bims-mecosi 2025-08-31 papers

bims-mecosi

Biomed News

on Membrane contact sites

Issue of 2025–08–31
fourteen papers selected by
Verena Kohler, Umeå University

Structural basis for lipid transport at membrane contact sites by the IST2-OSH6 complex.
Mission cholesterol: Uncovering its hidden role in ALS neurodegeneration.
Ageing-Dependent Thyroid Hormone Receptor α Reduction Activates IP3R1-Meditated Ca2+ Transfer in MAM and Exacerbates Skeletal Muscle Atrophy in Mice.
Schisandra chinensis mixture attenuates diabetic kidney disease via VDAC1/Grp75/IP3R-mediated MAMs stabilization and apoptosis-autophagy regulation.
Ultrastructural analysis of mitochondria-associated membranes in lymphocytes of newly diagnosed type 2 diabetes mellitus.
Allicin Attenuates Mitochondrial Calcium (Ca2+) Overload Induced by Acrylamide in Hepatocytes via the NAD+/SIRT3-FoxO3 Axis.
Intracristal space proteome mapping using super-resolution proximity labeling with isotope-coded probes.
Inducible skeletal muscle-specific p53 deletion alleviates high-fat diet-induced insulin resistance by modulating mitochondria-associated membrane in obese mice.
ER-mitochondrial crosstalk (ERMES) regulates cell wall composition in pathogenic fungi.
Highly Oligomeric DRP1 Strategic Positioning at Mitochondria-Sarcoplasmic Reticulum Contacts in Adult Murine Heart Through ACTIN Anchoring.
Programming of Extra- and Intracellular Protein Coronation through Thiol-Independent Ligand Engineering.
Sigma-1 receptor: A potential target for modulating chronic pain and depression.
Mitochondria and lysosomes in T cell immunometabolism.
A TRPM2-Driven Signalling Cycle Orchestrates Abnormal Inter-Organelle Crosstalk in Cardiovascular and Metabolic Diseases.

Nat Struct Mol Biol. 2025 Aug 27.

Structural basis for lipid transport at membrane contact sites by the IST2-OSH6 complex.

Melanie Arndt, Angela Schweri, Raimund Dutzler.

Membrane contact sites are hubs for interorganellar lipid transport within eukaryotic cells. As a principal tether bridging the endoplasmic reticulum (ER) and the plasma membrane in Saccharomyces cerevisiae, the protein IST2 has a major role during lipid transport between both compartments. Here, we show a comprehensive investigation elucidating the structural and mechanistic properties of IST2 and its interaction with the soluble lipid transfer protein OSH6. The ER-embedded transmembrane domain of IST2 is homologous to the TMEM16 family and acts as a constitutively active lipid scramblase. The extended C terminus binds to the plasma membrane and the phosphatidylserine-phosphatidylinositol 4-phosphate exchanger OSH6. Through cellular growth assays and biochemical and structural studies, we characterized the interaction between both proteins and show that OSH6 remains associated with IST2 during lipid shuttling between membranes. These results highlight the role of the IST2-OSH6 complex in lipid trafficking and offer initial insights into the relevance of scramblases for carrier-like lipid transport mechanisms.

DOI: https://doi.org/10.1038/s41594-025-01660-z
Biochim Biophys Acta Mol Basis Dis. 2025 Aug 19. pii: S0925-4439(25)00369-2. [Epub ahead of print]1871(8): 168021

Mission cholesterol: Uncovering its hidden role in ALS neurodegeneration.

Anna Fernàndez-Bernal, Natàlia Mota, Reinald Pamplona, Estela Area-Gómez, Manuel Portero-Otin.

  Cholesterol is a central determinant of membrane architecture, signaling, and cellular homeostasis in the central nervous system (CNS). While historically viewed as a structural component, emerging evidence highlights its dynamic regulatory role in neuronal function, particularly through its compartmentalized synthesis, trafficking, and turnover. This review examines the complex landscape of cholesterol metabolism in the CNS, emphasizing the cooperative roles of astrocytes and neurons, the partitioning of biosynthetic pathways, and the barriers that distinguish brain cholesterol pools from peripheral sources. We focus on mitochondria-associated endoplasmic reticulum membranes (MAMs) as key regulatory platforms for cholesterol sensing, esterification, and signaling, underscoring their emerging role in neurodegenerative diseases. Disruptions in MAM integrity, lipid raft composition, and transcriptional regulation of cholesterol-handling genes have been linked to pathologies such as amyotrophic lateral sclerosis (ALS), particularly through the actions of TDP-43. By consolidating recent findings from lipidomics, cell biology, and disease models, we propose that cholesterol dyshomeostasis constitutes a shared mechanistic axis across diverse neurodegenerative conditions. Understanding this axis offers novel insights into the metabolic vulnerability of neurons and highlights cholesterol metabolism as a promising target for therapeutic intervention.

