bims-celmim Biomed News
on Cellular and mitochondrial metabolism
Issue of 2025–06–08
seventeen papers selected by
Marc Segarra Mondejar
  1. PLK1-mediated phosphorylation of PHGDH reprograms serine metabolism in advanced prostate cancer.
  2. Cellular metabolic state controls mitochondrial RNA kinetics.
  3. Pathway metabolite ratios reveal distinctive glutamine metabolism in a subset of proliferating cells.
  4. Charting unknown metabolic reactions by mass spectrometry-resolved stable-isotope tracing metabolomics.
  5. mTOR inhibition triggers mitochondrial fragmentation in cardiomyocytes through proteosome-dependent prohibitin degradation and OPA-1 cleavage.
  6. 2D versus 3D tumor-on-chip models to study the impact of tumor organization on metabolic patterns in vitro.
  7. Metabolic modeling reveals a multi-level deregulation of host-microbiome metabolic networks in IBD.
  8. Effector Tc17 cells resist shift from OXPHOS to aerobic glycolysis.
  9. Metabolic reprogramming by endothelial ANGPTL4 depletion protects against diabetic kidney disease.
  10. Hyperpolarized [1-13C]pyruvate NMR spectroscopy reveals transition of tumor energy metabolism in microscale multicellular spheroids.
  11. Lysosomal TMEM165 controls cellular ion homeostasis and survival by mediating lysosomal Ca2+ import and H+ efflux.
  12. HDAC7 promotes renal cancer progression by reprogramming branched-chain amino acid metabolism.
  13. Atlas-scale metabolic activities inferred from single-cell and spatial transcriptomics.
  14. An AI-assisted fluorescence microscopic system for screening mitophagy inducers by simultaneous analysis of mitophagic intermediates.
  15. Selective Vulnerability of Cancer Cells by Inhibition of Ca2+ Transfer from Endoplasmic Reticulum to Mitochondria.
  16. Targeting SLC7A11-mediated cysteine metabolism for the treatment of trastuzumab-resistant HER2-positive breast cancer.
  17. An integrated bioinformatic investigation of succinic acid metabolism related genes in ccRCC followed by preliminary validation of SLC25A4 in tumorigenesis.
  1. bioRxiv. 2025 May 24. pii: 2025.05.21.655274. [Epub ahead of print]
    PLK1-mediated phosphorylation of PHGDH reprograms serine metabolism in advanced prostate cancer.
    Xiongjian Rao, Derek B Allison, Robert M Flight, Penghui Lin, Daheng He, Zhiguo Li, Yanquan Zhang, Ruixin Wang, Chaohao Li, Jianlin Wang, Xinyi Wang, Jia Peng, Ka Wing Fong, Qing Shao, Chi Wang, Eunus S Ali, Hunter Nb Moseley, Xiaoqi Liu.
      Metabolic reprogramming is a hallmark of cancer, enabling tumor cells to meet their increased biosynthetic and energetic demands. While cells possess the capacity for de novo serine biosynthesis, most transformed cancer cells heavily depend on exogenous serine uptake to sustain their growth, yet the regulatory mechanisms driving this metabolic dependency remain poorly understood. Here, we uncover a novel mechanism by which Polo-like kinase 1 (PLK1), often overexpressed in prostate cancer, orchestrates a metabolic shift in serine and lipid metabolism through the phosphorylation of phosphoglycerate dehydrogenase (PHGDH), the rate-limiting enzyme of the serine synthesis pathway (SSP). We demonstrate that PLK1 phosphorylates PHGDH at three specific sites (S512, S513, S517), leading to a marked reduction in its protein level and enzymatic activity. This downregulation of SSP forces cancer cells to increase their reliance on exogenous serine uptake via the ASCT2 transporter, which, in turn, fuels the biosynthesis of lipids, including sphingolipids essential for tumor growth and survival. Targeting the SSP, serine uptake, or downstream lipid biosynthetic pathways may offer promising therapeutic avenues in PLK1-high advanced cancers.
