bims-celmim Biomed News
on Cellular and mitochondrial metabolism
Issue of 2025–04–13
24 papers selected by
Marc Segarra Mondejar
  1. Mitochondrial dynamics at the intersection of macrophage polarization and metabolism.
  2. Multiple roles of branched-chain amino acid metabolism in tumour progression.
  3. Amino acids in cancer: Understanding metabolic plasticity and divergence for better therapeutic approaches.
  4. ARMC1 partitions between distinct complexes and assembles MIRO with MTFR to control mitochondrial distribution.
  5. Metabolite tunes MDV pathway to maintain mitochondrial fitness.
  6. Rab GTPases are evolutionarily conserved signals mediating selective autophagy.
  7. Inhibition of mitochondrial complex I induces mitochondrial ferroptosis by regulating CoQH2 levels in cancer.
  8. TMEM65 joins the mitochondrial Ca2+ club.
  9. Metabolic reprogramming in T cell senescence: a novel strategy for cancer immunotherapy.
  10. Citrate oscillations during cell cycle are a targetable vulnerability in cancer cells.
  11. Unraveling the nexus: Genomic instability and metabolism in cancer.
  12. Sleep loss is a metabolic disorder.
  13. Malvidin-3-glucoside induces insulin secretion by activating the PLC/IP3 pathway and enhancing Ca2+ influx in INS-1 pancreatic β-cells.
  14. MIRO1 Is Required for Dynamic Increases in Mitochondria-ER Contact Sites and Mitochondrial ATP During the Cell Cycle.
  15. Flux-sum coupling analysis of metabolic network models.
  16. Small molecule BLVRB redox inhibitor promotes megakaryocytopoiesis and stress thrombopoiesis in vivo.
  17. Multiple cAMP/PKA complexes at the STIM1 ER/PM junction specified by E-Syt1 and E-Syt2 reciprocally gates ANO1 (TMEM16A) via Ca2.
  18. GPAT4 sustains endoplasmic reticulum homeostasis in endocardial cells and safeguards heart development.
  19. The Futile Creatine Cycle powers UCP1-independent thermogenesis in classical BAT.
  20. A pilot metabolomics study on clear cell renal cell carcinoma.
  21. Optical Photothermal Infrared Imaging Using Metabolic Probes in Biological Systems.
  22. Improving mitochondria-associated endoplasmic reticulum membranes integrity as converging therapeutic strategy for rare neurodegenerative diseases and cancer.
  23. FAO-fueled OXPHOS and NRF2-mediated stress resilience in MICs drive lymph node metastasis.
  24. Far-red fluorescent genetically encoded calcium ion indicators.
  1. Front Immunol. 2025 ;16 1520814
    Mitochondrial dynamics at the intersection of macrophage polarization and metabolism.
    Pan Li, Zhengbo Fan, Yanlan Huang, Liang Luo, Xiaoyan Wu.
      Macrophages are vital sentinels in innate immunity, and their functions cannot be performed without internal metabolic reprogramming. Mitochondrial dynamics, especially mitochondrial fusion and fission, contributes to the maintenance of mitochondrial homeostasis. The link between mitochondrial dynamics and macrophages in the past has focused on the immune function of macrophages. We innovatively summarize and propose a link between mitochondrial dynamics and macrophage metabolism. Among them, fusion-related FAM73b, MTCH2, SLP-2 (Stomatin-like protein 2), and mtSIRT, and fission-related Fis1 and MTP18 may be the link between mitochondrial dynamics and macrophage metabolism association. Furthermore, post-translational modifications (PTMs) of mtSIRT play prominent roles in mitochondrial dynamics-macrophage metabolism connection, such as deacetylates and hypersuccinylation. MicroRNAs such as miR-150, miR-15b, and miR-125b are also possible entry points. The metabolic reprogramming of macrophages through the regulation of mitochondrial dynamics helps improve their adaptability and resistance to adverse environments and provides therapeutic possibilities for various diseases.
    Keywords:  fission; fusion; macrophage; metabolism; mitochondrial dynamics
    DOI:  https://doi.org/10.3389/fimmu.2025.1520814
  2. J Biomed Sci. 2025 Apr 09. 32(1): 41
    Multiple roles of branched-chain amino acid metabolism in tumour progression.
    Lin Wang, Feng Shi, Ya Cao, Longlong Xie.
      Metabolic reprogramming enables tumour cells to sustain their continuous proliferation and adapt to the ever-changing microenvironment. Branched-chain amino acids (BCAAs) and their metabolites are involved in intracellular protein synthesis and catabolism, signal transduction, epigenetic modifications, and the maintenance of oxidative homeostasis. Alterations in BCAA metabolism can influence the progression of various tumours. However, how BCAA metabolism is dysregulated differs among depending on tumour type; for example, it can manifest as decreased BCAA metabolism leading to BCAA accumulation, or as enhanced BCAA uptake and increased catabolism. In this review, we describe the role of BCAA metabolism in the progression of different tumours. As well as discuss how BCAA metabolic reprogramming drives tumour therapy resistance and evasion of the antitumour immune response, and how these pro-cancer effects are achieved in part by activating the mTORC signalling pathway. In-depth investigations into the potential mechanisms by which BCAA metabolic reprogramming affects tumorigenesis and tumour progression can enhance our understanding of the relationship between metabolism and cancer and provide new strategies for cancer therapy.
