bims-camemi 2025-02-16 papers

bims-camemi

Biomed News

on Mitochondrial metabolism in cancer

Issue of 2025–02–16
37 papers selected by
Christian Frezza, Universität zu Köln

Mitofusin 2 displays fusion-independent roles in proteostasis surveillance.
BBOX1 restrains TBK1-mTORC1 oncogenic signaling in clear cell renal cell carcinoma.
A microscopy-based screen identifies cellular kinases modulating mitochondrial translation.
Mitochondrial succinate feeds T cell exhaustion in cancer.
Serine starvation suppresses the progression of esophageal cancer by regulating the synthesis of purine nucleotides and NADPH.
Disruption of mitochondrial homeostasis and permeability transition pore opening in OPA1 iPSC-derived retinal ganglion cells.
Mitochondria-targeting siRNA screening identifies mitochondrial calcium uniporter as a factor involved in nucleoid morphology.
Clear cell renal carcinoma essentially requires CDKL3 for oncogenesis.
ArfGAP2 promotes STING proton channel activity, cytokine transit, and autoinflammation.
Diverse routes to mitophagy governed by ubiquitylation and mitochondrial import.
Adenylate cyclase 10 promotes brown adipose tissue thermogenesis.
The fundamental role of mitochondria-endoplasmic reticulum contacts in ageing and declining healthspan.
Ezrin defines TSC complex activation at endosomal compartments through EGFR-AKT signaling.
Lactate controls cancer stemness and plasticity through epigenetic regulation.
Metabolic heterogeneity in tumor cells impacts immunology in lung squamous cell carcinoma.
Intrinsic electrical activity drives small-cell lung cancer progression.
Mitochondrial DNA removal is essential for sperm development and activity.
PHGDH inhibition and FOXO3 modulation drives PUMA-dependent apoptosis in osteosarcoma.
Acetyl-CoA synthesis in the skin is a key determinant of systemic lipid homeostasis.
A relative metabolic flux analysis model of glucose anaplerosis.
Metformin inhibits the histone methyltransferase CARM1 and attenuates H3 histone methylation during gluconeogenesis.
Loss of long-chain acyl-CoA dehydrogenase protects against acute kidney injury.
TRAF3 loss protects glioblastoma cells from lipid peroxidation and immune elimination via dysregulated lipid metabolism.
Intracellular signalling in arterial chemoreceptors during acute hypoxia and glucose deprivation: role of ATP.
Isoform usage as a distinct regulatory layer driving nutrient-responsive metabolic adaptation.
Pharmacologic activation of integrated stress response kinases inhibits pathologic mitochondrial fragmentation.
Intercellular mitochondrial transfer contributes to microenvironmental redirection of cancer cell fate.
Metabolic control of replisome plasticity in genome surveillance.
α-Ketoglutarate inhibits the pluripotent-to-totipotent state transition in stem cells.
Metabolic signature of renal cell carcinoma tumours and its correlation with the urinary metabolome.
A microRNA-regulated transcriptional state defines intratumoral CD8+ T cells that respond to immunotherapy.
Extracellular vesicles from the lung pro-thrombotic niche drive cancer-associated thrombosis and metastasis via integrin beta 2.
Integration of metabolomic and transcriptomic analyses reveals regulatory functions of the ChREBP transcription factor in energy metabolism.
Metabolite signaling promotes the recruitment of immunosuppressive cells to tumors.
Genomic mediators of acquired resistance to immunotherapy in metastatic melanoma.
Interactions Between Ploidy and Resource Availability Shape Clonal Evolution in Glioblastoma.
Fluoxetine promotes IL-10-dependent metabolic defenses to protect from sepsis-induced lethality.

Nat Commun. 2025 Feb 10. 16(1): 1501

Mitofusin 2 displays fusion-independent roles in proteostasis surveillance.

Mariana Joaquim, Selver Altin, Maria-Bianca Bulimaga, Tânia Simões, Hendrik Nolte, Verian Bader, Camilla Aurora Franchino, Solenn Plouzennec, Karolina Szczepanowska, Elena Marchesan, Kay Hofmann, Marcus Krüger, Elena Ziviani, Aleksandra Trifunovic, Arnaud Chevrollier, Konstanze F Winklhofer, Elisa Motori, Margarete Odenthal, Mafalda Escobar-Henriques.

Mitochondria are essential organelles and their functional state dictates cellular proteostasis. However, little is known about the molecular gatekeepers involved, especially in absence of external stress. Here we identify a role of MFN2 in quality control independent of its function in organellar shape remodeling. MFN2 ablation alters the cellular proteome, marked for example by decreased levels of the import machinery and accumulation of the kinase PINK1. Moreover, MFN2 interacts with the proteasome and cytosolic chaperones, thereby preventing aggregation of newly translated proteins. Similarly to MFN2-KO cells, patient fibroblasts with MFN2-disease variants recapitulate excessive protein aggregation defects. Restoring MFN2 levels re-establishes proteostasis in MFN2-KO cells and rescues fusion defects of MFN1-KO cells. In contrast, MFN1 loss or mitochondrial shape alterations do not alter protein aggregation, consistent with a fusion-independent role of MFN2 in cellular homeostasis. In sum, our findings open new possibilities for therapeutic strategies by modulation of MFN2 levels.

DOI: https://doi.org/10.1038/s41467-025-56673-5
Nat Commun. 2025 Feb 11. 16(1): 1543

BBOX1 restrains TBK1-mTORC1 oncogenic signaling in clear cell renal cell carcinoma.

Chengheng Liao, Lianxin Hu, Liwei Jia, Jin Zhou, Tao Wang, Kangsan Kim, Hua Zhong, Hongwei Yao, Lei Dong, Lei Guo, Qian Liang, Cheng Zhang, Fangzhou Zhao, Jun Fang, Hongyi Liu, Shina Li, Lin Xu, Jeremy M Simon, Srinivas Malladi, Payal Kapur, James Brugarolas, Ralph J DeBerardinis, Qing Zhang.

Clear cell renal cell carcinoma (ccRCC), a metabolic disease originating from renal proximal convoluted tubule (PCT) epithelial cells, remains incompletely understood in terms of its initiating signaling events. Here, we identify γ-butyrobetaine hydroxylase 1 (BBOX1), a key enzyme in carnitine synthesis predominantly expressed in PCT cells, as a tumor suppressor in ccRCC. BBOX1 expression is lost during ccRCC malignant transformation, and its restoration reduces cell viability in physiological medium and inhibits xenograft tumor growth. Transcriptomic analyses reveal that BBOX1 suppresses critical metabolic pathways including mTORC1 signaling and glycolysis in ccRCC. Further, we identify TANK-binding kinase 1 (TBK1) as an essential mediator of mTORC1 and glycolysis activation and as a target of BBOX1-mediated tumor suppression. Mechanistically, BBOX1 disrupts TBK1 activation by preventing its interaction with the upstream activator doublecortin-like kinase 2 (DCLK2). This BBOX1-DCLK2-TBK1 axis unveils an important mechanism in ccRCC metabolic dysregulation and highlights potential therapeutic strategies.

DOI: https://doi.org/10.1038/s41467-025-56955-y
Cell Rep. 2025 Jan 28. pii: S2211-1247(24)01494-3. [Epub ahead of print]44(1): 115143

A microscopy-based screen identifies cellular kinases modulating mitochondrial translation.

Roya Yousefi, Luis Daniel Cruz-Zaragoza, Anusha Valpadashi, Carina Hansohn, Drishan Dahal, Ricarda Richter-Dennerlein, Silvio Rizzoli, Henning Urlaub, Peter Rehling, David Pacheu-Grau.

  Mitochondrial DNA encodes 13 subunits of the oxidative phosphorylation (OXPHOS) system, which are synthesized inside the organelle and essential for cellular energy supply. How mitochondrial gene expression is regulated and integrated into cellular physiology is little understood. Here, we perform a high-throughput screen combining fluorescent labeling of mitochondrial translation products with small interfering RNA (siRNA)-mediated knockdown to identify cellular kinases regulating translation. As proof of principle, the screen identifies known kinases that affect mitochondrial translation, and it also reveals several kinases not yet linked to this process. Among the latter, we focus on the primarily cytosolic kinase, fructosamine 3 kinase (FN3K), which localizes partially to the mitochondria to support translation. FN3K interacts with the mitochondrial ribosome and modulates its assembly, thereby affecting translation. Overall, our work provides a reliable approach to identify protein functions for mitochondrial gene expression in a high-throughput manner.