    DOI:  https://doi.org/10.1101/2025.05.21.655274
  2. bioRxiv. 2025 May 27. pii: 2025.05.13.653903. [Epub ahead of print]
    Cellular metabolic state controls mitochondrial RNA kinetics.
    Sean D Reardon, Clarisa Bautista, Shannon C Cole, Julien Cicero, Tatiana V Mishanina.
      Human mitochondrial genome encodes essential genes for the oxidative phosphorylation (OXPHOS) complexes. These genes must be transcribed and translated in coordination with nuclear-encoded OXPHOS components to ensure correct stoichiometry during OXPHOS complex assembly in the mitochondria. While much is known about nuclear gene regulation during metabolic stresses like glucose deprivation, little is known about the accompanying transcriptional response in mitochondria. Using microscopy, roadblocking qPCR, and transcriptomics, we studied mitochondrial transcription in cells subjected to glucose deprivation, which is known to cause nuclear transcription downregulation and to activate the integrated stress response (ISR). We found that glucose deprivation stabilizes mitochondrial RNAs and slows mitochondrial transcription, effects that are quickly reversed with glucose reintroduction. Although transcriptomics revealed strong upregulation of the ISR, mitochondrial RNA stabilization was not upregulated by pharmacological activation of the ISR, but was promoted by inhibition of glycolysis, unveiling a direct connection between metabolism and regulation of mitochondrial gene expression.
    DOI:  https://doi.org/10.1101/2025.05.13.653903
  3. Mol Syst Biol. 2025 Jun 05.
    Pathway metabolite ratios reveal distinctive glutamine metabolism in a subset of proliferating cells.
    Nancy T Santiappillai, Yue Cao, Mariam F Hakeem-Sanni, Jean Yang, Lake-Ee Quek, Andrew J Hoy.
      Large-scale metabolomic analyses of pan-cancer cell line panels have provided significant insights into the relationships between metabolism and cancer cell biology. Here, we took a pathway-centric approach by transforming targeted metabolomic data into ratios to study associations between reactant and product metabolites in a panel of cancer and non-cancer cell lines. We identified five clusters of cells from various tissue origins. Of these, cells in Cluster 4 had high ratios of TCA cycle metabolites relative to pyruvate, produced more lactate yet consumed less glucose and glutamine, and greater OXPHOS activity compared to Cluster 3 cells with low TCA cycle metabolite ratios. This was due to more glutamine cataplerotic efflux and not glycolysis in cells of Cluster 4. In silico analyses of loss-of-function and drug sensitivity screens showed that Cluster 4 cells were more susceptible to gene deletion and drug targeting of glutamine metabolism and OXPHOS than cells in Cluster 3. Our results highlight the potential of pathway-centric approaches to reveal new aspects of cellular metabolism from metabolomic data.
    Keywords:  Cancer Cell Lines; Glucose Metabolism; Glutamine Metabolism; Metabolic Pathways; Metabolomics
    DOI:  https://doi.org/10.1038/s44320-025-00099-0
  4. Nat Commun. 2025 May 31. 16(1): 5059
    Charting unknown metabolic reactions by mass spectrometry-resolved stable-isotope tracing metabolomics.
    Yang Gao, Mingdu Luo, Hongmiao Wang, Zhiwei Zhou, Yandong Yin, Ruohong Wang, Beizi Xing, Xiaohua Yang, Yuping Cai, Zheng-Jiang Zhu.