    Keywords:  BCAA metabolism; Metabolic reprogramming; Tumour immunity; Tumour progression; Tumour resistance; mTORC signalling pathway
    DOI:  https://doi.org/10.1186/s12929-025-01132-y
  3. Cell Rep. 2025 Apr 05. pii: S2211-1247(25)00300-6. [Epub ahead of print]44(4): 115529
    Amino acids in cancer: Understanding metabolic plasticity and divergence for better therapeutic approaches.
    Linda K Do, Hyun Min Lee, Yun-Sok Ha, Chan-Hyeong Lee, Jiyeon Kim.
      Metabolic reprogramming is a hallmark of malignant transformation. While initial studies in the field of cancer metabolism focused on central carbon metabolism, the field has expanded to metabolism beyond glucose and glutamine and uncovered the important role of amino acids in tumorigenesis and tumor immunity as energy sources, signaling molecules, and precursors for (epi)genetic modification. As a result of the development and application of new technologies, a multifaceted picture has emerged, showing that context-dependent heterogeneity in amino acid metabolism exists between tumors and even within distinct regions of solid tumors. Understanding the complexity and flexibility of amino acid metabolism in cancer is critical because it can influence therapeutic responses and predict clinical outcomes. This overview discusses the current findings on the heterogeneity in amino acid metabolism in cancer and how understanding the metabolic diversity of amino acids can be translated into more clinically relevant therapeutic interventions.
    Keywords:  CP: Cancer; CP: Metabolism; amino acids; cancer metabolism; metabolic heterogeneity
    DOI:  https://doi.org/10.1016/j.celrep.2025.115529
  4. Sci Adv. 2025 Apr 11. 11(15): eadu5091
    ARMC1 partitions between distinct complexes and assembles MIRO with MTFR to control mitochondrial distribution.
    Michael J McKenna, Felix Kraus, João P L Coelho, Muskaan Vasandani, Jiuchun Zhang, Benjamin M Adams, Joao A Paulo, J Wade Harper, Sichen Shao.
      Maintaining an optimal mitochondrial distribution is critical to ensure an adequate supply of energy and metabolites to support important cellular functions. How cells balance dynamic mitochondrial processes to achieve homeostasis is incompletely understood. Here, we show that ARMC1 partitioning between distinct mitochondrial protein complexes is a key determinant of mitochondrial distribution. In one complex, the mitochondrial trafficking adaptor MIRO recruits ARMC1, which mediates the assembly of a mitochondrial fission regulator (MTFR). MTFR stability depends on ARMC1, and MIRO-MTFR complexes specifically antagonize retrograde mitochondrial movement. In another complex, DNAJC11 facilitates ARMC1 release from mitochondria. Disrupting MIRO-MTFR assembly fails to rescue aberrant mitochondrial distributions clustered in the perinuclear area observed with ARMC1 deletion, while disrupting ARMC1 interaction with DNAJC11 leads to excessive mitochondrially localized ARMC1 and distinct mitochondrial defects. Thus, the abundance and trafficking impact of MIRO-MTFR complexes require ARMC1, whose mito-cytoplasmic shuttling balanced by DNAJC11 tunes steady-state mitochondrial distributions.
    DOI:  https://doi.org/10.1126/sciadv.adu5091
  5. Mol Cell. 2025 Apr 03. pii: S1097-2765(25)00189-3. [Epub ahead of print]85(7): 1253-1255
    Metabolite tunes MDV pathway to maintain mitochondrial fitness.
    Shiori Sekine, Yusuke Sekine.
      In this issue of Molecular Cell, Tang et al.1 demonstrate that the ketone body β-hydroxybutyrate (BHB) promotes the biogenesis of mitochondrial-derived vesicles (MDVs) via lysine β-hydroxybutyrylation (Kbhb) on SNX9, revealing a way to fine-tune the mitochondrial quality control pathway with metabolites.
    DOI:  https://doi.org/10.1016/j.molcel.2025.02.027
  6. J Cell Biol. 2025 May 05. pii: e202410150. [Epub ahead of print]224(5):
    Rab GTPases are evolutionarily conserved signals mediating selective autophagy.
    Pengwei Zhao, Rui Tian, Dandan Song, Qi Zhu, Xianming Ding, Jianqin Zhang, Beibei Cao, Mengyuan Zhang, Yilu Xu, Jie Fang, Jieqiong Tan, Cong Yi, Hongguang Xia, Wei Liu, Wei Zou, Qiming Sun.