Keywords:  Amyotrophic Lateral Sclerosis; Astrocyte; Blood-brain-barrier; Endoplasmic reticulum; Neuron

DOI:  https://doi.org/10.1016/j.bbadis.2025.168021
Cell Prolif. 2025 Aug 24. e70120

Ageing-Dependent Thyroid Hormone Receptor α Reduction Activates IP3R1-Meditated Ca2+ Transfer in MAM and Exacerbates Skeletal Muscle Atrophy in Mice.

Runqing Shi, Yusheng Zhang, Gong Chen, Jiru Zhang, Jing Liu, Hao Zhu, Minne Sun, Yu Duan.

  Sarcopenia profoundly impacts the quality of life and longevity in elderly populations. Notably, alterations in thyroid hormone (TH) levels during ageing are intricately linked to the development of sarcopenia. In skeletal muscle, the primary action of TH is mediated through the thyroid hormone receptor alpha (TRα). Emerging evidence suggests that decreased TRα expression may precipitate mitochondrial dysfunction in ageing skeletal muscle tissues. Yet, the precise mechanisms and the potential causative role of TRα deficiency in sarcopenia are not fully understood. This study suggests that TRα may regulate mitochondrial calcium (Ca2+) transport across membranes by targeting the inositol 1,4,5-trisphosphate receptor 1 (IP3R1), as evidenced by ChIP-seq and RNA-seq analyses. Experiments using naturally aged mice, skeletal muscle-specific TRα knockout (SKT) mice, and C2C12 myoblasts were conducted to investigate this process further. Findings include increased IP3R1, mitochondria-associated endoplasmic reticulum membranes (MAM), and mitochondrial Ca2+ in aged skeletal muscle. Additionally, SKT mice exhibited smaller muscle fibres, increased IP3R1 and MAM, and mitochondrial dysfunction. ChIP-qPCR and TRα manipulation in C2C12 cells showed that TRα negatively regulates IP3R1 transcription. Moreover, TRα knockdown cells exhibited increased Ca2+ transfer in MAM and mitochondrial dysfunction, which was ameliorated by the IP3R1 inhibitor 2-aminoethoxydiphenyl borate. Reintroduction of TRα improved IP3R1-mediated mitochondrial Ca2+ overload in aged cells. Our findings uncover a novel mechanism by which TRα deficiency induces mitochondrial Ca2+ overload through IP3R1-mediated Ca2+ transfer in MAM, exacerbating skeletal muscle atrophy during ageing. The TRα/IP3R1 pathway in MAM Ca2+ transfer presents a potential therapeutic target for sarcopenia.

Keywords:  IP3R1; MAM; mitochondrial Ca2+ overload; sarcopenia; senescence; thyroid hormone receptor α

DOI:  https://doi.org/10.1111/cpr.70120
Phytomedicine. 2025 Aug 12. pii: S0944-7113(25)00803-7. [Epub ahead of print]147 157164

Schisandra chinensis mixture attenuates diabetic kidney disease via VDAC1/Grp75/IP3R-mediated MAMs stabilization and apoptosis-autophagy regulation.

Hongdian Li, Ao Dong, Cong Liu, Pengfei He, Yu Ma, Shu Chen, Shaoning Dong, Sai Zhang, Minying Zhang, Mianzhi Zhang.