      Metabolic reactions play important roles in organisms such as providing energy, transmitting signals, and synthesizing biomacromolecules. Charting unknown metabolic reactions in cells is hindered by limited technologies, restricting the holistic understanding of cellular metabolism. Using mass spectrometry-resolved stable-isotope tracing metabolomics, we develop an isotopologue similarity networking strategy, namely IsoNet, to effectively deduce previously unknown metabolic reactions. The strategy uncovers ~300 previously unknown metabolic reactions in living cells and mice. Specifically, we elaborately chart the metabolic reaction network related to glutathione, unveiling three previously unreported reactions nestled within glutathione metabolism. Among these, a transsulfuration reaction, synthesizing γ-glutamyl-seryl-glycine directly from glutathione, underscores the role of glutathione as a sulfur donor. Functional metabolomics studies systematically characterize biochemical effects of previously unknown reactions in glutathione metabolism, showcasing their diverse functions in regulating cellular metabolism. Overall, these newly uncovered metabolic reactions fill gaps in the metabolic network maps, facilitating exploration of uncharted territories in cellular biochemistry.
    DOI:  https://doi.org/10.1038/s41467-025-60258-7
  5. Cell Commun Signal. 2025 May 31. 23(1): 256
    mTOR inhibition triggers mitochondrial fragmentation in cardiomyocytes through proteosome-dependent prohibitin degradation and OPA-1 cleavage.
    Hugo E Verdejo, Valentina Parra, Andrea Del Campo, Cesar Vasquez-Trincado, Damian Gatica, Camila Lopez-Crisosto, Jovan Kuzmicic, Leslye Venegas-Zamora, Ursula Zuñiga-Cuevas, Mayarling F Troncoso, Rodrigo Troncoso, Beverly A Rothermel, Mario Chiong, E Dale Abel, Sergio Lavandero.
       INTRODUCTION: Cardiac mitochondrial function is intricately regulated by various processes, ultimately impacting metabolic performance. Additionally, protein turnover is crucial for sustained metabolic homeostasis in cardiomyocytes.
    OBJECTIVE: Here, we studied the role of mTOR in OPA-1 cleavage and its consequent effects on mitochondrial dynamics and energetics in cardiomyocytes.
    RESULTS: Cultured rat cardiomyocytes treated with rapamycin for 6-24 h showed a significant reduction in phosphorylation of p70S6K, indicative of sustained inhibition of mTOR. Structural and functional analysis revealed increased mitochondrial fragmentation and impaired bioenergetics characterized by decreases in ROS production, oxygen consumption, and cellular ATP. Depletion of either the mitochondrial protease OMA1 or the mTOR regulator TSC2 by siRNA, coupled with an inducible, cardiomyocyte-specific knockout of mTOR in vivo, suggested that inhibition of mTOR promotes mitochondrial fragmentation through a mechanism involving OMA1 processing of OPA-1. Under homeostatic conditions, OMA1 activity is kept under check through an interaction with microdomains in the inner mitochondrial membrane that requires prohibitin proteins (PHB). Loss of these microdomains releases OMA1 to cleave its substrates. We found that rapamycin both increased ubiquitination of PHB1 and decreased its abundance, suggesting proteasomal degradation. Consistent with this, the proteasome inhibitor MG-132 maintained OPA-1 content in rapamycin-treated cardiomyocytes. Using pharmacological activation and inhibition of AMPK our data supports the hypothesis that this mTOR-PHB1-OMA-OPA-1 pathway impacts mitochondrial morphology under stress conditions, where it mediates dynamic changes in metabolic status.
    CONCLUSIONS: These data suggest that mTOR inhibition disrupts mitochondrial integrity in cardiomyocytes by promoting the degradation of prohibitins and OPA-1, leading to mitochondrial fragmentation and metabolic dysfunction, particularly under conditions of metabolic stress.
    Keywords:  AMPK; Mitochondrial fusion; OMA1; OPA-1; Prohibitin; Rapamycin; mTOR
    DOI:  https://doi.org/10.1186/s12964-025-02240-w
  6. Sci Rep. 2025 Jun 04. 15(1): 19506
    2D versus 3D tumor-on-chip models to study the impact of tumor organization on metabolic patterns in vitro.