      Selective autophagy plays a crucial role in maintaining cellular homeostasis by specifically targeting unwanted cargo labeled with "autophagy cues" signals for autophagic degradation. In this study, we identify Rab GTPases as a class of such autophagy cues signals involved in selective autophagy. Through biochemical and imaging screens, we reveal that human Rab GTPases are common autophagy substrates. Importantly, we confirm the conservation of Rab GTPase autophagic degradation in different model organisms. Rab GTPases translocate to damaged mitochondria, lipid droplets, and invading Salmonella-containing vacuoles (SCVs) to serve as degradation signals. Furthermore, they facilitate mitophagy, lipophagy, and xenophagy, respectively, by recruiting receptors. This interplay between Rab GTPases and receptors may ensure the de novo synthesis of isolation membranes around Rab-GTPase-labeled cargo, thereby mediating selective autophagy. These processes are further influenced by upstream regulators such as LRRK2, GDIs, and RabGGTase. In conclusion, this study unveils a conserved mechanism involving Rab GTPases as autophagy cues signals and proposes a model for the spatiotemporal control of selective autophagy.
    DOI:  https://doi.org/10.1083/jcb.202410150
  7. Cell Death Dis. 2025 Apr 05. 16(1): 254
    Inhibition of mitochondrial complex I induces mitochondrial ferroptosis by regulating CoQH2 levels in cancer.
    Ru Deng, Lingyi Fu, Haoyu Liang, Xixiong Ai, Fangyi Liu, Nai Li, Liyan Wu, Shuo Li, Xia Yang, Yansong Lin, Yuhua Huang, Jingping Yun.
      Ferroptosis, a novel form of regulated cell death induced by the excessive accumulation of lipid peroxidation products, plays a pivotal role in the suppression of tumorigenesis. Two prominent mitochondrial ferroptosis defense systems are glutathione peroxidase 4 (GPX4) and dihydroorotate dehydrogenase (DHODH), both of which are localized within the mitochondria. However, the existence of supplementary cellular defense mechanisms against mitochondrial ferroptosis remains unclear. Our findings unequivocally demonstrate that inactivation of mitochondrial respiratory chain complex I (MCI) induces lipid peroxidation and consequently invokes ferroptosis across GPX4 low-expression cancer cells. However, in GPX4 high expression cancer cells, the MCI inhibitor did not induce ferroptosis, but increased cell sensitivity to ferroptosis induced by the GPX4 inhibitor. Overexpression of the MCI alternative protein yeast NADH-ubiquinone reductase (NDI1) not only quells ferroptosis induced by MCI inhibitors but also confers cellular protection against ferroptosis inducers. Mechanically, MCI inhibitors actuate an elevation in the NADH level while concomitantly diminishing the CoQH2 level. The manifestation of MCI inhibitor-induced ferroptosis can be reversed by supplementation with mitochondrial-specific analogues of CoQH2. Notably, MCI operates in parallel with mitochondrial-localized GPX4 and DHODH to inhibit mitochondrial ferroptosis, but independently of cytosolically localized GPX4 or ferroptosis suppressor protein 1(FSP1). The MCI inhibitor IACS-010759, is endowed with the ability to induce ferroptosis while concurrently impeding tumor proliferation in vivo. Our results identified a ferroptosis defense mechanism mediated by MCI within the mitochondria and suggested a therapeutic strategy for targeting ferroptosis in cancer treatment.
    DOI:  https://doi.org/10.1038/s41419-025-07510-6
  8. Nat Metab. 2025 Apr 08.
    TMEM65 joins the mitochondrial Ca2+ club.
    Yasemin Sancak.
      
    DOI:  https://doi.org/10.1038/s42255-025-01271-4
  9. Cell Death Discov. 2025 Apr 09. 11(1): 161
    Metabolic reprogramming in T cell senescence: a novel strategy for cancer immunotherapy.
    Li Liu, Zhanying Hao, Xi Yang, Yan Li, Siyang Wang, Linze Li.
      The complex interplay between cancer progression and immune senescence is critically influenced by metabolic reprogramming in T cells. As T cells age, especially within the tumor microenvironment, they undergo significant metabolic shifts that may hinder their proliferation and functionality. This manuscript reviews how metabolic alterations contribute to T cell senescence in cancer and discusses potential therapeutic strategies aimed at reversing these metabolic changes. We explore interventions such as mitochondrial enhancement, glycolytic inhibition, and lipid metabolism adjustments that could rejuvenate senescent T cells, potentially restoring their efficacy in tumor suppression. This review also focuses on the significance of metabolic interventions in T cells with aging and further explores the future direction of the metabolism-based cancer immunotherapy in senescent T cells.
    DOI:  https://doi.org/10.1038/s41420-025-02468-y
  10. Biochim Biophys Acta Rev Cancer. 2025 Apr 09. pii: S0304-419X(25)00055-1. [Epub ahead of print] 189313
    Citrate oscillations during cell cycle are a targetable vulnerability in cancer cells.
    Philippe Icard, Marco Alifano, Luca Simula.