Keywords:  CP: Metabolism; CP: Molecular biology; cellular kinases; click chemistry; mito-FUNCAT; mitochondrial translation; siRNA library

DOI:  https://doi.org/10.1016/j.celrep.2024.115143
Cancer Cell. 2025 Feb 10. pii: S1535-6108(25)00023-6. [Epub ahead of print]43(2): 168-170

Mitochondrial succinate feeds T cell exhaustion in cancer.

Lorenzo Galluzzi, Emma Guilbaud, Abhishek D Garg.

Mitochondrial fitness is critical for effector CD8+ T cell responses against cancer. In this issue of Cancer Cell, Ma et al. delineate a novel mechanism linking defects in mitochondrial metabolism as elicited by prolyl 4-hydroxylase subunit alpha 1 (P4HA1) to T cell exhaustion and reduced tumor sensitivity to immunotherapy.

DOI: https://doi.org/10.1016/j.ccell.2025.01.005
Cancer Metab. 2025 Feb 13. 13(1): 10

Serine starvation suppresses the progression of esophageal cancer by regulating the synthesis of purine nucleotides and NADPH.

Hui Jie, Jing Wei, Zhuoling Li, Min Yi, Xinying Qian, Yan Li, Chunqi Liu, Chuan Li, Liang Wang, Pengchi Deng, Lunxu Liu, Xiaobo Cen, Yinglan Zhao.

  Serine metabolism provides important metabolic intermediates that support the rapid proliferation of tumor cells. However, the role of serine metabolism in esophageal squamous cell carcinoma (ESCC) and the underlying mechanism remains unclear. Here, we show that serine starvation predominantly inhibits ESCC cell proliferation by suppressing purine nucleotides and NADPH synthesis. Mechanistically, serine depletion led to the accumulation of aminoimidazole carboxamide ribonucleoside (AICAR), an intermediate metabolite of de novo purine synthesis, and AMP/ATP ratio. These increases activated 5'-AMP-activated kinase (AMPK), which subsequently inhibited the mTORC1 pathway by phosphorylating Raptor at Ser792. Moreover, serine depletion decreased NADPH level followed by elevated reactive oxygen species (ROS) production and DNA damage, which induced p53-p21 mediated G1 phase cell cycle arrest. Conversely, serine starvation activated transcription factor 4 (ATF4)-mediated robust expression of phosphoserine aminotransferase 1 (PSAT1) which in turn promoted compensatory endogenous serine synthesis, thus maintaining ESCC cell survival under serine-limited conditions. Accordingly, serine deprivation combined with PSAT1 inhibition significantly suppressed ESCC tumor growth both in vitro and in vivo. Taken together, our findings demonstrate that serine starvation suppresses the proliferation of ESCC cells by disturbing the synthesis of purine nucleotides and NADPH, and the combination of serine deprivation and PSAT1 inhibition significantly impairs ESCC tumor growth. Our study provides a theoretical basis for targeting serine metabolism as a potential therapeutic strategy for ESCC.

Keywords:  AMPKα / mTORC1 pathway; ESCC cell proliferation; Purine synthesis; Serine starvation

DOI:  https://doi.org/10.1186/s40170-025-00376-4
Acta Neuropathol Commun. 2025 Feb 13. 13(1): 28

Disruption of mitochondrial homeostasis and permeability transition pore opening in OPA1 iPSC-derived retinal ganglion cells.

Michael Whitehead, Joshua P Harvey, Paul E Sladen, Giada Becchi, Kritarth Singh, Yujiao Jennifer Sun, Thomas Burgoyne, Michael R Duchen, Patrick Yu-Wai-Man, Michael E Cheetham.

  Dominant optic atrophy (DOA) is the most common inherited optic neuropathy, characterised by the selective loss of retinal ganglion cells (RGCs). Over 60% of DOA cases are caused by pathogenic variants in the OPA1 gene, which encodes a dynamin-related GTPase protein. OPA1 plays a key role in the maintenance of the mitochondrial network, mitochondrial DNA integrity and bioenergetic function. However, our current understanding of how OPA1 dysfunction contributes to vision loss in DOA patients has been limited by access to patient-derived RGCs. Here, we used induced pluripotent stem cell (iPSC)-RGCs to study how OPA1 dysfunction affects cellular homeostasis in human RGCs. iPSCs derived from a DOA+ patient with the OPA1 R445H variant and isogenic CRISPR-Cas9-corrected iPSCs were differentiated to iPSC-RGCs. Defects in mitochondrial networks and increased levels of reactive oxygen species were observed in iPSC-RGCs carrying OPA1 R445H. Ultrastructural analyses also revealed changes in mitochondrial shape and cristae structure, with decreased endoplasmic reticulum (ER): mitochondrial contact length in DOA iPSC-RGCs. Mitochondrial membrane potential was reduced and its maintenance was also impaired following inhibition of the F1Fo-ATP synthase with oligomycin, suggesting that mitochondrial membrane potential is maintained in DOA iPSC-RGCs through reversal of the ATP synthase and ATP hydrolysis. These impairments in mitochondrial structure and function were associated with defects in cytosolic calcium buffering following ER calcium release and store-operated calcium entry, and following stimulation with the excitatory neurotransmitter glutamate. In response to mitochondrial calcium overload, DOA iPSC-RGCs exhibited increased sensitivity to opening of the mitochondrial permeability transition pore. These data reveal novel aspects of DOA pathogenesis in R445H patient-derived RGCs. The findings suggest a mechanism in which primary defects in mitochondrial network dynamics disrupt core mitochondrial functions, including bioenergetics, calcium homeostasis, and opening of the permeability transition pore, which may contribute to vision loss in DOA patients.

Keywords:  Calcium homeostasis; Dominant optic atrophy; Mitochondrial networks; Neurodegeneration; OPA1; Retinal ganglion cells; iPSCs

DOI:  https://doi.org/10.1186/s40478-025-01942-z
J Biochem. 2025 Feb 10. pii: mvaf008. [Epub ahead of print]

Mitochondria-targeting siRNA screening identifies mitochondrial calcium uniporter as a factor involved in nucleoid morphology.

Hirotaka Kanon, Takaya Ishihara, Reiko Ban-Ishihara, Azusa Ota, Tatsuki Yasuda, Aoi Ichikawa, Ruo Ueyama, Taiki Baba, Kohsuke Takeda, Emi Ogasawara, Naotada Ishihara.

  Mitochondria are believed to have originated from the endosymbiosis of bacteria and they still contain their own genome, which is called mitochondrial DNA (mtDNA). Under fluorescence microscopy of cultured mammalian cells, mtDNA is observed as numerous tiny dot-like structures called mitochondrial nucleoids. In live-imaging, the morphology and distribution of nucleoids are change dynamically, but the molecular details remain poorly understood. In this study, we constructed a custom siRNA library targeting 1,164 human mitochondria-related genes, and from live-imaging-based screening of HeLa cells, we identified that mitochondria calcium uniporter (MCU), a pore-forming subunit of the mitochondrial Ca2+ channel, is involved in nucleoid morphology. We found that suppression of MCU by RNAi induced the formation of highly enlarged nucleoids as well as respiratory dysfunction and that the re-introduction of MCU or treatment with Ca2+ ionophore recovered the enlarged nucleoid morphology. These results suggest that mitochondrial Ca2+ uptake via MCU is associated with nucleoid morphology. The constructed siRNA library might be widely applied to analyze the roles of mitochondrial proteins in various cellular events, making it useful to understand the multifaceted functions of mitochondria in human cells.

Keywords:  Mitochondria; mitochondrial calcium ion; mitochondrial calcium uniporter; mitochondrial nucleoid; siRNA screening

DOI:  https://doi.org/10.1093/jb/mvaf008
Proc Natl Acad Sci U S A. 2025 Feb 18. 122(7): e2415244122

Clear cell renal carcinoma essentially requires CDKL3 for oncogenesis.

Lanjing Ma, Zhongqiu Pang, Haijiao Zhang, Xueling Yang, Shaoqin Zheng, Yi Chen, Weijie Ding, Qing Han, Xi Zhang, Liu Cao, Teng Fei, Qiang Wang, Daming Gao, Aina He, Ke-Bang Hu, Xuexin Li, Ren Sheng.