    Paula Guerrero-López, Ana Martín-Pardillos, Javier Bonet-Aleta, Andrea Mosseri, Jose L Hueso, Jesus Santamaria, Jose Manuel Garcia-Aznar.
      Despite the limitations of in vitro models to investigate cancer cell metabolism, their study can provide new insights essential for understanding tumorigenesis and effectively aiding in the development of novel therapies. The innovative tumor-on-chip models offer a more physiologically relevant platform than the traditional 2D cultures. These 3D cultures incorporate cell-cell and cell-matrix interactions, as well as diffusion dynamics through both the matrix and tumor spheroid, modeling in vivo diffusion within the tumor. Therefore, this work focuses on a quantitative comparison between 2D and 3D cultures through a microfluidic chip that allows daily monitoring of cancer cell key metabolites such as glucose, glutamine and lactate, unveiling critical differences. Our analysis reveals reduced proliferation rates in 3D models, likely due to limited diffusion of nutrients and oxygen. Additionally, 3D cultures showed distinct metabolic profiles, including elevated glutamine consumption under glucose restriction and higher lactate production, indicating an enhanced Warburg effect. The microfluidic chip enabled continuous monitoring, revealing increased per-cell glucose consumption in 3D models, highlighting fewer but more metabolically active cells than in 2D cultures. These findings underscore the importance of using microfluidic-based 3D models to provide a more accurate representation of tumor metabolism and progression compared to traditional 2D cultures.
    Keywords:  2D cell culture; 3D cell culture; Cancer; Glucose; Metabolism; Spheroid
    DOI:  https://doi.org/10.1038/s41598-025-03504-8
  7. Nat Commun. 2025 Jun 02. 16(1): 5120
    Metabolic modeling reveals a multi-level deregulation of host-microbiome metabolic networks in IBD.
    Jan Taubenheim, A Samer Kadibalban, Johannes Zimmermann, Claudia Taubenheim, Florian Tran, Philip Rosenstiel, Konrad Aden, Christoph Kaleta.
      Inflammatory bowel diseases (IBDs) are chronic disorders involving dysregulated immune responses. Despite the role of disrupted host-microbial interaction in the pathophysiology of IBD, the underlying metabolic principles are not fully understood. We densely profiled microbiome, transcriptome and metabolome signatures from longitudinal IBD cohorts before and after advanced drug therapy initiation and reconstructed metabolic models of the gut microbiome and the host intestine to study host-microbiome metabolic cross-talk in the context of inflammation. Here, we identified concomitant changes in metabolic activity across data layers involving NAD, amino acid, one-carbon and phospholipid metabolism. In particular on the host level, elevated tryptophan catabolism depleted circulating tryptophan, thereby impairing NAD biosynthesis. Reduced host transamination reactions disrupted nitrogen homeostasis and polyamine/glutathione metabolism. The suppressed one-carbon cycle in patient tissues altered phospholipid profiles due to limited choline availability. Simultaneously, microbiome metabolic shifts in NAD, amino acid and polyamine metabolism exacerbated these host metabolic imbalances. Leveraging host and microbe metabolic models, we predicted dietary interventions remodeling the microbiome to restore metabolic homeostasis, suggesting novel therapeutic strategies for IBD.
    DOI:  https://doi.org/10.1038/s41467-025-60233-2
  8. Front Immunol. 2025 ;16 1571221
    Effector Tc17 cells resist shift from OXPHOS to aerobic glycolysis.
    Reni John, Srinivasu Mudalagiriyappa, Nagabhushan Chandrashekar, Som G Nanjappa.