      Cell cycle progression is timely interconnected with oscillations in cellular metabolism. Here, we first describe how these metabolic oscillations allow cycling cells to meet the bioenergetic needs specifically for each phase of the cell cycle. In parallel, we highlight how the cytosolic level of citrate is dynamically regulated during these different phases, being low in G1 phase, increasing in S phase, peaking in G2/M, and decreasing in mitosis. Of note, in cancer cells, a dysregulation of such citrate oscillation can support cell cycle progression by promoting a deregulated Warburg effect (aerobic glycolysis), activating oncogenic signaling pathways (such as PI3K/AKT), and promoting acetyl-CoA production via alternative routes, such as overconsumption of acetate. Then, we review how administration of sodium citrate (at high doses) arrests the cell cycle in G0/G1 or G2/M, inhibits glycolysis and PI3K/AKT, induces apoptosis, and significantly reduces tumor growth in various in vivo models. Last, we reason on the possibility to implement citrate administration to reinforce the effectiveness of cell cycle inhibitors to better cure cancer.
    Keywords:  Cancer; Cell cycle; Citrate; Drug resistance; F-1,6-BP; GAPDH; Metabolism; PFKFB3; Warburg effect
    DOI:  https://doi.org/10.1016/j.bbcan.2025.189313
  11. Cell Rep. 2025 Apr 08. pii: S2211-1247(25)00311-0. [Epub ahead of print]44(4): 115540
    Unraveling the nexus: Genomic instability and metabolism in cancer.
    Vaibhavi Gujar, Haojian Li, Tanya T Paull, Carola A Neumann, Urbain Weyemi.
      The DNA-damage response (DDR) is a signaling network that enables cells to detect and repair genomic damage. Over the past three decades, inhibiting DDR has proven to be an effective cancer therapeutic strategy. Although cancer drugs targeting DDR have received approval for treating various cancers, tumor cells often develop resistance to these therapies, owing to their ability to undergo energetic metabolic reprogramming. Metabolic intermediates also influence tumor cells' ability to sense oxidative stress, leading to impaired redox metabolism, thus creating redox vulnerabilities. In this review, we summarize recent advances in understanding the crosstalk between DDR and metabolism. We discuss combination therapies that target DDR, metabolism, and redox vulnerabilities in cancer. We also outline potential obstacles in targeting metabolism and propose strategies to overcome these challenges.
    Keywords:  CP: Cancer; DNA damage response; DNA repair; cancer therapy; metabolism; redox metabolism; therapy resistance
    DOI:  https://doi.org/10.1016/j.celrep.2025.115540
  12. Sci Signal. 2025 Apr 08. 18(881): eadp9358
    Sleep loss is a metabolic disorder.
    Sierra P Feeney, Jordan M McCarthy, Cecilia R Petruconis, Jennifer C Tudor.
      Sleep loss dysregulates cellular metabolism and energy homeostasis. Highly metabolically active cells, such as neurons, enter a catabolic state during periods of sleep loss, which consequently disrupts physiological functioning. Specific to the central nervous system, sleep loss results in impaired synaptogenesis and long-term memory, effects that are also characteristic of neurodegenerative diseases. In this review, we describe how sleep deprivation increases resting energy expenditure, leading to the development of a negative energy balance-a state with insufficient metabolic resources to support energy expenditure-in highly active cells like neurons. This disruption of energetic homeostasis alters the balance of metabolites, including adenosine, lactate, and lipid peroxides, such that energetically costly processes, such as synapse formation, are attenuated. During sleep loss, metabolically active cells shunt energetic resources away from those processes that are not acutely essential, like memory formation, to support cell survival. Ultimately, these findings characterize sleep loss as a metabolic disorder.
    DOI:  https://doi.org/10.1126/scisignal.adp9358
  13. Sci Rep. 2025 Apr 11. 15(1): 12529
    Malvidin-3-glucoside induces insulin secretion by activating the PLC/IP3 pathway and enhancing Ca2+ influx in INS-1 pancreatic β-cells.
    Pilailak Channuwong, Yuanying Yuan, Shaomian Yao, Fernando Vicosa Bauermann, Henrique Cheng, Tanyawan Suantawee, Sirichai Adisakwattana.
      Malvidin-3-glucoside (M3G), an anthocyanin found in blueberries and grapes, shows promise as a natural anti-diabetic agent. However, its effect on insulin secretion and its underlying mechanisms remains unclear. This study investigated the impact of M3G on β-cells (INS-1) through real-time Ca2+ imaging and insulin secretion assays. M3G increased intracellular Ca2+ levels in a concentration-dependent manner, specifically targeting β-cells without affecting other pancreatic cell types. It enhanced insulin secretion under both basal (4 mM) and stimulatory (11 mM) glucose conditions while maintaining cell viability at concentrations up to 100 µM. Pharmacological inhibitors revealed that M3G-induced Ca2+ signals resulted from both Ca influx through L-type voltage-dependent calcium channels (L-type VDCCs) and Ca2+ release from the endoplasmic reticulum (ER) via the PLC/IP3 pathway. Nimodipine, an L-type VDCC blocker, inhibited M3G-induced Ca2+ influx, while U73122 (a PLC inhibitor) and 2-aminoethoxydiphenyl borate (2-APB), an IP3 receptor blocker, suppressed Ca2+ release from the ER. Additionally, M3G upregulated the expression of key glucose-stimulated insulin secretion (GSIS)-related genes, including Ins1 (insulin), Slc2a2 (GLUT2), and Gck (glucokinase). These findings suggest that M3G stimulates insulin secretion by promoting Ca2+ influx through L-type VDCCs, facilitating Ca2+ release from the ER, and upregulating GSIS-related genes. M3G holds promise as a natural anti-diabetic agent by enhancing insulin secretion and supporting β-cell function.