   BACKGROUND: Diabetic kidney disease (DKD) is a major cause of end-stage renal disease, with mitochondrial dysfunction-mediated tubular injury implicated in its pathogenesis. Mitochondria-associated membranes (MAMs) coordinate apoptosis and autophagy in diabetic tubular injury. While Schisandra chinensis Mixture (SM) shows renoprotective effects, its mechanism in counteracting hyperglycemia-induced tubular cell death and fibrosis via MAMs integrity remains unclear.
OBJECTIVE: This study investigated whether SM alleviates renal fibrosis by restoring MAMs integrity under high glucose (HG) conditions, thereby regulating renal tubular cell apoptosis and autophagy.
METHODS: DKD was induced in Sprague-Dawley rats through high-fat/high-glucose diet and streptozotocin injection, followed by 12-week treatment with SM (1.5/3/6 g/kg/d). Renal function, injury markers and histopathology were assessed. Apoptosis, autophagy, and fibrosis were characterized by immunohistochemical localization, western blotting quantification, and TUNEL assay. Mitochondria-endoplasmic reticulum (ER) interactions and MAMs integrity were evaluated through ultrastructural and molecular analyses. In vitro, the protective mechanism of SM was validated through lentiviral-mediated manipulation of MAMs integrity. Serum components of SM were characterized by ultra-performance liquid chromatography/tandem mass spectrometry (UPLC-MS/MS).
RESULTS: In DKD rats, SM treatment restored mitochondrial-ER ultrastructure and coupling, evidenced by enhanced interactions of MAMs tethering proteins. SM dose-dependently improved renal function, attenuated tubular apoptosis, restored HG-impaired autophagy, and mitigated fibrosis. In HG-stimulated HK-2 cells, SM similarly rescued mitochondrial-ER proximity and suppressed fibrotic markers. Lentiviral models further confirmed that SM alleviates tubular injury by preserving MAMs integrity. UPLC-MS/MS identified major serum constituents of SM (e.g., schisandrin C); their individual bioactivities were not assessed in this study.
CONCLUSION: SM treats DKD by MAMs integrity through the VDAC1-Grp75-IP3R axis, regulating HG-stimulated apoptosis and autophagy in renal tubular cells, improving mitochondrial function, and suppressing fibrotic progression.

Keywords:  Apoptosis; Autophagy; Diabetic kidney disease; Mitochondria-associated membranes; Schisandra chinensis Mixture

DOI:  https://doi.org/10.1016/j.phymed.2025.157164
Ultrastruct Pathol. 2025 Aug 27. 1-9

Ultrastructural analysis of mitochondria-associated membranes in lymphocytes of newly diagnosed type 2 diabetes mellitus.

Tamara Martinovic, Aleksa Zivkovic, Darko Ciric, Katarina Lalic, Iva Rasulic, Danica Djuricic, Ana Júlia Bonine de Melo, Andjelija Stankovic, Vladimir Bumbasirevic, Tamara Kravic-Stevovic.

  There is a growing number of evidence that mitochondrial dysfunction plays an important role in pathogenesis of diabetes mellitus. At near-contact sites between mitochondria and the ER, membranes of these organelles are juxtaposed within distance of 50 nm, referred to as mitochondria-associated membranes (MAMs). The aim of this study was to carry out an ultrastructural analysis of mitochondria-associated membranes in peripheral blood lymphocytes of patients with newly discovered type 2 diabetes mellitus and compare them with the same structures in lymphocytes of healthy persons. Transmission electron microscopy was employed to study peripheral blood lymphocytes from newly diagnosed patients not undergoing any metabolic therapy or antidiabetic medications, as well as from healthy persons. Lymphocytes of diabetic patients had more mitochondria, albeit with unchanged mitochondrial fractional volume, and more MAMs compared to lymphocytes from healthy individuals. An increase in the number of mitochondria and MAMs in peripheral blood lymphocytes could reflect disturbed mitochondrial dynamics and immunological changes that are present in patients with type 2 diabetes mellitus. In conclusion, the results obtained in our study emphasize the possible role of mitochondria and mitochondria-associated membranes in the metabolic changes of type 2 diabetes mellitus.

Keywords:  Lymphocytes; mitochondria-associated membranes; transmission electron microscopy; type 2 diabetes mellitus

DOI:  https://doi.org/10.1080/01913123.2025.2550634
J Agric Food Chem. 2025 Aug 27.

Allicin Attenuates Mitochondrial Calcium (Ca2+) Overload Induced by Acrylamide in Hepatocytes via the NAD+/SIRT3-FoxO3 Axis.

Lu Li, Ziyue Wang, Haiyang Yan, Ping Zhao, Yuan Yuan.