      IL-17A-expressing lymphocytes, including Tc17 cells, are instrumental in immunity, immunopathology, and autoimmunity. We have previously shown that experimental attenuated live fungal vaccine-induced Tc17 cells are stable, long-lived without plasticity, and necessary to mediate sterilizing immunity during CD4+ T cell deficiency, which poses higher susceptibility to fungal infections. Cell metabolism is integral for T cell homeostasis but the metabolic adaptations of Tc17 cells are poorly defined. In this study, we hypothesized that effector Tc17 cells adopt high energy-yielding metabolic pathways to form stable, long-lived memory cells in vivo. Using a mouse model of attenuated fungal vaccination, we found that effector Tc17 cells were metabolically highly active with higher proliferation and protein synthesis than IFNγ+ CD8+ T (Tc1) cells. Glucose was necessary for effector Tc17 cell expansion but with less dependency during the late expansion despite the active metabolism. Contrary to established dogma, we found that the effector Tc17 cells preferentially channeled the glucose to OXPHOS than glycolysis, which was correlated with higher mitochondrial mass and membrane potential. Inhibition of OXPHOS shrunk the Tc17 responses while sparing Tc1 cell responses. Tc17 cells actively relied on OXPHOS throughout the expansion period, resisting adaptation to aerobic glycolysis. Our data showed that the effector Tc17 cells predominantly utilize glucose for metabolism through OXPHOS rather than aerobic glycolysis. Our study has implications in vaccine design to enhance the efficacy and immunotherapeutics to modulate the immunity and autoimmunity.
    Keywords:  CD8+ T cell; OXPHOS; T cell activation; Tc17 cell; antifungal; glycolysis; vaccine responses
    DOI:  https://doi.org/10.3389/fimmu.2025.1571221
  9. bioRxiv. 2025 May 12. pii: 2025.05.08.652142. [Epub ahead of print]
    Metabolic reprogramming by endothelial ANGPTL4 depletion protects against diabetic kidney disease.
    Swayam Prakash Srivastava, Han Zhou, Rachel Shenoi, Myshal Morris, Begoña Lainez-Mas, Yuta Takagaki, Barani Kumar Rajendran, Ocean Setia, Binod Aryal, Keizo Kanasaki, Daisuke Koya, Ken Inoki, Alan Dardik, Carlos Fernández-Hernando, Gerald I Shulman, Julie E Goodwin.
      The role of cell-specific ANGPTL4 is not well known in the context of ECs, specifically in pathological angiogenesis and its relation to diabetic kidney disease. Here, we demonstrate that endothelial ANGPTL4 is required to induce a metabolic phenotype that favors mesenchymal activation in ECs and tubules in diabetic conditions. Diabetes accelerates mesenchymal activation and fibrogenesis in control mice however, the same effects were not observed in endothelial-cell specific knock out mice. This mesenchymal activation in diabetes is directly linked with pathological neovascularization, endothelial leakage, lipid and glycolysis metabolite load, de novo lipogenesis (DNL) and related mitochondrial damage, activation of the immune system, c-GAS-STING activation and transcription of pro-inflammatory cytokines. However, endothelial ANGPTL4-depleted mice had stable vessels, improved levels of lipid and glucose metabolism, suppressed levels of DNL, restored mitochondrial function, and mitigated levels of c-GAS-STING-mediated inflammation. Moreover, Inhibition of DNL, and STING via small molecule inhibitors suppressed pathological neovascularization and endothelial leakage, normalized fatty acid oxidation and reduced pathological glycolysis and de novo lipogenesis (DNL). These data demonstrate the crucial roles of endothelial ANGPTL4 in regulating pathogenic angiogenesis in the renal vasculature during diabetes.
    DOI:  https://doi.org/10.1101/2025.05.08.652142
  10. Sci Rep. 2025 Jun 02. 15(1): 19303
    Hyperpolarized [1-13C]pyruvate NMR spectroscopy reveals transition of tumor energy metabolism in microscale multicellular spheroids.
    Yoichi Takakusagi, Kaori Takakusagi, Kaori Inoue, Keita Saito, Yoshimi Homma, Kazuhiro Ichikawa.