  Clear cell renal cell carcinoma (ccRCC) is the predominant human renal cancer with surging incidence and fatality lately. Hyperactivation of hypoxia-inducible factor (HIF) and mammalian target of rapamycin (mTOR) signaling are the common signatures in ccRCC. Herein, we employed spontaneous ccRCC model to demonstrate the indispensability of an underappreciated Ser/Thr kinase, CDKL3, in the initiation and progression of ccRCC. Ablation of CDKL3 does not affect normal kidney, but abrogates Akt-mTOR hyperactivity and thoroughly prevents the formation and growth of the HIF-agitated ccRCC in vivo. Remarkable clinical correlations also supported the oncogenic role of CDKL3. Mechanism-wise, cytosolic CDKL3 unexpectedly behaves as the adaptor to physically potentiate mTORC2-dependent Akt activation without functioning through kinase activity. And mTORC2 can phosphorylate and stabilize CDKL3 to form a positive feedback loop to sustain the cancer-favored Akt-mTOR overactivation. Together, we revealed the pathological importance and molecular mechanism of CDKL3-mediated Akt-mTOR axis in ccRCC initiation and progression.

Keywords:  Akt; CDKL3; ccRCC; mTOR; oncogene

DOI:  https://doi.org/10.1073/pnas.2415244122
Cell. 2025 Feb 05. pii: S0092-8674(25)00096-0. [Epub ahead of print]

ArfGAP2 promotes STING proton channel activity, cytokine transit, and autoinflammation.

Subhajit Poddar, Samuel D Chauvin, Christopher H Archer, Wei Qian, Jean A Castillo-Badillo, Xin Yin, W Miguel Disbennett, Cathrine A Miner, Joe A Holley, Teresa V Naismith, W Alexander Stinson, Xiaochao Wei, Yue Ning, Jiayuan Fu, Trini A Ochoa, Nehalee Surve, Shivam A Zaver, Kimberly A Wodzanowski, Katherine R Balka, Rajan Venkatraman, Canyu Liu, Kelly Rome, Will Bailis, Yoko Shiba, Sara Cherry, Sunny Shin, Clay F Semenkovich, Dominic De Nardo, Sunnie Yoh, Elisha D O Roberson, Sumit K Chanda, David J Kast, Jonathan J Miner.

  Stimulator of interferon genes (STING) transmits signals downstream of the cytosolic DNA sensor cyclic guanosine monophosphate-AMP synthase (cGAS), leading to transcriptional upregulation of cytokines. However, components of the STING signaling pathway, such as IRF3 and IFNAR1, are not essential for autoinflammatory disease in STING gain-of-function (STING-associated vasculopathy with onset in infancy [SAVI]) mice. Recent discoveries revealed that STING also functions as a proton channel that deacidifies the Golgi apparatus. Because pH impacts Golgi enzyme activity, protein maturation, and trafficking, we hypothesized that STING proton channel activity influences multiple Golgi functions. Here, we show that STING-mediated proton efflux non-transcriptionally regulates Golgi trafficking of protein cargos. This process requires the Golgi-associated protein ArfGAP2, a cell-type-specific dual regulator of STING-mediated proton efflux and signaling. Deletion of ArfGAP2 in hematopoietic and endothelial cells markedly reduces STING-mediated cytokine and chemokine secretion, immune cell activation, and autoinflammatory pathology in SAVI mice. Thus, ArfGAP2 facilitates STING-mediated signaling and cytokine release in hematopoietic cells, significantly contributing to autoinflammatory disease pathogenesis.

Keywords:  ArfGAP2; Golgi trafficking; SAVI; STING; antiviral immunity; autoinflammation; cGAS; chemokines; cytokines; interferon

DOI:  https://doi.org/10.1016/j.cell.2025.01.027
Trends Cell Biol. 2025 Feb 07. pii: S0962-8924(25)00003-0. [Epub ahead of print]

Diverse routes to mitophagy governed by ubiquitylation and mitochondrial import.

Michael J Clague, Sylvie Urbé.

  The selective removal of mitochondria by mitophagy proceeds via multiple mechanisms and is essential for human well-being. The PINK1/Parkin and NIX/BNIP3 pathways are strongly linked to mitochondrial dysfunction and hypoxia, respectively. Both are regulated by ubiquitylation and mitochondrial import. Recent studies have elucidated how the ubiquitin kinase PINK1 acts as a sensor of mitochondrial import stress through stable interaction with a mitochondrial import supercomplex. The stability of BNIP3 and NIX is regulated by the SCFFBXL4 ubiquitin ligase complex. Substrate recognition requires an adaptor molecule, PPTC7, whose availability is limited by mitochondrial import. Unravelling the functional implications of each mode of mitophagy remains a critical challenge. We propose that mitochondrial import stress prompts a switch between these two pathways.

Keywords:  BNIP3; FBXL4; PINK1; PPTC7; mitophagy; ubiquitin

DOI:  https://doi.org/10.1016/j.tcb.2025.01.003
iScience. 2025 Feb 21. 28(2): 111833

Adenylate cyclase 10 promotes brown adipose tissue thermogenesis.

Anupam Das, Christine Mund, Eman Hagag, Ruben Garcia-Martin, Eleftheria Karadima, Anke Witt, Mirko Peitzsch, Andreas Deussen, Triantafyllos Chavakis, Thomas Noll, Vasileia Ismini Alexaki.

  Brown adipose tissue (BAT) thermogenesis dissipates energy through heat production and thereby it opposes metabolic disease. It is mediated by mitochondrial membrane uncoupling, yet the mechanisms sustaining the mitochondrial membrane potential (ΔΨm) in brown adipocytes are poorly understood. Here we show that isocitrate dehydrogenase (IDH) activity and the expression of the soluble adenylate cyclase 10 (ADCY10), a CO2/bicarbonate sensor residing in mitochondria, are upregulated in BAT of cold-exposed mice. IDH inhibition or ADCY10 deficiency reduces cold resistance of mice. Mechanistically, IDH increases the ΔΨm in brown adipocytes via ADCY10. ADCY10 sustains complex I activity and the ΔΨm via exchange protein activated by cAMP1 (EPAC1). However, neither IDH nor ADCY10 inhibition affect uncoupling protein 1 (UCP1) expression. Hence, we suggest that ADCY10, acting as a CO2/bicarbonate sensor, mediates the effect of IDH on complex I activity through cAMP-EPAC1 signaling, thereby maintaining the ΔΨm and enabling thermogenesis in brown adipocytes.

Keywords:  Cell biology; Molecular biology; Physiology

DOI:  https://doi.org/10.1016/j.isci.2025.111833
Open Biol. 2025 Feb;15(2): 240287

The fundamental role of mitochondria-endoplasmic reticulum contacts in ageing and declining healthspan.

Richard M Monaghan.

  This open question research article highlights mitochondria-associated endoplasmic reticulum (ER) membranes (MAMs), which have emerged as crucial cellular structures that challenge our traditional understanding of organelle function. This review highlights the critical importance of MAMs as a frontier in cell biology with far-reaching implications for health, disease and ageing. MAMs serve as dynamic communication hubs between the ER and mitochondria, orchestrating essential processes such as calcium signalling, lipid metabolism and cellular stress responses. Recent research has implicated MAM dysfunction in a wide array of conditions, including neurodegenerative diseases, metabolic disorders, cardiovascular diseases and cancer. The significant lack of biological knowledge behind MAM function emphasizes the need to study these enigmatic subcellular sites in greater detail. Key open questions include the mechanisms controlling MAM formation and disassembly, the full complement of MAM-associated proteins and how MAMs contribute to cellular decision-making and ageing processes. Advancing our understanding of MAMs through interdisciplinary approaches and cutting-edge technologies promises to reveal new insights into fundamental cellular signalling pathways and potentially lead to innovative therapeutic strategies for a range of diseases. As such, MAM research represents a critical open question in biology with the potential to transform our understanding of cellular life and human health.

Keywords:  ageing; endoplasmic reticulum; healthspan; membrane contact sites; metabolism; mitochondria

DOI:  https://doi.org/10.1098/rsob.240287
Elife. 2025 Feb 12. pii: RP98523. [Epub ahead of print]13

Ezrin defines TSC complex activation at endosomal compartments through EGFR-AKT signaling.

Giuliana Giamundo, Daniela Intartaglia, Eugenio Del Prete, Elena Polishchuk, Fabrizio Andreone, Marzia Ognibene, Sara Buonocore, Bruno Hay Mele, Francesco Giuseppe Salierno, Jlenia Monfregola, Dario Antonini, Paolo Grumati, Alessandra Eva, Rossella De Cegli, Ivan Conte.