    Keywords:  Calcium signals; Insulin secretion; L-type voltage-dependent Ca2+ channels; Malvidin-3-glucoside; PLC/IP3 ; Pancreatic β-cells
    DOI:  https://doi.org/10.1038/s41598-025-95808-y
  14. Cells. 2025 Mar 22. pii: 482. [Epub ahead of print]14(7):
    MIRO1 Is Required for Dynamic Increases in Mitochondria-ER Contact Sites and Mitochondrial ATP During the Cell Cycle.
    Benney T Endoni, Olha M Koval, Chantal Allamargot, Tara Kortlever, Lan Qian, Riley J Sadoski, Denise Juhr, Isabella M Grumbach.
      Mitochondria-ER contact sites (MERCS) are vital for mitochondrial dynamics, lipid exchange, Ca2+ homeostasis, and energy metabolism. We examined whether mitochondrial metabolism changes during the cell cycle depend on MERCS dynamics and are regulated by the outer mitochondrial protein mitochondrial rho GTPase 1 (MIRO1). Wound healing was assessed in mice with fibroblast-specific deletion of MIRO1. Wild-type and MIRO1-/- fibroblasts and vascular smooth muscle cells were evaluated for proliferation, cell cycle progression, number of MERCS, distance, and protein composition throughout the cell cycle. Restoration of MIRO1 mutants was used to test the role of MIRO1 domains; Ca2+ transients and mitochondrial metabolism were evaluated using biochemical, immunodetection, and fluorescence techniques. MERCS increased in number during G1/S compared with during G0, which was accompanied by a notable rise in protein-protein interactions involving VDAC1 and IP3R as well as GRP75 and MIRO1 by proximity-ligation assays. Split-GFP ER/mitochondrial contacts of 40 nm also increased. Mitochondrial Ca2+ concentration ([Ca2+]), membrane potential, and ATP levels correlated with the formation of MERCS during the cell cycle. MIRO1 deficiency blocked G1/S progression and the cell-cycle-dependent formation of MERCS and altered ER Ca2+ release and mitochondrial Ca2+ uptake. MIRO1 mutants lacking the Ca2+-sensitive EF hands or the transmembrane domain did not rescue cell proliferation or the formation of MERCS. MIRO1 controls an increase in the number of MERCS during cell cycle progression and increases mitochondrial [Ca2+], driving metabolic activity and proliferation through its EF hands.
    Keywords:  Ca2+; ER; MAM; MERCS; MIRO1; cell cycle; fibroblasts; mitochondria; vascular smooth muscle cells
    DOI:  https://doi.org/10.3390/cells14070482
  15. PLoS Comput Biol. 2025 Apr 07. 21(4): e1012972
    Flux-sum coupling analysis of metabolic network models.
    Mihriban Seyis, Zahra Razaghi-Moghadam, Zoran Nikoloski.
      Metabolites acting as substrates and regulators of all biochemical reactions play an important role in maintaining the functionality of cellular metabolism. Despite advances in the constraint-based framework for metabolic modeling at a genome-scale, we lack reliable proxies for metabolite concentrations that can be efficiently determined and that allows us to investigate the relationship between concentrations of metabolites in specified metabolic states in the absence of measurements. Here, we introduce a constraint-based approach, the flux-sum coupling analysis (FSCA), which facilitates the study of the interdependencies between metabolite concentrations by determining coupling relationships based on the flux-sum of metabolites. Application of FSCA on metabolic models of Escherichia coli, Saccharomyces cerevisiae, and Arabidopsis thaliana showed that the three coupling relations are present in all models and pinpointed similarities in coupled metabolite pairs. Using the available concentration measurements of E. coli metabolites, we demonstrated that the coupling relationships identified by FSCA can capture the qualitative associations between metabolite concentrations and that flux-sum is a reliable proxy for metabolite concentration. Therefore, FSCA provides a novel tool for exploring and understanding the intricate interdependencies between the concentration of metabolites, advancing the understanding of metabolic regulation, and improving flux-centered systems biology approaches.
    DOI:  https://doi.org/10.1371/journal.pcbi.1012972
  16. Nat Commun. 2025 Apr 11. 16(1): 3480
    Small molecule BLVRB redox inhibitor promotes megakaryocytopoiesis and stress thrombopoiesis in vivo.
    Natasha M Nesbitt, Gian Luca Araldi, Lisa Pennacchia, Natalia Marchenko, Zahra Assar, Kendall M Muzzarelli, Rahul Raghavan Thekke Veedu, Brian Medel-Lacruz, Eunjeong Lee, Elan Z Eisenmesser, Dale F Kreitler, Wadie F Bahou.