      Hyperpolarized (HP) [1-13C]pyruvate nuclear magnetic resonance (NMR) spectroscopy was employed to investigate tumor energy metabolism in microscale multicellular spheroids of a few hundred micrometers in diameter, serving as a model of early-phase tumorigenesis in vivo. A three-dimensional static culture of murine squamous cell carcinoma (SCCVII) cells formed uniform smaller multicellular spheroids (~ 150 μm in diameter), without hypoxic or necrotic cores, yet these spheroids exhibited resistance to anti-tumor drugs. HP [1-13C]pyruvate NMR spectroscopy of SCCVII spheroids revealed an increased conversion of pyruvate to lactate compared to monolayer cultures, indicating enhanced aerobic glycolysis in the aggregated cells. Additionally, HP spectroscopy differentiated the degree of aerobic glycolysis in human prostate tumor spheroids-DU145 (~ 120 μm) and PC-3 (~ 230 μm)-as evidenced by the upregulation of genes associated with lactate production and cellular transport. The Lac/Pyr ratio among spheroids correlated with those observed in homogenate samples of corresponding tumors grown in mice. These findings suggest that HP [1-13C]pyruvate NMR spectroscopy may serve as a metabolic biomarker for early-phase tumorigenesis in vivo.
    Keywords:  Hyperpolarization; NMR; Prostate tumor; Pyruvate; SCC; Spheroid
    DOI:  https://doi.org/10.1038/s41598-025-03454-1
  11. Nat Commun. 2025 Jun 05. 16(1): 5209
    Lysosomal TMEM165 controls cellular ion homeostasis and survival by mediating lysosomal Ca2+ import and H+ efflux.
    Ran Chen, Bin Liu, Dawid Jaślan, Lucija Kucej, Veronika Kudrina, Belinda Warnke, Yvonne E Klingl, Arnas Petrauskas, Sandra Prat Castro, Kenji Maeda, Christian Grimm, Marja Jäättelä.
      The proper function of lysosomes depends on their ability to store and release calcium. While several lysosomal calcium release channels have been described, how lysosomes replenish their calcium stores in placental mammals has not been determined. Using genetic depletion and overexpression techniques combined with electrophysiology and visualization of subcellular ion concentrations and their fluxes across the lysosomal membrane, we show here that TMEM165 imports calcium to the lysosomal lumen and mediates calcium-induced lysosomal proton leakage. Accordingly, TMEM165 accelerates the recovery of cells from cytosolic calcium overload thereby enhancing cell survival while causing a significant acidification of the cytosol. These data indicate that in addition to its previously identified role in the glycosylation of proteins and lipids in the Golgi, a fraction of TMEM165 localizes on the lysosomal limiting membrane, where its putative calcium/proton antiporter activity plays an essential role in the regulation of intracellular ion homeostasis and cell survival.
    DOI:  https://doi.org/10.1038/s41467-025-60349-5
  12. Sci Adv. 2025 Jun 06. 11(23): eadt3552
    HDAC7 promotes renal cancer progression by reprogramming branched-chain amino acid metabolism.
    Hyeyoung Nam, Anirban Kundu, Suman Karki, Richard L Kirkman, Darshan S Chandrashekar, Jeremy B Foote, Guofang Zhang, Wentao He, Sooryanarayana Varambally, Han-Fei Ding, Sunil Sudarshan.
      Clear cell renal cell carcinoma (ccRCC), the most common subtype of kidney cancer, exhibits notable metabolic reprogramming. We previously reported elevated HDAC7, a class II histone deacetylase, in ccRCC. Here, we demonstrate that HDAC7 promotes aggressive phenotypes and in vivo tumor progression in RCC. HDAC7 suppresses the expression of genes mediating branched-chain amino acid (BCAA) catabolism. Notably, lower expression of BCAA catabolism genes is strongly associated with worsened survival in ccRCC. Suppression of BCAA catabolism promotes expression of SNAIL1, a central mediator of aggressive phenotypes including migration and invasion. HDAC7-mediated suppression of the BCAA catabolic program promotes SNAI1 messenger RNA transcription via NOTCH signaling activation. Collectively, our findings provide innovative insights into the role of metabolic remodeling in ccRCC tumor progression.