  Acrylamide (AA) is a byproduct of the Maillard reaction, with mitochondrial damage playing a pivotal role in mediating its hepatotoxicity. Allicin, a potent dietary phytochemical, has been used to mitigate the hepatotoxicity of AA. This study confirmed that allicin attenuated mitochondrial structural damage in AA-treated livers and AML-12 cells. Liver RNA-seq analysis identified that Ca2+ transport and nicotinamide adenine dinucleotide (NAD+) metabolism, which were associated with mitochondrial function, contributed to the hepatoprotective effects of allicin. Subsequent experiments demonstrated that allicin inhibited AA-caused excessive formation of the mitochondrial-associated endoplasmic reticulum membrane (MAM) and activation of the Ca2+ channel components. Additionally, allicin restored AA-suppressed NAD+ content and the expression of its dependent deacetylase SIRT3, thereby promoting FoxO3 deacetylation and protecting hepatocytes from mitochondrial Ca2+ overload. Deficiency of SIRT3 eliminated the protective effect of allicin, confirming that allicin antagonized AA-induced hepatotoxicity by regulating mitochondrial Ca2+ homeostasis through the NAD+/SIRT3-FoxO3 axis.

Keywords:  FoxO3; SIRT3; acrylamide (AA); allicin; mitochondrial calcium (Ca2+)

DOI:  https://doi.org/10.1021/acs.jafc.5c04431
Nat Commun. 2025 Aug 20. 16(1): 7757

Intracristal space proteome mapping using super-resolution proximity labeling with isotope-coded probes.

Myeong-Gyun Kang, Sanghee Shin, Dong-Gi Jang, Ohyeon Kwon, Song-Yi Lee, Pratyush Kumar Mishra, Minkyo Jung, Ji Young Mun, Jung-Min Kee, Jong-Seo Kim, Hyun-Woo Rhee.

Proximity labeling with engineered ascorbate peroxidase (APEX) has been widely used to identify proteomes within various membrane-enclosed subcellular organelles. However, constructing protein distribution maps between two non-partitioned proximal spaces remains challenging with the current proximity labeling tools. Here, we introduce a proximity labeling approach using isotope-coded phenol probes for APEX labeling (ICAX) that enables the quantitative analysis of the spatial proteome at nanometer resolution between two distinctly localized APEX enzymes. Using this technique, we identify the spatial proteomic architecture of the mitochondrial intracristal space (ICS), which is not physically separated from the peripheral space. ICAX analysis further reveals unexpected dynamics of the mitochondrial spatiome under mitochondrial contact site and cristae organizing system (MICOS) complex inhibition and mitochondrial uncoupling, respectively. Overall, these findings highlight the importance of ICS for mitochondrial quality control under dynamic stress conditions.

DOI: https://doi.org/10.1038/s41467-025-62756-0
Redox Biol. 2025 Aug 20. pii: S2213-2317(25)00341-6. [Epub ahead of print]86 103828

Inducible skeletal muscle-specific p53 deletion alleviates high-fat diet-induced insulin resistance by modulating mitochondria-associated membrane in obese mice.

Soyoung Park, Jin Ki Jung, Jung-Yoon Heo, Themis Thoudam, Su-Yeon Jeong, Seok-Hui Kang, Chang-Hoon Woo, Hyoung Chul Choi, In-Kyu Lee, Jinmyoung Dan, Jongsoon Lee, Jae-Ryong Kim, So-Young Park.

  p53 has been implicated in metabolic regulation, but its role in obesity-induced skeletal muscle insulin resistance remains incompletely understood. This study aimed to determine the functional contribution of skeletal muscle p53 to insulin resistance and mitochondrial dysfunction, particularly in the context of obesity. We demonstrate that inducible, skeletal muscle-specific deletion of p53 (iMp53 KO) significantly improves insulin sensitivity in high-fat diet (HFD)-induced obese mice, with no effect in chow-fed controls. This metabolic improvement was accompanied by enhanced mitochondrial respiration and membrane potential, as well as reduced mitochondrial calcium overload in palmitate-treated C2C12 myotubes. Electron microscopy and immunoblotting revealed a marked reduction in mitochondria-associated membrane (MAM) area and decreased levels of MAM components (IP3R, VDAC, GRP75) in iMp53 KO muscle. Co-immunoprecipitation assays demonstrated physical interactions between p53 and MAM proteins, supporting a role for p53 in promoting MAM formation under obese conditions. Consistently, skeletal muscle from patients with type 2 diabetes exhibited elevated expression of both p53 and MAM markers, with a positive correlation between them. These findings suggest that p53 plays an important role in modulating ER-mitochondrial contacts and mitochondrial homeostasis in skeletal muscle and suggest its contribution to obesity-induced insulin resistance. This study provides new mechanistic insight into the pathological role of p53 in muscle metabolism.