      Biliverdin IXβ reductase (BLVRB) is an NADPH-dependent enzyme previously implicated in a redox-regulated mechanism of thrombopoiesis distinct from the thrombopoietin (TPO)/c-MPL axis. Here, we apply computational modeling to inform molecule design, followed by de novo syntheses and screening of unique small molecules retaining the capacity for selective BLVRB inhibition as a novel platelet-enhancing strategy. Two distinct classes of molecules are identified, and NMR spectroscopy and co-crystallization studies confirm binding modes within the BLVRB active site and ring stacking between the nicotinamide moiety of the NADP+ cofactor. A diazabicyclo derivative displaying minimal off-target promiscuity and excellent bioavailability characteristics promotes megakaryocyte speciation in biphenotypic (erythro/megakaryocyte) cellular models and synergizes with TPO-dependent megakaryocyte formation in hematopoietic stem cells. Upon oral delivery into mice, this inhibitor expands platelet recovery in stress thrombopoietic models with no adverse effects. In this work, we identify and validate a cellular redox inhibitor retaining the potential to selectively promote megakaryocytopoiesis and enhance stress-associated platelet formation in vivo distinct from TPO receptor agonists.
    DOI:  https://doi.org/10.1038/s41467-025-58497-9
  17. Nat Commun. 2025 Apr 09. 16(1): 3378
    Multiple cAMP/PKA complexes at the STIM1 ER/PM junction specified by E-Syt1 and E-Syt2 reciprocally gates ANO1 (TMEM16A) via Ca2.
    Wei-Yin Lin, Woo Young Chung, Seonghee Park, Ava Movahed Abtahi, Benjamin Leblanc, Malini Ahuja, Shmuel Muallem.
      ANO1 plays a crucial role in determining numerous physiological functions, including epithelial secretion, yet its regulatory mechanisms remain incompletely understood. Here, we describe a fundamental dynamic regulation of ANO1 surface expression and Ca2+-dependent gating via the cAMP/PKA pathway at the STIM1 ER/PM junctions. At these junctions, STIM1 assembles AC-AKAP-PKA complexes, while E-Syt1 mediates formation of ANO1-VAPA-IRBIT-E-Syt1-AC8-AKAP5-PKA complex, that phosphorylates ANO1 S673, increasing ANO1 Ca2+ affinity. Within these complexes, the Ca2+ and cAMP pathways act synergistically to enhance ANO1 function. By contrast, E-Syt2 dissociates the ANO1-VAPA interaction, forming ANO1-IRBIT-E-Syt2-AC6-AKAP11-PKA complex that phosphorylates ANO1 S221, which markedly reduces ANO1 Ca2+ affinity. The effects of the E-Syts are primarily mediated by their reciprocal regulation of junctional PI(4)P, PI(4,5)P2 and PtdSer. Accordingly, IRBIT deletion in mice impairs receptor-stimulated activation of ANO1 and fluid secretion. These findings should have broad implications for ANO1 roles and functions across various tissues.
    DOI:  https://doi.org/10.1038/s41467-025-58682-w
  18. Nat Commun. 2025 Apr 08. 16(1): 3345
    GPAT4 sustains endoplasmic reticulum homeostasis in endocardial cells and safeguards heart development.
    Tianyang Zhao, Kuipei Jin, Xiaodong Wang, Xiong Su, Youjun Wang, Mingming Gao, Wen Luo, Hongyuan Yang, Zhongzhou Yang.
      The endocardium plays a pivotal role in governing myocardial development, and understanding the intrinsic regulatory insights will help apprehend pathological cardiomyopathy. Glycerol-3-phosphate acyltransferase 4 (GPAT4) is an endoplasmic reticulum (ER) membrane anchored protein. While the role of GPAT4 in glycerophospholipid biosynthesis is well established, its function in the ER is less explored. Here, we generate Gpat4 global and tissue-specific knockout mice and identify the essential role of GPAT4 in endocardial development. Deficiency of GPAT4 provokes endocardial ER stress response and enhances ER-mitochondrial (ER-mito) communications, leading to mitochondrial DNA (mtDNA) escape. As a result, the cGAS-STING pathway is triggered to stimulate type-I-interferon response, which affects heart development. Finally, abolishment of the cGAS-STING-type-I-interferon pathway rescues the heart defects of Gpat4 deletion mice. These findings uncover the pivotal role of GPAT4 in the maintenance of ER homeostasis during endocardial and heart development. Meanwhile, this study highlights the importance of the cGAS-STING pathway in cardiac organogenesis.
    DOI:  https://doi.org/10.1038/s41467-025-58722-5
  19. Nat Commun. 2025 Apr 04. 16(1): 3221
    The Futile Creatine Cycle powers UCP1-independent thermogenesis in classical BAT.
    Jakub Bunk, Mohammed F Hussain, Maria Delgado-Martin, Bozena Samborska, Mina Ersin, Abhirup Shaw, Janane F Rahbani, Lawrence Kazak.