    DOI:  https://doi.org/10.1126/sciadv.adt3552
  13. bioRxiv. 2025 May 14. pii: 2025.05.09.653038. [Epub ahead of print]
    Atlas-scale metabolic activities inferred from single-cell and spatial transcriptomics.
    Erick Armingol, James Ashcroft, Magda Mareckova, Martin Prete, Valentina Lorenzi, Cecilia Icoresi Mazzeo, Jimmy Tsz Hang Lee, Marie Moullet, Omer Ali Bayraktar, Christian Becker, Krina Zondervan, Luz Garcia-Alonso, Nathan E Lewis, Roser Vento-Tormo.
      Metabolism supplies energy, building blocks, and signaling molecules vital for cell function and communication, but methods to directly measure it at single-cell and/or spatial resolutions remain technically challenging and inaccessible for most researchers. Single-cell and spatial transcriptomics offer high-throughput data alternatives with a rich ecosystem of computational tools. Here, we present scCellFie, a computational framework to infer metabolic activities from human and mouse transcriptomic data at single-cell and spatial resolution. Applied to ~30 million cell profiles, we generated a comprehensive metabolic atlas across human organs, identifying organ- and cell-type-specific activities. In the endometrium, scCellFie reveals metabolic programs contributing to healthy tissue remodeling during the menstrual cycle, with temporal patterns replicated in data from in vitro cultures. We also uncover disease-associated metabolic alterations in endometriosis and endometrial carcinoma, linked to proinflammatory macrophages, and metabolite-mediated epithelial cell communication, respectively. Ultimately, scCellFie provides a scalable toolbox for extracting interpretable metabolic functionalities from transcriptomic data.
    DOI:  https://doi.org/10.1101/2025.05.09.653038
  14. Nat Commun. 2025 Jun 04. 16(1): 5179
    An AI-assisted fluorescence microscopic system for screening mitophagy inducers by simultaneous analysis of mitophagic intermediates.
    Yicheng Wang, Pengfei Song, Heqing Zhou, Pengwei Wang, Yan Li, Zhiyong Shao, Lu Wang, Yan You, Zuhai Lei, Jinhua Yu, Cong Li.
      Mitophagy, the selective autophagic elimination of mitochondria, is essential for maintaining mitochondrial quality and cell homeostasis. Impairment of mitophagy flux, a process involving multiple sequential intermediates, is implicated in the onset of numerous neurodegenerative diseases. Screening mitophagy inducers, particularly understanding their impact on mitophagic intermediates, is crucial for neurodegenerative disease treatment. However, existing techniques do not allow simultaneous visualization of distinct mitophagic intermediates in live cells. Here, we introduce an artificial intelligence-assisted fluorescence microscopic system (AI-FM) that enables the uninterrupted recognition and quantification of key mitophagic intermediates by extracting mitochondrial pH and morphological features. Using AI-FM, we identify a potential mitophagy modulator, Y040-7904, which enhances mitophagy by promoting mitochondria transport to autophagosomes and the fusion of autophagosomes with autolysosomes. Y040-7904 also reduces amyloid-β pathologies in both in vitro and in vivo models of Alzheimer's disease. This work offers an approach for visualizing the entire mitophagy flux, advancing the understanding of mitophagy-related mechanisms and enabling the discovery of mitophagy inducers for neurodegenerative diseases.
    DOI:  https://doi.org/10.1038/s41467-025-60315-1
  15. Cell Rep. 2025 Jun 05. pii: S2211-1247(25)00640-0. [Epub ahead of print]44(6): 115869
    Selective Vulnerability of Cancer Cells by Inhibition of Ca2+ Transfer from Endoplasmic Reticulum to Mitochondria.