Keywords:  Insulin resistance; Mitochondria-associated membrane; Obesity; Skeletal muscle; p53

DOI:  https://doi.org/10.1016/j.redox.2025.103828
Arch Microbiol. 2025 Aug 27. 207(10): 237

ER-mitochondrial crosstalk (ERMES) regulates cell wall composition in pathogenic fungi.

Deepika Kumari, Vinay Kumar Bari, Ritu Pasrija.

  Fungal infections pose a significant global health challenge, exacerbated by limited antifungal therapies and the rise of drug-resistant strains. The cell wall is a critical determinant of fungal pathogenicity, as it maintains structural integrity and mediates host-pathogen interactions. Notably, the cell wall compositions of Cryptococcus neoformans and Candida albicans differ substantially. In C. albicans, the inner layer is rich in chitin, β-1,3-glucans and β-1,6-glucans, while the outer layer comprises N-linked and O-linked mannoproteins. Conversely, C. neoformans includes additional components such as α-1,3-glucan and chitosan, and is characterized by an outermost capsule layer containing glucuronoxylomannan (GXM) and galactoxylomannan (GalXM), along with minor mannoproteins. In this study, we explored the role of a unique fungal multi-subunit complex known as the Endoplasmic Reticulum-Mitochondria Encounter Structure (ERMES) in regulating cell wall architecture. The ERMES complex is composed of four key subunits: Mmm1, Mdm10, Mdm12 and Mdm34. It plays critical roles across various fungal species, including maintaining mitochondrial morphology and function, facilitating phospholipid transport, supporting mitophagy and contributing to virulence. Notably, disruption of ERMES components has been linked to enhanced susceptibility of both planktonic and biofilm-forming fungal cells to echinocandin-class antifungal drugs. Our investigation revealed that deletion or impairment of ERMES subunits significantly alters the cell wall composition in C. neoformans and C. albicans, suggesting a previously underappreciated connection between mitochondrial contact sites and fungal cell wall integrity. Using staining techniques, we assessed changes in key cell wall components, including reduced β-1,3-glucans, chitin, chitosan and mannoproteins in deletion mutants (Δmmm1, Δmdm10, Δmdm12 and Δmdm34) of both species. Transmission electron microscopy (TEM) analysis confirmed alterations in cell wall thickness, with the most pronounced effects observed in Δmmm1 and Δmdm10 mutants. The ERMES mutants were also impaired in hyphal development. These findings underscore the essential role of ER-mitochondrial communication in regulating cell wall biosynthesis and structural remodeling.

Keywords:   Candida albicans ; Cryptococcus neoformans ; Cell wall; ERMES complex; Fungal infections

DOI:  https://doi.org/10.1007/s00203-025-04448-3
Cells. 2025 Aug 14. pii: 1259. [Epub ahead of print]14(16):

Highly Oligomeric DRP1 Strategic Positioning at Mitochondria-Sarcoplasmic Reticulum Contacts in Adult Murine Heart Through ACTIN Anchoring.

Celia Fernandez-Sanz, Sergio De la Fuente, Zuzana Nichtova, Marilen Federico, Stephane Duvezin-Caubet, Sebastian Lanvermann, Hui-Ying Tsai, Yanguo Xin, Gyorgy Csordas, Wang Wang, Arnaud Mourier, Shey-Shing Sheu.