  Endosomes have emerged as major signaling hubs where different internalized ligand-receptor complexes are integrated and the outcome of signaling pathways are organized to regulate the strength and specificity of signal transduction events. Ezrin, a major membrane-actin linker that assembles and coordinates macromolecular signaling complexes at membranes, has emerged recently as an important regulator of lysosomal function. Here, we report that endosomal-localized EGFR/Ezrin complex interacts with and triggers the inhibition of the Tuberous Sclerosis Complex (TSC complex) in response to EGF stimuli. This is regulated through activation of the AKT signaling pathway. Loss of Ezrin was not sufficient to repress TSC complex by EGF and culminated in translocation of TSC complex to lysosomes triggering suppression of mTORC1 signaling. Overexpression of constitutively active EZRINT567D is sufficient to relocalize TSC complex to the endosomes and reactivate mTORC1. Our findings identify EZRIN as a critical regulator of autophagy via TSC complex in response to EGF stimuli and establish the central role of early endosomal signaling in the regulation of mTORC1. Consistently, Medaka fish deficient for Ezrin exhibit defective endo-lysosomal pathway, attributable to the compromised EGFR/AKT signaling, ultimately leading to retinal degeneration. Our data identify a pivotal mechanism of endo-lysosomal signaling involving Ezrin and its associated EGFR/TSC complex, which are essential for retinal function.

Keywords:  EGFR; EZRIN; TSC complex; cell biology; endosome; lysosome; mTORC1

DOI:  https://doi.org/10.7554/eLife.98523
Cell Metab. 2025 Feb 04. pii: S1550-4131(25)00002-6. [Epub ahead of print]

Lactate controls cancer stemness and plasticity through epigenetic regulation.

Nguyen T B Nguyen, Sira Gevers, Rutger N U Kok, Lotte M Burgering, Hannah Neikes, Ninouk Akkerman, Max A Betjes, Marlies C Ludikhuize, Can Gulersonmez, Edwin C A Stigter, Yvonne Vercoulen, Jarno Drost, Hans Clevers, Michiel Vermeulen, Jeroen S van Zon, Sander J Tans, Boudewijn M T Burgering, Maria J Rodríguez Colman.

  Tumors arise from uncontrolled cell proliferation driven by mutations in genes that regulate stem cell renewal and differentiation. Intestinal tumors, however, retain some hierarchical organization, maintaining both cancer stem cells (CSCs) and cancer differentiated cells (CDCs). This heterogeneity, coupled with cellular plasticity enabling CDCs to revert to CSCs, contributes to therapy resistance and relapse. Using genetically encoded fluorescent reporters in human tumor organoids, combined with our machine-learning-based cell tracker, CellPhenTracker, we simultaneously traced cell-type specification, metabolic changes, and reconstructed cell lineage trajectories during tumor organoid development. Our findings reveal distinctive metabolic phenotypes in CSCs and CDCs. We find that lactate regulates tumor dynamics, suppressing CSC differentiation and inducing dedifferentiation into a proliferative CSC state. Mechanistically, lactate increases histone acetylation, epigenetically activating MYC. Given that lactate's regulation of MYC depends on the bromodomain-containing protein 4 (BRD4), targeting cancer metabolism and BRD4 inhibitors emerge as a promising strategy to prevent tumor relapse.

Keywords:  cancer metabolism; cell plasticity; cell types; cell-cell interactions; differentiation; heterogeneity; live imaging; organoids; single-cell tracking; stem cells

DOI:  https://doi.org/10.1016/j.cmet.2025.01.002
Oncoimmunology. 2025 Dec;14(1): 2457797

Metabolic heterogeneity in tumor cells impacts immunology in lung squamous cell carcinoma.

Qian Wang, Na Sun, Chaoyang Zhang, Thomas Kunzke, Philipp Zens, Annette Feuchtinger, Sabina Berezowska, Axel Walch.

  Metabolic processes are crucial in immune regulation, yet the impact of metabolic heterogeneity on immunological functions remains unclear. Integrating metabolomics into immunology allows the exploration of the interactions of multilayered features in the biological system and the molecular regulatory mechanism of these features. To elucidate such insight in lung squamous cell carcinoma (LUSC), we analyzed 106 LUSC tumor tissues. We performed high-resolution matrix-assisted laser desorption/ionization (MALDI) mass spectrometry imaging (MSI) to obtain spatial metabolic profiles, and immunohistochemistry to detect tumor-infiltrating T lymphocytes (TILs). Unsupervised k-means clustering and Simpson's diversity index were employed to assess metabolic heterogeneity, identifying five distinct metabolic tumor subpopulations. Our findings revealed that TILs are specifically associated with metabolite distributions, not randomly distributed. Integrating a validation cohort, we found that heterogeneity-correlated metabolites interact with CD8+ TIL-associated genes, affecting survival. High metabolic heterogeneity was linked to worse survival and lower TIL levels. Pathway enrichment analyses highlighted distinct metabolic pathways in each subpopulation and their potential responses to chemotherapy. This study uncovers the significant impact of metabolic heterogeneity on immune functions in LUSC, providing a foundation for tailoring therapeutic strategies.

Keywords:  Immunology; Spatial metabolomics; lung cancer; metabolic heterogeneity; metabolic tumor subpopulation

DOI:  https://doi.org/10.1080/2162402X.2025.2457797
Nature. 2025 Feb 12.

Intrinsic electrical activity drives small-cell lung cancer progression.

Paola Peinado, Marco Stazi, Claudio Ballabio, Michael-Bogdan Margineanu, Zhaoqi Li, Caterina I Colón, Min-Shu Hsieh, Shreoshi Pal Choudhuri, Victor Stastny, Seth Hamilton, Alix Le Marois, Jodie Collingridge, Linus Conrad, Yinxing Chen, Sheng Rong Ng, Margaret Magendantz, Arjun Bhutkar, Jin-Shing Chen, Erik Sahai, Benjamin J Drapkin, Tyler Jacks, Matthew G Vander Heiden, Maksym V Kopanitsa, Hugh P C Robinson, Leanne Li.

Elevated or ectopic expression of neuronal receptors promotes tumour progression in many cancer types1,2; neuroendocrine (NE) transformation of adenocarcinomas has also been associated with increased aggressiveness3. Whether the defining neuronal feature, namely electrical excitability, exists in cancer cells and impacts cancer progression remains mostly unexplored. Small-cell lung cancer (SCLC) is an archetypal example of a highly aggressive NE cancer and comprises two major distinct subpopulations: NE cells and non-NE cells4,5. Here we show that NE cells, but not non-NE cells, are excitable, and their action potential firing directly promotes SCLC malignancy. However, the resultant high ATP demand leads to an unusual dependency on oxidative phosphorylation in NE cells. This finding contrasts with the properties of most cancer cells reported in the literature, which are non-excitable and rely heavily on aerobic glycolysis. Additionally, we found that non-NE cells metabolically support NE cells, a process akin to the astrocyte-neuron metabolite shuttle6. Finally, we observed drastic changes in the innervation landscape during SCLC progression, which coincided with increased intratumoural heterogeneity and elevated neuronal features in SCLC cells, suggesting an induction of a tumour-autonomous vicious cycle, driven by cancer cell-intrinsic electrical activity, which confers long-term tumorigenic capability and metastatic potential.

DOI: https://doi.org/10.1038/s41586-024-08575-7
EMBO J. 2025 Feb 11.

Mitochondrial DNA removal is essential for sperm development and activity.

Zhe Chen, Fan Zhang, Annie Lee, Michaela Yamine, Zong-Heng Wang, Guofeng Zhang, Christian Combs, Hong Xu.

  Active mitochondrial DNA (mtDNA) elimination during spermatogenesis has emerged as a conserved mechanism ensuring the uniparental mitochondrial inheritance in animals. However, given the existence of post-fertilization processes degrading sperm mitochondria, the physiological significance of mtDNA removal during spermatogenesis is not clear. Here we show that mtDNA clearance is indispensable for sperm development and activity. We uncover a previously unappreciated role of Poldip2 as a mitochondrial exonuclease that is specifically expressed in late spermatogenesis and required for sperm mtDNA elimination in Drosophila. Loss of Poldip2 impairs mtDNA clearance in elongated spermatids and impedes the progression of individualization complexes that strip away cytoplasmic materials and organelles. Over time, poldip2 mutant sperm exhibit marked nuclear genome fragmentation, and the flies become completely sterile. Notably, these phenotypes were rescued by expressing a mitochondrially targeted bacterial exonuclease, which ectopically removes mtDNA. Our work illustrates the developmental necessity of mtDNA clearance for effective cytoplasm removal at the end of spermatid morphogenesis, and for preventing potential nuclear-mitochondrial genome imbalance in mature sperm, in which nuclear genome activity is shut down.