    César Cárdenas, Marioly Müller, Andrew McNeal, Alenka Lovy, Fabian Jaňa, Galdo Bustos, Felix Urra, Natalia Smith, Jordi Molgó, J Alan Diehl, Todd W Ridky, J Kevin Foskett.
      
    DOI:  https://doi.org/10.1016/j.celrep.2025.115869
  16. Elife. 2025 Jun 04. pii: RP103953. [Epub ahead of print]14
    Targeting SLC7A11-mediated cysteine metabolism for the treatment of trastuzumab-resistant HER2-positive breast cancer.
    Yijia Hua, Ningjun Duan, Chunxiao Sun, Fan Yang, Min Tian, Yanting Sun, Shuhan Zhao, Jue Gong, Qian Liu, Xiang Huang, Yan Liang, Ziyi Fu, Wei Li, Yongmei Yin.
      Trastuzumab resistance remains a challenge for HER2-positive breast cancer treatment. Targeting metabolic reprogramming would provide novel insights for therapeutic strategies. Here, we integrated metabolomics, transcriptomics, and epigenomics data of trastuzumab-sensitive and primary-resistant HER2-positive breast cancer to identify metabolic alterations. Aberrant cysteine metabolism was discovered in trastuzumab primary-resistant breast cancer at both circulating and intracellular levels. The inhibition of SLC7A11 and cysteine starvation could synergize with trastuzumab to induce ferroptosis. Mechanistically, increased H3K4me3 and decreased DNA methylation enhanced SLC7A11 transcription and cystine uptake in trastuzumab-resistant breast cancer. The regulation of epigenetic modifications modulated cysteine metabolism and ferroptosis sensitivity. These results revealed an innovative approach for overcoming trastuzumab resistance by targeting specific amino acid metabolism.
    Keywords:  HER2-positive breast cancer; cancer biology; cysteine metabolism; epigenetic modifications; human; mouse; trastuzumab primary resistance
    DOI:  https://doi.org/10.7554/eLife.103953
  17. Sci Rep. 2025 Jun 05. 15(1): 19736
    An integrated bioinformatic investigation of succinic acid metabolism related genes in ccRCC followed by preliminary validation of SLC25A4 in tumorigenesis.
    Dong Yue, Fengyun Dong, Sen Wang, Miao Zheng.
      The defective function of succinate dehydrogenase promotes the development and progression of kidney renal clear cell renal cell carcinoma (ccRCC). However, the molecular mechanism of succinate metabolism-related genes (SMRGs) has not been extensively studied in KIRC. First, differentially expressed SMRGs (DE-SMRGs) were screened among genesets. Next, functional enrichment analysis was performed to investigate the functions of DE-SMRGs. The univariate Cox algorithm, LASSO, and multivariate Cox analysis were performed to obtain biomarkers and build a prognostic model. Afterward, enrichment and immune microenvironment analysis were carried out in two different risk subgroups. Finally, expression validation and expression intensity of prognostic gene was verified by in situ and in vitro experiments. In total, 138 DE-SMRGs were screened by overlapping SMRGs and differentially expressed genes. The functional enrichment results revealed that DE-SMRGs were implicated in retinoic acid metabolic process and retinol metabolism. Then, 8 succinate metabolism-related biomarkers were obtained, and prognostic model was developed and SLC25A4 ranked the highest in importance. SLC25A4 was down-regulated in KIRC, and its upregulation was related to better overall survival in patients from public datasets and in clinical cases. SLC25A4 attenuated cell proliferation, cell invasion, and exerted its biological function by inhibiting the STAT3 signaling pathway. Our study reveals that succinate metabolism-related biomarkers can provide a basis for exploring the prediction of prognosis in ccRCC.
    Keywords:  Clear cell renal cell carcinoma; Prognosis; Risk score; Succinate metabolism-related genes
    DOI:  https://doi.org/10.1038/s41598-025-03102-8
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