  Mitochondrial fission and fusion appear to be relatively infrequent in cardiac cells compared to other cell types; however, the proteins involved in these events are highly expressed in adult cardiomyocytes (ACM). Therefore, these proteins likely have additional non-canonical roles. We have previously shown that DRP1 not only participates in mitochondrial fission processes but also regulates mitochondrial bioenergetics in cardiac tissue. However, it is still unknown where the DRP1 that does not participate in mitochondrial fission is located and what its role is at those non-fission spots. Therefore, this manuscript will clarify whether oligomeric DRP1 is located at the SR-mitochondria interface, a specific region that harbors the Ca2+ microdomains created by Ca2+ release from the SR through the RyR2. The high Ca2+ microdomains and the subsequent Ca2+ uptake by mitochondria through the mitochondrial Ca2+ uniporter complex (MCUC) are essential to regulate mitochondrial bioenergetics during excitation-contraction (EC) coupling. Herein, we aimed to test the hypothesis that mitochondria-bound DRP1 preferentially accumulates at the mitochondria-SR contacts to deploy its function on regulating mitochondrial bioenergetics and that this strategic position is modulated by calcium in a beat-to-beat manner. In addition, the mechanism responsible for such a biased distribution and its functional implications was investigated. High-resolution imaging approaches, cell fractionation, Western blot, 2D blue native gel electrophoresis, and immunoprecipitations were applied to both electrically paced ACM and Langendorff-perfused beating hearts to elucidate the mechanisms of the strategic DRP1 localization. Our data show that in ACM, mitochondria-bound DRP1 clusters in high molecular weight protein complexes at mitochondria-associated membrane (MAM). This clustering requires DRP1 interaction with β-ACTIN and is fortified by EC coupling-mediated Ca2+ transients. In ACM, DRP1 is anchored at the mitochondria-SR contacts through interactions with β-ACTIN and Ca2+ transients, playing a fundamental role in regulating mitochondrial physiology.

Keywords:  DRP1 oligomers; adult cardiomyocytes (ACM); dynamin-related protein 1 (DRP1); high Ca2+ microdomains; mitochondria-associated membranes (MAM); sarcoplasmic reticulum (SR); β-ACTIN

DOI:  https://doi.org/10.3390/cells14161259
Nano Lett. 2025 Aug 25.

Programming of Extra- and Intracellular Protein Coronation through Thiol-Independent Ligand Engineering.

Meng-Die Xue, Yue-Wen Yin, Liuting Zheng, Xinyue Li, Wei Tang, Xuanyi Jin, XiYu Zhang, Huiyue Zhao, Yu-Qiang Ma, Hong-Ming Ding, Da Huo.

  Variation in the distal end of ligands can impact biological functions, but the effects of the proximal end of the ligand (PEL) are less clear. This study presents poly(ethylene glycol) (PEG) ligands that bind to gold beyond the gold-thiol chemistry. Biotin-PEG-modified nanomaterials showed unique protein corona-assisted uptake due to the TMSB4x orientation. All-atom molecular dynamics and super-resolution imaging reveal that TMSB4x facilitates receptor-ligand binding by expanding the pocket. Photoproximity labeling with chemoetching confirms PEL-dependent intracellular effects. For PEL as lipoic acid, gold functionalization allows nanomaterials to inhibit microfilament assembly and destabilize organelle contact sites, providing an anticancer effect without chemotherapy.

Keywords:  PEGylation; gold nanomaterials; ligand; organelle dynamics; protein corona

DOI:  https://doi.org/10.1021/acs.nanolett.5c03113
Eur J Pharmacol. 2025 Aug 21. pii: S0014-2999(25)00838-6. [Epub ahead of print]1005 178084

Sigma-1 receptor: A potential target for modulating chronic pain and depression.

Yue Zhang, Yafan Bai, Yingjie Du, Min Liu, Mingru Zhang, Guyan Wang.

  Sigma 1 receptor (S1R), a ligand-regulated chaperone mainly located in the mitochondrion-associated endoplasmic reticulum membrane (MAM), has emerged as a potential target for chronic pain and depression. Over the past decades, numerous studies on chronic pain and depression have been conducted, aiming to find more effective therapies. However, the complex pathophysiological processes of these conditions limit the effectiveness of many clinical treatments. Hence, this review provides an overview of the elucidation of the modulatory effects and underlying mechanisms of S1R in chronic pain and depression, as well as their comorbidity. Preclinical studies have demonstrated that S1R antagonists or S1R knockout (KO) mice may provide potential benefits in reversing hypersensitivity in various animal pain models. Meanwhile, S1R agonists have the potential to alleviate depression-like behaviors in rodents. Notably, controversy remains regarding the effect of S1R on comorbid conditions in preclinical studies. Since S1R antagonists may result in depression and agonists might trigger hyperalgesia, receptor diversity should be considered in drug development to avoid side effects. The mechanisms underlying the analgesic and antidepressant-like effects of S1R may involve interactions with TRPA1 and TRPV1 ion channels; NMDA and MOR receptors; modulation of glutamatergic/GABAergic neurotransmission; and regulation of the BDNF/TrkB signaling pathway. Consequently, S1R serves as a possible target for the development of painkillers and antidepressants.