Keywords:   Drosophila spermatogenesis; EndoG; Exonuclease; Male Sterile; Maternal Inheritance

DOI:  https://doi.org/10.1038/s44318-025-00377-5
Cell Death Dis. 2025 Feb 12. 16(1): 89

PHGDH inhibition and FOXO3 modulation drives PUMA-dependent apoptosis in osteosarcoma.

Toshinao Oyama, Caitlyn B Brashears, Richa Rathore, Heather Benect-Hamilton, Katharine E Caldwell, Naomi Dirckx, William G Hawkins, Brian A Van Tine.

Osteosarcoma is a bone cancer that has been found to be metabolically dependent on the conversion of glucose to serine through the rate-limiting enzyme 3-phosphoglycerate dehydrogenase (PHGDH). The upregulation of PHGDH has been correlated with poor patient survival, and the inhibition of the serine synthesis pathway using targeted small-molecule inhibition of PHGDH induces a rapid metabolic adaptation that prevents cell death due to pro-survival signaling through the mammalian target of rapamycin complex 1 (mTORC1) pathway. Here, PHGDH inhibition in combination with mTORC1 signaling modulation for the treatment of osteosarcoma was evaluated. When combined with PHGDH inhibition, several non-rapalog inhibitors of mTORC1 activated Forkhead box O (FOXO) transcription factor 3 (FOXO3), a transcription factor associated with various cellular processes driving apoptosis. The activation of FOXO3 led to transcriptional activation of the pro-apoptotic gene p53 upregulated modulator of apoptosis (PUMA), inducing apoptosis when combined with PHGDH inhibition. These data suggest a path for the clinical development of PHGDH inhibitors in conjunction with mTORC1 pathway modulators in osteosarcoma.

DOI: https://doi.org/10.1038/s41419-025-07378-6
Cell Rep. 2025 Feb 10. pii: S2211-1247(25)00055-5. [Epub ahead of print]44(2): 115284

Acetyl-CoA synthesis in the skin is a key determinant of systemic lipid homeostasis.

Phuong T T Nguyen, Mia Shiue, Nina Kuprasertkul, Pedro Costa-Pinheiro, Luke T Izzo, Laura V Pinheiro, Hayley A Affronti, Gabriel Gugiu, Shivani Ghaisas, Joyce Y Liu, Jordan C Harris, Charles W Bradley, John T Seykora, Xiaolu Yang, Taku Kambayashi, Clementina Mesaros, Brian C Capell, Kathryn E Wellen.

  ATP-citrate lyase (ACLY) generates cytosolic acetyl-coenzyme A (acetyl-CoA) for lipid synthesis and is a promising therapeutic target in diseases with altered lipid metabolism. Here, we developed inducible whole-body Acly-knockout mice to determine the requirement for ACLY in normal tissue functions, uncovering its crucial role in skin homeostasis. ACLY-deficient skin upregulates the acetyl-CoA synthetase ACSS2; deletion of both Acly and Acss2 from the skin exacerbates skin abnormalities, with differential effects on two major lipid-producing skin compartments. While the epidermis is depleted of barrier lipids, the sebaceous glands increase production of sebum, supplied at least in part by circulating fatty acids and coinciding with adipose lipolysis and fat depletion. Dietary fat supplementation further boosts sebum production and partially rescues both the lipoatrophy and the aberrant skin phenotypes. The data establish a critical role for cytosolic acetyl-CoA synthesis in maintaining skin barrier integrity and highlight the skin as a key organ in systemic lipid regulation.

Keywords:  ACLY; ACSS2; CP: Metabolism; acetyl-CoA; adipose; epidermis; lipid metabolism; sebaceous glands; skin; skin barrier

DOI:  https://doi.org/10.1016/j.celrep.2025.115284
Arch Biochem Biophys. 2025 Feb 06. pii: S0003-9861(25)00043-8. [Epub ahead of print] 110330

A relative metabolic flux analysis model of glucose anaplerosis.

Heesoo Jeong, Nathaniel M Vacanti.

  Glucose provides substrate for the predominant anaplerotic pathway which involves the activity of pyruvate carboxylase (PC). PC-mediated anaplerosis has been extensively studied as a metabolic regulator in glycolytic cells during tumorigenesis and metastasis. Herein, inaccuracies in established methods to measure relative intracellular flux through PC are highlighted and a compartmentalized condensed metabolic network (CCMN) is used to resolve the total malate pool into relative contributions from PC and other sources by metabolic flux analysis (MFA) with [U-13C6]glucose tracing. Performance of the CCMN method is evaluated in breast cancer cell lines that are exposed to small molecules targeting metabolism. Across conditions and cell lines, the CCMN approach yields results nearest to an accepted gold-standard methodology, using [3-13C]glucose, or even exposes the gold standard's limitations. The CCMN method does not require a separate experiment with a much more costly and generally less informative metabolic tracer, such as [3-13C]glucose, and in some cases, may outperform its application.

Keywords:  breast cancer; metabolic flux; pyruvate carboxylase; stable-isotope tracing; systems biology

DOI:  https://doi.org/10.1016/j.abb.2025.110330
J Biol Chem. 2025 Feb 06. pii: S0021-9258(25)00119-X. [Epub ahead of print] 108271

Metformin inhibits the histone methyltransferase CARM1 and attenuates H3 histone methylation during gluconeogenesis.

Sinjini Dhang, Atanu Mondal, Chandrima Das, Siddhartha Roy.

  Hyperglycemia is a hallmark of metabolic disorders, yet the precise mechanisms linking epigenetic regulation to glucose metabolism remain underexplored. Coactivator-associated arginine methyltransferase 1 (CARM1), a type I histone methyltransferase, promotes transcriptional activation through the methylation of histone H3 at arginine residues H3R17 and H3R26. Here, we identify a novel mechanism by which metformin, a widely prescribed antidiabetic drug, inhibits CARM1 activity. Using biochemical and biophysical assays, we show that metformin binds to the substrate-binding site of CARM1, reducing histone H3 methylation levels in CARM1-overexpressing hepatic cells and liver tissues from metformin-fed mice. This epigenetic modulation suppresses the expression of gluconeogenic enzymes (G6Pase, FBPase, and PCK1), thereby reversing CARM1-induced glycolytic suppression and regulating gluconeogenesis. Importantly, metformin does not alter CARM1 protein levels and its recruitment to gluconeogenic gene promoters but diminishes H3R17me2a marks at these loci. Our findings reveal a previously unrecognized epigenetic mechanism of metformin action, offering new therapeutic insights for hyperglycemia management.

Keywords:  CARM1; Enzymes; Epigenetics; Gene expression; Histone methylation; Metformin

DOI:  https://doi.org/10.1016/j.jbc.2025.108271
JCI Insight. 2025 Feb 11. pii: e186073. [Epub ahead of print]

Loss of long-chain acyl-CoA dehydrogenase protects against acute kidney injury.

Takuto Chiba, Akira Oda, Yuxun Zhang, Katherine E Pfister, Joanna Bons, Sivakama S Bharathi, Ayako Kinoshita, Bob B Zhang, Adam C Richert, Birgit Schilling, Eric S Goetzman, Sunder Sims-Lucas.

  The renal tubular epithelial cells (RTECs) are particularly vulnerable to acute kidney injury (AKI). While fatty acids are the preferred energy source for RTECs via fatty acid oxidation (FAO), FAO-mediated H2O2 production in mitochondria has been shown to be a major source of oxidative stress. We have previously shown that a mitochondrial flavoprotein, long-chain acyl-CoA dehydrogenase (LCAD), which catalyzes a key step in mitochondrial FAO, directly produces H2O2 in vitro. Further, we showed that renal LCAD becomes hyposuccinylated during AKI. Here, we demonstrated that succinylation of recombinant LCAD protein suppresses the production of H2O2. Following two distinct models of AKI, cisplatin treatment or renal ischemia/reperfusion injury (IRI), LCAD-/- mice demonstrated renoprotection. Specifically, LCAD-/- kidneys displayed mitigated renal tubular injury, decreased oxidative stress, preserved mitochondrial function, enhanced peroxisomal FAO, and decreased ferroptotic cell death. LCAD deficiency confers protection against two distinct models of AKI. This suggests a therapeutically attractive mechanism whereby preserved mitochondrial respiration as well as enhanced peroxisomal FAO by loss of LCAD mediates renoprotection against AKI.