      Classical brown adipose tissue (BAT) is traditionally viewed as relying exclusively on uncoupling protein 1 (UCP1) for thermogenesis via inducible proton leak. However, the physiological significance of UCP1-independent mechanisms linking substrate oxidation to ATP turnover in classical BAT has remained unclear. Here, we identify the Futile Creatine Cycle (FCC), a mitochondrial-localized energy-wasting pathway involving creatine phosphorylation by creatine kinase b (CKB) and phosphocreatine hydrolysis by tissue-nonspecific alkaline phosphatase (TNAP), as a key UCP1-independent thermogenic mechanism in classical BAT. Reintroducing mitochondrial-targeted CKB exclusively into interscapular brown adipocytes in vivo restores thermogenesis and cold tolerance in mice lacking native UCP1 and CKB, in a TNAP-dependent manner. Furthermore, mice with inducible adipocyte-specific co-deletion of TNAP and UCP1 exhibit severe cold-intolerance. These findings challenge the view that BAT thermogenesis depends solely on UCP1 because of insufficient ATP synthase activity and establishes the FCC as a physiologically relevant thermogenic pathway in classical BAT.
    DOI:  https://doi.org/10.1038/s41467-025-58294-4
  20. BMC Urol. 2025 Apr 09. 25(1): 82
    A pilot metabolomics study on clear cell renal cell carcinoma.
    Ying Gan, Zheng Li, Mingjian Ruan, Yang Yang.
      Clear cell renal cell carcinoma (ccRCC) is fundamentally a metabolic disease. To investigate the underlying metabolite changes in the occurrence of ccRCC, we analyzed untargeted metabolomics of 15 ccRCC samples and paired adjacent non-malignant renal tissues by UHPLC-MS/MS analyses. In this study, 511 differential metabolites were screened, of which the top ten up-regulated metabolites in ccRCC were histamine, 1-methylnicotinamide, L-kynurenine, cortisol, tetrahydrocorticosterone, calcitriol, D-erythrose 4-phosphate, citric acid, sedoheptulose 1,7-bisphosphate, and UDP-alpha-D-galactose, and the top down-regulated metabolites were D-cysteine, acetylcholine, pantothenic acid, cytosine, UMP, biocytin, dUMP, 5-phosphoribosyl 1-pyrophosphate, cytidine-5'-monophosphate, and 16α-hydroxyestrone. KEGG pathways enrichment analysis further demonstrated several highlighted pathways: steroid hormone biosynthesis, pyrimidine metabolism, and vitamin digestion and absorption. Our study reveals metabolic patterns of ccRCC and provides insight into the potential biomarker panel to diagnose ccRCC.
    Keywords:  Clear cell renal cell carcinoma; Differential metabolites; KEGG pathway; Metabolomics
    DOI:  https://doi.org/10.1186/s12894-025-01767-x
  21. Anal Chem. 2025 Apr 10.
    Optical Photothermal Infrared Imaging Using Metabolic Probes in Biological Systems.
    Sydney O Shuster, Anna E Curtis, Caitlin M Davis.
      Infrared spectroscopy is a powerful tool for identifying biomolecules. In biological systems, infrared spectra provide information on structure, reaction mechanisms, and conformational change of biomolecules. However, the promise of applying infrared imaging to biological systems has been hampered by low spatial resolution and the overwhelming water background arising from the aqueous nature of in-cell and in vivo work. Recently, optical photothermal infrared microscopy (OPTIR) has overcome these barriers and achieved both spatially and spectrally resolved images of live cells and organisms. Here, we determine the most effective modes of collection on a commercial OPTIR microscope for work in biological samples. We examine three cell lines (Huh-7, differentiated 3T3-L1, and U2OS) and three organisms (Escherichia coli, tardigrades, and zebrafish). Our results suggest that the information provided by multifrequency imaging is comparable to hyperspectral imaging while reducing imaging times 20-fold. We also explore the utility of IR active probes for OPTIR using global and site-specific noncanonical azide containing amino acid probes of proteins. We find that photoreactive IR probes are not compatible with OPTIR. We demonstrate live imaging of cells in buffers with water. 13C glucose metabolism monitored in live fat cells and E. coli highlights that the same probe may be used in different pathways. Further, we demonstrate that some drugs (e.g., neratinib) have IR active moieties that can be imaged by OPTIR. Our findings illustrate the versatility of OPTIR and, together, provide a direction for future dynamic imaging of living cells and organisms.
    DOI:  https://doi.org/10.1021/acs.analchem.4c03752
  22. Biochim Biophys Acta Mol Cell Res. 2025 Apr 09. pii: S0167-4889(25)00059-X. [Epub ahead of print] 119954
    Improving mitochondria-associated endoplasmic reticulum membranes integrity as converging therapeutic strategy for rare neurodegenerative diseases and cancer.
    Michal Cagalinec, Mohd Adnan, Silvia Borecka, Geert Bultynck, Vinay Choubey, Shira Yanovsky-Dagan, Shlomit Ezer, Daniela Gasperikova, Tamar Harel, Dana Jurkovicova, Allen Kaasik, Jean-Charles Liévens, Tangui Maurice, Marco Peviani, Elodie Marie Richard, Jan Skoda, Martina Skopkova, Pauline Tarot, Robbe Van Gorp, Liga Zvejniece, Benjamin Delprat.