Keywords:  Agonist; Antagonist; Chronic pain; Depression; Sigma-1 receptor

DOI:  https://doi.org/10.1016/j.ejphar.2025.178084
Trends Immunol. 2025 Aug 22. pii: S1471-4906(25)00181-4. [Epub ahead of print]

Mitochondria and lysosomes in T cell immunometabolism.

Erienne G Norton, Nicole M Chapman, Hongbo Chi.

  Metabolic reprogramming and signaling are key orchestrators of T cell immunity. Recent studies have illustrated important roles for intracellular organelles, especially mitochondria and lysosomes, in enforcing T cell metabolism and signaling in response to various extracellular cues. As such, mitochondrial and lysosomal function contributes to adaptive immunity by regulating T cell activation, differentiation, and functional adaptation. In this Review, we discuss how the interplay between organelle biology and metabolism instructs T cell-mediated immunity, with a particular focus on mitochondria and lysosomes. We also summarize how mitochondria and lysosomes, or their crosstalk with other organelles, orchestrate downstream signaling processes and functional reprogramming of T cells. We conclude with a discussion of the pathophysiological outcomes associated with dysregulation of these organelles.

Keywords:  T cells; immunometabolism; lysosomes; metabolic signaling; mitochondria; organelle crosstalk

DOI:  https://doi.org/10.1016/j.it.2025.07.014
Biomolecules. 2025 Aug 19. pii: 1193. [Epub ahead of print]15(8):

A TRPM2-Driven Signalling Cycle Orchestrates Abnormal Inter-Organelle Crosstalk in Cardiovascular and Metabolic Diseases.

Maali AlAhmad, Esra Elhashmi Shitaw, Asipu Sivaprasadarao.

  Cardiovascular and metabolic disorders significantly reduce healthspan and lifespan, with oxidative stress being a major contributing factor. Oxidative stress, marked by elevated reactive oxygen species (ROS), disrupts cellular and systemic functions. One proposed mechanism involves TRPM2 (Transient Receptor Potential Melastatin2)-dependent Ca2+ dysregulation. These channels, activated by ROS (via ADP-ribose), not only respond to ROS but also amplify it, creating a self-sustaining cycle. Recent studies suggest that TRPM2 activation triggers a cascade of signals from intracellular organelles, enhancing ROS production and affecting cell physiology and viability. This review examines the role of TRPM2 channels in oxidative stress-associated cardiovascular and metabolic diseases. Oxidative stress induces TRPM2-mediated Ca2+ influx, leading to lysosomal damage and the release of Zn2+ from lysosomal stores to the mitochondria. In mitochondria, Zn2+ facilitates electron leakage from respiratory complexes, reducing membrane potential, increasing ROS production, and accelerating mitochondrial degradation. Excess ROS activates PARP1 in the nucleus, releasing ADP-ribose, a TRPM2 agonist, thus perpetuating the cycle. Lysosomes act as Ca2+-sensitive signalling platforms, delivering toxic Zn2+ signals to mitochondria. This represents a paradigm shift, proposing that the toxic effects of Ca2+ on mitochondria are not direct, but are instead mediated by lysosomes and subsequent Zn2+ release. This cycle exhibits a 'domino' effect, causing sequential and progressive decline in the function of lysosomes, mitochondria, and the nucleus-hallmarks of ageing and oxidative stress-related cardiovascular and metabolic diseases. These insights could lead to new therapeutic strategies for addressing the widespread issue of cardiovascular and metabolic diseases.

Keywords:  NOX2; PARP; TRPM2; ageing; calcium; cardiovascular diseases; inter-organelle communication; lysosomes; metabolic diseases; metabolic syndrome; mitochondria; oxidative stress; reactive oxygen species; zinc

DOI:  https://doi.org/10.3390/biom15081193