Keywords:  Cell stress; Fatty acid oxidation; Metabolism; Nephrology

DOI:  https://doi.org/10.1172/jci.insight.186073
J Clin Invest. 2025 Feb 11. pii: e178550. [Epub ahead of print]

TRAF3 loss protects glioblastoma cells from lipid peroxidation and immune elimination via dysregulated lipid metabolism.

Yu Zeng, Liqian Zhao, Kunlin Zeng, Ziling Zhan, Zhengming Zhan, Shangbiao Li, Hongchao Zhan, Peng Chai, Cheng Xie, Shengfeng Ding, Yuxin Xie, Li Wang, Cuiying Li, Xiaoxia Chen, Daogang Guan, Enguang Bi, Jian-You Liao, Fan Deng, Xiaochun Bai, Ye Song, Aidong Zhou.

  Glioblastoma (GBM) is a highly aggressive form of brain tumor characterized by dysregulated metabolism. Increased fatty acid oxidation (FAO) protects tumor cells from lipid peroxidation-induced cell death, although the precise mechanisms involved remain unclear. Herein, we report that loss of tumor necrosis factor receptor-associated factor 3 (TRAF3) in GBM critically regulates lipid peroxidation and tumorigenesis by controlling the oxidation of polyunsaturated fatty acids (PUFAs). TRAF3 is frequently repressed in GBM due to promoter hypermethylation. TRAF3 interacts with enoyl-CoA hydratase 1 (ECH1), an enzyme catalyzing the isomerization of unsaturated fatty acids (UFAs), and mediates K63-linked ubiquitination of ECH1 at Lys214. ECH1 ubiquitination impedes TOMM20-dependent mitochondrial translocation of ECH1, which otherwise promotes the oxidation of UFAs, preferentially the PUFAs, and limits lipid peroxidation. Overexpression of TRAF3 enhances the sensitivity of GBM to ferroptosis and anti-PD-L1 immunotherapy in mice. Thus, the TRAF3-ECH1 axis plays a key role in the metabolism of PUFAs, and is crucial for lipid peroxidation damage and immune elimination in GBM.

Keywords:  Brain cancer; Cancer immunotherapy; Cell biology; Fatty acid oxidation; Metabolism

DOI:  https://doi.org/10.1172/JCI178550
J Physiol. 2025 Feb 12.

Intracellular signalling in arterial chemoreceptors during acute hypoxia and glucose deprivation: role of ATP.

María Torres-López, Patricia González-Rodríguez, Olalla Colinas, Hee-Sool Rho, Hortensia Torres-Torrelo, Antonio Castellano, Lin Gao, Patricia Ortega-Sáenz, José López-Barneo.

  The carotid body (CB) is the main oxygen (O2) sensing organ that mediates reflex hyperventilation and increased cardiac output in response to hypoxaemia. Acute O2 sensing is an intrinsic property of CB glomus cells, which contain special mitochondria to generate signalling molecules (NADH and H2O2) that modulate membrane K+ channels in response to lowered O2 tension (hypoxia). In parallel with these membrane-associated events, glomus cells are highly sensitive to mitochondrial electron transport chain (ETC) inhibitors. It was suggested that a decrease in oxidative production of ATP is a critical event mediating hypoxia-induced cell depolarization. Here, we show that rotenone [an inhibitor of mitochondrial complex (MC) I] activates rat and mouse glomus cells but abolishes their responsiveness to hypoxia. Rotenone does not prevent further activation of the cells by cyanide (a blocker of MCIV) or glucose deprivation. Responsiveness to glucose deprivation is enhanced in O2-insenstive glomus cells with genetic disruption of MCI. These findings suggest that acute O2 sensing requires a functional MCI but that a decrease in intracellular ATP, presumably produced by the simultaneous inhibition of MCI and MCIV, is not involved in hypoxia signalling. In support of this concept, ATP levels in single glomus cells were unaltered by hypoxia, but rapidly declined following exposure of the cells to low glucose or to inhibitors of oxidative phosphorylation. These observations indicate that a reduction in intracellular ATP does not participate in physiological acute O2 sensing. However, local decreases in ATP of glycolytic origin may contribute to low glucose signalling in glomus cells. KEY POINTS: The carotid body contains oxygen-sensitive glomus cells with specialized mitochondria that generate signalling molecules (NADH and H2O2) to inhibit membrane K+ channels in response to hypoxia. Glomus cells are highly sensitive to electron transport chain (ETC) blockers. It was suggested that a decrease in intracellular ATP is the main signal inducing K+ channel inhibition and depolarization in response to hypoxia or ETC blockade. Rotenone, an inhibitor of mitochondrial complex (MC) I, activates glomus cells but abolishes their responsiveness to hypoxia. However, rotenone does not prevent further activation of glomus cells by cyanide (an MCIV blocker) or glucose deprivation. Single-cell ATP levels were unaltered by hypoxia, but decreased rapidly following exposure of glomus cells to 0 mM glucose or inhibitors of oxidative phosphorylation. A reduction in intracellular ATP does not participate in signalling acute hypoxia. However, it may contribute to hypoglycaemia signalling in glomus cells.

Keywords:  H2O2; NADH; TASK3 channels; acute oxygen sensing; carotid body glomus cells; cytosolic ATP; electron transport chain inhibitors; glucose sensing; hypoxia; mitochondria‐to‐membrane signalling

DOI:  https://doi.org/10.1113/JP287130
Cell Metab. 2025 Feb 05. pii: S1550-4131(25)00009-9. [Epub ahead of print]

Isoform usage as a distinct regulatory layer driving nutrient-responsive metabolic adaptation.

Jia Li, Chaoqun Cai, Wei Wen Teo, Kai Shin Chin, Yadanar Than Naing, Shengren Song, Franklin Nelson, Li Qiang, Dan Xu, Lei Sun.

  Transcriptome modulation is essential for metabolic adaptation to nutrient environments. However, the role of isoform usage, a crucial transcriptome component, is not yet fully understood. This study outlines the landscape of isoform-usage modulations across major metabolic organs in both mice and monkeys, spanning diverse metabolic states. Our in-depth analysis identifies numerous isoform-usage events, intricately influenced by nutrient challenges and largely independent of gene expression regulation. Comparative analyses of mice and monkeys highlight hundreds of conserved isoform events that exhibit consistent responses to nutrient challenges across species and correlate with human metabolic traits. When analyzing splicing factor-binding motifs in nutrient-regulated events, HuR emerges as the predominant orchestrator of the isoform network in adipocytes, which is validated using an adipose tissue-specific knockout and an Ap2-promoter-driven transgenic mouse model. In summary, our results offer a comprehensive perspective on isoform usage in metabolic regulation, setting a platform for future functional inquiries.

Keywords:  Elavl1; HuR; adipose tissue; aging; isoform usage; liver; muscle; nutrient challenge; obesity; splicing

DOI:  https://doi.org/10.1016/j.cmet.2025.01.009
Elife. 2025 Feb 12. pii: RP100541. [Epub ahead of print]13

Pharmacologic activation of integrated stress response kinases inhibits pathologic mitochondrial fragmentation.

Kelsey R Baron, Samantha Oviedo, Sophia Krasny, Mashiat Zaman, Rama Aldakhlallah, Prerona Bora, Prakhyat Mathur, Gerald Pfeffer, Michael J Bollong, Timothy E Shutt, Danielle A Grotjahn, R Luke Wiseman.

  Excessive mitochondrial fragmentation is associated with the pathologic mitochondrial dysfunction implicated in the pathogenesis of etiologically diverse diseases, including many neurodegenerative disorders. The integrated stress response (ISR) - comprising the four eIF2α kinases PERK, GCN2, PKR, and HRI - is a prominent stress-responsive signaling pathway that regulates mitochondrial morphology and function in response to diverse types of pathologic insult. This suggests that pharmacologic activation of the ISR represents a potential strategy to mitigate pathologic mitochondrial fragmentation associated with human disease. Here, we show that pharmacologic activation of the ISR kinases HRI or GCN2 promotes adaptive mitochondrial elongation and prevents mitochondrial fragmentation induced by the calcium ionophore ionomycin. Further, we show that pharmacologic activation of the ISR reduces mitochondrial fragmentation and restores basal mitochondrial morphology in patient fibroblasts expressing the pathogenic D414V variant of the pro-fusion mitochondrial GTPase MFN2 associated with neurological dysfunctions, including ataxia, optic atrophy, and sensorineural hearing loss. These results identify pharmacologic activation of ISR kinases as a potential strategy to prevent pathologic mitochondrial fragmentation induced by disease-relevant chemical and genetic insults, further motivating the pursuit of highly selective ISR kinase-activating compounds as a therapeutic strategy to mitigate mitochondrial dysfunction implicated in diverse human diseases.

