct drug prediction analyses, and investigate the correlations between prognostic genes and immune cells.
    MATERIALS AND METHODS: We obtained 1136 MRGs from the MitoCarta3.0 database and analyzed the causal relationship between MRGs expression, methylation, and protein abundance and CRC by Mendelian randomization and sensitivity testing. Prognostic genes were screened via protein-protein interaction networks, enrichment, multi-omics, and survival analyses. Selected key genes were subjected to drug prediction analyses. The prognostic genes and immune cell correlations were explored using Spearman's correlation.
    RESULTS: The results indicated that 44 MRGs showed causal relationships with CRC. Six genes (sterol carrier protein2 [SCP2], ATP binding cassette subfamily D member 3 [ABCD3], cytochrome coxidase assembly factor heme A: farnesyltransferase [COX10], mitochondrial contact site and cristae organizing system subunit 10 [MiCOS 10], glutaryl-Coenzyme A dehydrogenase [GCDH], and mitochondrial translational release factor 1-like [MTRF1L] were causally associated with CRC and showed better prognostic significance when their expression levels were high, and there were 106 drugs targeting them. SCP2, ABCD3, MICOS10, GCDH, and MTRF1L were associated with most immune cells, while COX10 was not associated with any of the 96 immune cells.
    DISCUSSION: The identification of causal MRGs and their prognostic significance provides new insights into mitochondria's role in CRC. Drug prediction and immune correlations may guide therapy, but validation in larger cohorts and models is needed.
    CONCLUSION: This study reveals causal associations between specific MRGs and CRC, identifies prognostic genes with therapeutic potential, and clarifies immune cell relationships, advancing CRC pathogenesis understanding and treatment development.
    Keywords:  Mendelian randomization; colorectal cancer; mitochondria‐related genes; potential targets; prognosis
    DOI:  https://doi.org/10.1002/cam4.71012
  15. Neurobiol Dis. 2025 Jul 04. pii: S0969-9961(25)00235-9. [Epub ahead of print]213 107019
    Increased BNIP3-mediated mitophagy attenuates GDAP1 loss of function - implications for Charcot-Marie-Tooth disease 4A.
    Li Zhang, Alireza Pouya, Janina Kopetzky, Sara Bitar, Christina Wolf, Federica Dal Bello, David Gomez-Zepeda, Stefan Tenzer, Axel Methner.
      Charcot-Marie-Tooth disease type 4 A ((CMT4A), an autosomal recessive neuropathy, is caused by mutations in ganglioside-induced differentiation-associated protein 1 (GDAP1). GDAP1 resides in the outer mitochondrial membrane facing the cytosol and is involved in mitochondrial dynamics and function. Its perturbation affects mitochondrial shape, contact sites, redox homeostasis and cellular metabolism. In response to GDAP1 knockdown in a human neuronal cell line, we found increased mitochondrial turnover, biogenesis and mitophagy. This was associated with more lysosomal proteins in mitochondrial fractions including BCL2/adenovirus E1B 19 kDa protein-interacting protein 3 (BNIP3) and its homolog BNIP3-like (BNIP3L) - proteins involved in the recruitment of autophagy machinery via direct interaction. Flies with neural Gdap1 knockdown also exhibited upregulated levels of the sole BNIP3 ortholog. Neural expression of human BNIP3 reduced the detrimental effects of Gdap1 knockdown on eclosion and climbing ability in adult flies, while simultaneous knockdown of both genes was detrimental. These findings suggest that increased BNIP3-driven mitophagy may act as a protective mechanism, partially counteracting the cellular dysfunction caused by GDAP1 loss of function, and highlight the potential of targeting mitophagy pathways as a therapeutic strategy for CMT4A.
    Keywords:  BNIP3; Charcot-Marie-tooth (CMT) disease; Drosophila; GDAP1; Mitophagy
    DOI:  https://doi.org/10.1016/j.nbd.2025.107019
  16. Sci Rep. 2025 Jul 09. 15(1): 24602
    Integrated bioinformatics and experimental analysis of mitochondrial-associated membrane function and mechanism in acute respiratory distress syndrome​​.
    Yanqiong Zhou, Qiuying Chen, Xiaoxia Wang, Kaimin Lv, Hui Huang, Jifeng Feng, Bijun Luo.
      Acute respiratory distress syndrome (ARDS) is a life-threatening lung condition characterized by severe inflammation, immune dysregulation, and oxidative stress, leading to high mortality (30-40%). This study explores the involvement of MAM-related genes in ARDS pathogenesis through bioinformatics and experimental validation. Publicly available RNA-sequencing data from ARDS and control samples were analyzed to identify differentially expressed genes (DEGs). Functional enrichment, gene set variation analysis (GSVA), and weighted gene co-expression network analysis (WGCNA) were performed to explore pathway alterations and hub gene interactions. Immune cell infiltration analysis was conducted using CIBERSORT. Candidate MAM-related genes were validated in a Poly I: C-induced ARDS mouse model and MLE-12 murine lung epithelial cells. The mouse model was assessed for lung histopathology, wet-to-dry lung weight ratio, bronchoalveolar lavage fluid (BALF) inflammatory cytokine levels (IL-1β and TNF-α), and lung injury scores. MLE-12 cells were treated with Poly I: C, and cell viability, lactate dehydrogenase (LDH) release, and apoptosis were evaluated. Protein-protein interaction (PPI) network analysis and drug prediction were used to identify potential therapeutic targets. A total of 3152 DEGs including 1549 upregulated and 1603 downregulated were identified in ARDS samples. Pathway analysis revealed autophagy suppression and immune activation, with 14 immune cell types significantly elevated in ARDS patients. Experimental validation confirmed that Poly I: C-induced ARDS mice exhibited severe lung injury and increased inflammatory reaction, while Poly I: C-treated MLE-12 cells showed increased cytotoxicity and LDH release. ZMAT2 and HBB were identified as key MAM-related hub genes, with ZMAT2 positively associated with disease progression and HBB negatively correlating with lung injury severity. Drug prediction analysis identified 29 pharmacological agents interacting with HBB, suggesting therapeutic potential. This study identifies ZMAT2 and HBB as key MAM-related genes contributing to ARDS pathogenesis, with potential diagnostic and therapeutic applications. The integration of bioinformatics with in vivo and in vitro validation provides novel insights into ARDS molecular mechanisms. Further clinical studies are needed to explore their translational relevance.
    Keywords:  ARDS; Bioinformatics; Mitochondria-associated membrane; Therapeutic targets; Viral pneumonia
    DOI:  https://doi.org/10.1038/s41598-025-10405-3
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