      Membrane contact sites harbor a distinct set of proteins with varying biological functions, thereby emerging as hubs for localized signaling nanodomains underlying adequate cell function. Here, we will focus on mitochondria-associated endoplasmic reticulum membranes (MAMs), which serve as hotspots for Ca2+ signaling, redox regulation, lipid exchange, mitochondrial quality and unfolded protein response pathway. A network of MAM-resident proteins contributes to the structural integrity and adequate function of MAMs. Beyond endoplasmic reticulum (ER)-mitochondrial tethering proteins, MAMs contain several multi-protein complexes that mediate the transfer of or are influenced by Ca2+, reactive oxygen species and lipids. Particularly, IP3 receptors, intracellular Ca2+-release channels, and Sigma-1 receptors (S1Rs), ligand-operated chaperones, serve as important platforms that recruit different accessory proteins and intersect with these local signaling processes. Furthermore, many of these proteins are directly implicated in pathophysiological conditions, where their dysregulation or mutation is not only causing diseases such as cancer and neurodegeneration, but also rare genetic diseases, for example familial Parkinson's disease (PINK1, Parkin, DJ-1), familial Amyotrophic lateral sclerosis (TDP43), Wolfram syndrome1/2 (WFS1 and CISD2), Harel-Yoon syndrome (ATAD3A). In this review, we will discuss the current state-of-the-art regarding the molecular components, protein platforms and signaling networks underlying MAM integrity and function in cell function and how their dysregulation impacts MAMs, thereby driving pathogenesis and/or impacting disease burden. We will highlight how these insights can generate novel, potentially therapeutically relevant, strategies to tackle disease outcomes by improving the integrity of MAMs and the signaling processes occurring at these membrane contact sites.
    Keywords:  ATAD3A related disorders; Amyotrophic lateral sclerosis; Calcium signaling; Endoplasmic reticulum stress; Familial Parkinson's disease; Harel-Yoon syndrome; Metabolomics; Mitochondria quality control; Mitochondria-associated endoplasmic reticulum membranes; Rare neurodegenerative diseases; Wolfram syndrome; cancer
    DOI:  https://doi.org/10.1016/j.bbamcr.2025.119954
  23. Proc Natl Acad Sci U S A. 2025 Apr 15. 122(15): e2411241122
    FAO-fueled OXPHOS and NRF2-mediated stress resilience in MICs drive lymph node metastasis.
    Shan-Shan Li, Baifeng Zhang, Cuicui Huang, Yuying Fu, Yuying Zhao, Lanqi Gong, Yanan Tan, Huali Wang, Wenqi Chen, Jie Luo, Yu Zhang, Stephanie Ma, Li Fu, Chenli Liu, Jiandong Huang, Huai-Qiang Ju, Anne Wing-Mui Lee, Xin-Yuan Guan.
      Metastasis is an inefficient process requiring cancer cells to adapt metabolically for survival and colonization in new environments. The contributions of tumor metabolic reprogramming to lymph node (LN) metastasis and its underlying mechanisms remain elusive. Through single-cell RNA sequencing, we identified rare metastasis-initiating cells (MICs) with stem-like properties that drive early LN metastasis. Integrated transcriptome, lipidomic, metabolomic, and functional analyses demonstrated that MICs depend on oxidative phosphorylation (OXPHOS) fueled by fatty acid oxidation (FAO) in the lipid-rich LN microenvironment. Mechanistically, the NRF2-SLC7A11 axis promotes glutathione synthesis to mitigate oxidative stress, thereby enhancing stress resistance and metastatic potential of MICs. Inhibition of NRF2-SLC7A11 reduced LN metastasis and sensitized tumors to cisplatin. Clinically, elevated NRF2-SLC7A11 expression was observed in tumors, with high expression correlating with LN metastasis, chemoresistance, and poor prognosis in esophageal squamous cell carcinoma (ESCC). These findings highlight the pivotal roles of FAO-fueled OXPHOS and NRF2 in LN metastasis and suggest targeting these pathways as a promising therapeutic strategy for metastatic ESCC.
    Keywords:  NRF2; esophageal cancer; lymph node metastasis; metabolic reprogramming; oxidative phosphorylation
    DOI:  https://doi.org/10.1073/pnas.2411241122
  24. Nat Commun. 2025 Apr 07. 16(1): 3318
    Far-red fluorescent genetically encoded calcium ion indicators.
    GENIE Project Team
      Genetically encoded calcium ion (Ca2+) indicators (GECIs) are widely-used molecular tools for functional imaging of Ca2+ dynamics and neuronal activities with single-cell resolution. Here we report the design and development of two far-red fluorescent GECIs, FR-GECO1a and FR-GECO1c, based on the monomeric far-red fluorescent proteins mKelly1 and mKelly2. FR-GECOs have excitation and emission maxima at ~596 nm and ~644 nm, respectively, display large responses to Ca2+ in vitro (ΔF/F0 = 6 for FR-GECO1a, 18 for FR-GECO1c), are bright under both one-photon and two-photon illumination, and have high affinities (apparent Kd = 29 nM for FR-GECO1a, 83 nM for FR-GECO1c) for Ca2+. FR-GECOs offer sensitive and fast detection of single action potentials in neurons, and enable in vivo all-optical manipulation and measurement of cellular activities in combination with optogenetic actuators.
    DOI:  https://doi.org/10.1038/s41467-025-58485-z
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