Keywords:  cell biology; human; integrated stress response; mitochondrial fragmentation; mitochondrial morphology; mouse; stress signaling

DOI:  https://doi.org/10.7554/eLife.100541
FEBS J. 2025 Feb 11.

Intercellular mitochondrial transfer contributes to microenvironmental redirection of cancer cell fate.

Julie Sofie Bjerring, Yara Khodour, Emilee Anne Peterson, Patrick Christian Sachs, Robert David Bruno.

  The mammary microenvironment has been shown to suppress tumor progression by redirecting cancer cells to adopt a normal mammary epithelial progenitor fate in vivo. However, the mechanism(s) by which this alteration occurs has yet to be defined. Here, we test the hypothesis that mitochondrial transfer from normal mammary epithelial cells to breast cancer cells plays a role in this redirection process. We evaluate mitochondrial transfer in 2D and 3D organoids using our unique 3D bioprinting system to produce chimeric organoids containing normal and cancer cells. We demonstrate that breast cancer tumoroid growth is hindered following interaction with mammary epithelial cells in both 2D and 3D environments. Furthermore, we show mitochondrial transfer occurs between donor mammary epithelial cells and recipient cancer cells primarily through tunneling nanotubes (TNTs) with minimal amounts seen from extracellular transfer of mitochondria, likely via extracellular vesicles (EVs). This organelle exchange results in various cellular and metabolic alterations within cancer cells, reducing their proliferative potential, and making them susceptible to microenvironmental control. Our results demonstrate that mitochondrial transfer contributes to microenvironmental redirection of cancer cells through alteration of metabolic and molecular functions of the recipient cancer cells. To the best of our knowledge, this is the first description of a 3D bioprinter-assisted organoid system for studying mitochondrial transfer. These studies are also the first mechanistic insights into the process of mammary microenvironmental redirection of cancer and provide a framework for new therapeutic strategies to control cancer.

Keywords:  3D bioprinting; breast cancer; cellular redirection; microenvironment; mitochondrial transfer

DOI:  https://doi.org/10.1111/febs.70002
Trends Cell Biol. 2025 Feb 12. pii: S0962-8924(25)00028-5. [Epub ahead of print]

Metabolic control of replisome plasticity in genome surveillance.

Mikkel Bo Petersen, Gita Chhetri, Kumar Somyajit.

  Metabolic pathways and DNA replication are both adaptable and essential for early development and cancer progression. While each process is well understood individually, the mechanisms coordinating them are just beginning to emerge. Nucleotide biosynthesis serves as a crucial link, with fluctuating nucleotide pools leading to imbalanced deoxyribonucleotide (dNTP) and increased ribonucleotide (rNTP) levels, impairing DNA synthesis and triggering replication stress; ultimately driving developmental disorders and cancer. To counter these challenges, the replisome - the core machinery of DNA replication - continuously adjusts its architecture and speed in response to physiological changes, including nucleotide fluctuations. This review outlines recent insights into how the replisome aligns its function with metabolic changes in nucleotide levels and explores emerging links between metabolism and genome stability, and their roles in development and disease.

Keywords:  cancer targeting; nucleotide fluctuations; redox signaling; replication fork speed; replisome; ribonucleotide reductase

DOI:  https://doi.org/10.1016/j.tcb.2025.01.006
FEBS J. 2025 Feb 10.

α-Ketoglutarate inhibits the pluripotent-to-totipotent state transition in stem cells.

Mengran Yin, Yan Li, Zhenzhu Sun, Xinyu Wu, Liang Ding, Qiang Zhang, Hai Zhou, Man Zhang, Dajiang Qin, Baoming Qin, Lulu Wang.

  In early mouse embryogenesis, the distinct enrichment of α-ketoglutarate (αKG) in blastocysts and L-2-hydroxyglutarate (L-2HG) in 2-cell (2C) embryos serves as a key metabolic signature. While elevated L-2HG levels inhibit the resolution of totipotency during the transition from the 2C stage to the blastocyst, the role of αKG remains elusive. Mouse embryonic stem cells (mESCs) cultured in vitro naturally harbor a subpopulation that transitions dynamically into a 2C-like totipotent state, providing a convenient model to investigate the role of αKG in totipotency reprogramming. This study demonstrates that αKG significantly inhibits the pluripotency to totipotency transition through upregulating ten-eleven translocation (TET) DNA hydroxylases. We further show that reducing endogenous αKG levels via glutamine withdrawal or inhibiting αKG-dependent dioxygenases by blocking succinate dehydrogenase (SDH) markedly enhances the induction of 2C-like cells (2CLCs). Finally, leveraging the potent SDH inhibitor dimethyl malonate (DMM), we have developed a highly efficient protocol for 2CLC induction, producing cells that transcriptionally resemble mid-to-late 2C embryos. Our findings deepen the understanding of the metabolic regulation of totipotency and provide a previously undescribed approach for capturing totipotent-like stem cells in vitro.

Keywords:  DMM; TET; succinate; totipotency; α‐ketoglutarate

DOI:  https://doi.org/10.1111/febs.70008
Metabolomics. 2025 Feb 13. 21(2): 26

Metabolic signature of renal cell carcinoma tumours and its correlation with the urinary metabolome.

Filipa Amaro, Márcia Carvalho, Carina Carvalho-Maia, Carmen Jerónimo, Rui Henrique, Maria de Lourdes Bastos, Paula Guedes de Pinho, Joana Pinto.

   INTRODUCTION: Despite considerable advances in cancer research, the increasing prevalence and high mortality rate of clear cell renal cell carcinoma (ccRCC) remain a significant challenge. A more detailed comprehension of the distinctive metabolic characteristics of ccRCC is vital to enhance diagnostic, prognostic, and therapeutic strategies.
OBJECTIVES: This study aimed to investigate the metabolic signatures of ccRCC tumours and, for the first time, their correlation with the urinary metabolome of the same patients.
METHODS: We applied a gas chromatography-mass spectrometry (GC-MS)-based metabolomic approach to analyse matched tissue and urine samples from a cohort of 18 ccRCC patients and urine samples from 18 cancer-free controls. Multivariate and univariate statistical methods, as well as pathway and correlation analyses, were performed to assess metabolic dysregulations and correlations between tissue and urine.
RESULTS: The results showed a ccRCC metabolic signature characterized by reprogramming in amino acid, energy, and sugar and inositol phosphate metabolisms. Our study identified, for the first time, significantly decreased levels of asparagine, proline, gluconate, 3-aminoisobutanoate, 4-aminobutanoate and urea in ccRCC tumours, highlighting the involvement of arginine biosynthesis, β-alanine metabolism and purine and pyrimidine metabolism in ccRCC. The correlations between tissue and urine metabolomes provide evidence for the potential usefulness of urinary metabolites in understanding systemic metabolic changes driven by RCC tumours.
CONCLUSIONS: These findings significantly advance our understanding of metabolic reprogramming in ccRCC and the systemic metabolic changes associated with the disease. Future research is needed to validate these findings in larger cohorts and to determine their potential implications for diagnosis and targeted therapies.

Keywords:  Clear cell renal cell carcinoma (ccRCC); Gas-chromatography-mass spectrometry (GC-MS); Metabolomics; Tissue metabolome; Urine metabolome

DOI:  https://doi.org/10.1007/s11306-024-02212-0
Cell Rep. 2025 Feb 12. pii: S2211-1247(25)00072-5. [Epub ahead of print]44(2): 115301

A microRNA-regulated transcriptional state defines intratumoral CD8+ T cells that respond to immunotherapy.

William W Tang, Ben Battistone, Kaylyn M Bauer, Allison M Weis, Cindy Barba, Muhammad Zaki Hidayatullah Fadlullah, Arevik Ghazaryan, Van B Tran, Soh-Hyun Lee, Z Busra Agir, Morgan C Nelson, Emmanuel Stephen Victor, Amber Thibeaux, Colton Hernandez, Jacob Tantalla, Aik C Tan, Dinesh Rao, Matthew Williams, Micah J Drummond, Ellen J Beswick, June L Round, H Atakan Ekiz, Warren P Voth, Ryan M O'Connell.

  The rising incidence of advanced-stage colorectal cancer (CRC) and poor survival outcomes necessitate new and effective therapies. Immune checkpoint inhibitors (ICIs), specifically anti-PD-1 therapy, show promise, yet clinical determinants of a positive response are suboptimal. Here, we identify microRNA-155 (miR-155) as necessary for CD8+ T cell-infiltrated tumors through an unbiased in vivo CRISPR-Cas9 screen identifying functional tumor antigen-specific CD8+ T cell-expressed microRNAs. T cell miR-155 is required for anti-PD-1 responses and for a vital intratumor CD8+ T cell differentiation cascade by repressing Ship-1, inhibiting Tcf-1 and stemness, and subsequently enhancing Cxcr6 expression, anti-tumor immunity, and effector functions. Based on an underlying miR-155-dependent CD8+ T cell transcriptional profile, we identify a gene signature that predicts ICI responses across 12 diverse cancers. Together, our findings support a model whereby miR-155 serves as a central regulator of CD8+ T cell-dependent cancer immunity and ICI responses that may be leveraged for future therapeutics.

Keywords:  CD8(+) T cell; CP: Cancer; CP: Immunology; Cxcr6; Ship-1; Tcf-1; anti-PD-1; biomarker; colorectal cancer; immune checkpoint inhibition; immunotherapy; microRNA-155

DOI:  https://doi.org/10.1016/j.celrep.2025.115301
Cell. 2025 Feb 10. pii: S0092-8674(25)00094-7. [Epub ahead of print]

Extracellular vesicles from the lung pro-thrombotic niche drive cancer-associated thrombosis and metastasis via integrin beta 2.

Serena Lucotti, Yusuke Ogitani, Candia M Kenific, Jacob Geri, Young Hun Kim, Jinghua Gu, Uthra Balaji, Linda Bojmar, Lee Shaashua, Yi Song, Michele Cioffi, Pernille Lauritzen, Oveen M Joseph, Tetsuhiko Asao, Paul M Grandgenett, Michael A Hollingsworth, Christopher Peralta, Alexandra E Pagano, Henrik Molina, Harry B Lengel, Elizabeth G Dunne, Xiaohong Jing, Madeleine Schmitter, Lucia Borriello, Thomas Miller, Haiying Zhang, Yevgeniy Romin, Katia Manova, Doru Paul, H Lawrence Remmel, Eileen M O'Reilly, William R Jarnagin, David Kelsen, Sharon M Castellino, Lisa Giulino-Roth, David R Jones, John S Condeelis, Virginia Pascual, James B Bussel, Nancy Boudreau, Irina Matei, David Entenberg, Jacqueline F Bromberg, Diane M Simeone, David Lyden.

  Cancer is a systemic disease with complications beyond the primary tumor site. Among them, thrombosis is the second leading cause of death in patients with certain cancers (e.g., pancreatic ductal adenocarcinoma [PDAC]) and advanced-stage disease. Here, we demonstrate that pro-thrombotic small extracellular vesicles (sEVs) are secreted by C-X-C motif chemokine 13 (CXCL13)-reprogrammed interstitial macrophages in the non-metastatic lung microenvironment of multiple cancers, a niche that we define as the pro-thrombotic niche (PTN). These sEVs package clustered integrin β2 that dimerizes with integrin αX and interacts with platelet-bound glycoprotein (GP)Ib to induce platelet aggregation. Blocking integrin β2 decreases both sEV-induced thrombosis and lung metastasis. Importantly, sEV-β2 levels are elevated in the plasma of PDAC patients prior to thrombotic events compared with patients with no history of thrombosis. We show that lung PTN establishment is a systemic consequence of cancer progression and identify sEV-β2 as a prognostic biomarker of thrombosis risk as well as a target to prevent thrombosis and metastasis.

Keywords:  cancer; cancer metastasis; cancer-associated thrombosis; extracellular vesicles; integrin beta 2; platelets; pro-thrombotic niche

DOI:  https://doi.org/10.1016/j.cell.2025.01.025
Cell Rep. 2025 Feb 07. pii: S2211-1247(25)00049-X. [Epub ahead of print]44(2): 115278

Integration of metabolomic and transcriptomic analyses reveals regulatory functions of the ChREBP transcription factor in energy metabolism.

Jie An, Inna Astapova, Guofang Zhang, Andrew L Cangelosi, Olga Ilkayeva, Hannah Marchuk, Michael J Muehlbauer, Tabitha George, Joseph Brozinick, Mark A Herman, Christopher B Newgard.

  The transcription factor carbohydrate response element binding protein (ChREBP) activates genes of glucose, fructose, and lipid metabolism in response to carbohydrate feeding. Integrated transcriptomic and metabolomic analyses in rats with GalNac-siRNA-mediated suppression of ChREBP expression in liver reveal other ChREBP functions. GalNac-siChREBP treatment reduces expression of genes involved in coenzyme A (CoA) biosynthesis, with lowering of CoA and short-chain acyl-CoA levels. Despite suppression of pyruvate kinase, pyruvate levels are maintained, possibly via increased expression of pyruvate and amino acid transporters. In addition, expression of multiple anaplerotic enzymes is decreased by GalNac-siChREBP treatment, affecting TCA cycle intermediates. Finally, GalNAc-siChREBP treatment suppresses late steps in purine and NAD synthesis, with increases in precursors and lowering of end products in both pathways. In sum, our study reveals functions of ChREBP beyond its canonical roles in carbohydrate and lipid metabolism to include regulation of substrate transport, mitochondrial function, and energy balance.

Keywords:  CP: Metabolism; ChREBP; CoA; amino acids; lipids; metabolic regulation; nucleotides

DOI:  https://doi.org/10.1016/j.celrep.2025.115278
Nat Immunol. 2025 Feb 10.

Metabolite signaling promotes the recruitment of immunosuppressive cells to tumors.

DOI: https://doi.org/10.1038/s41590-025-02094-x
Cancer Cell. 2025 Feb 10. pii: S1535-6108(25)00027-3. [Epub ahead of print]43(2): 308-316.e6

Genomic mediators of acquired resistance to immunotherapy in metastatic melanoma.

Julia Schiantarelli, Mouadh Benamar, Jihye Park, Haley E Sax, Giacomo Oliveira, Alice Bosma-Moody, Katie M Campbell, David Liu, Douglas B Johnson, Scott Rodig, Catherine J Wu, F Stephen Hodi, Antoni Ribas, Eliezer Van Allen, Rizwan Haq.

  Although some patients with metastatic melanoma experience durable responses to immune checkpoint inhibitors (ICIs), most exhibit intrinsic or acquired resistance to these therapies. Here, we compare somatic genomic profiles from matched pre-treatment and post-resistance tumor biopsies in patients (n = 25) with metastatic melanoma who exhibited heterogeneous ICI responses to nominate additional mediators of acquired resistance. We find that several acquired resistance tumors exhibit defects in B2M or JAK1/2, consistent with prior findings. We also discover resistance-associated mutations in SEC24C and SEC24D in 3 patients. SEC24 has an essential role in the trafficking of the dsDNA sensor STING and has been linked to interferonopathies. Melanoma cells engineered to express the SEC24C mutations observed in patients exhibit diminished STING signaling, including decreased type I interferon production, antigen presentation, and a reduced capacity to activate cytotoxic T cells. This study nominates a role for aberrant STING trafficking in acquired resistance to ICIs.

Keywords:  SEC24; STING signaling; acquired resistance; immune checkpoint inhibitors; metastatic melanoma

DOI:  https://doi.org/10.1016/j.ccell.2025.01.009
Cancer Res. 2025 Feb 11.

Interactions Between Ploidy and Resource Availability Shape Clonal Evolution in Glioblastoma.

Zuzanna Nowicka, Frederika Rentzeperis, Vural Tagal, Jamie K Teer, Didem Ilter, Richard J Beck, Jackson P Cole, Ana M Forero Pinto, Joanne D Tejero, Elisa Scanu, Thomas Veith, William Dominguez-Viqueira, Konstantin Maksin, Francisco M Carrillo-Perez, Olivier Gevaert, Xiaonan Xu, Florian A Karreth, Mahmoud A Abdalah, Giada Fiandaca, Stefano Pasetto, Sandhya Prabhakaran, Andrew Schultz, Awino Maureiq E Ojwang', Jill S Barnholtz-Sloan, Joaquim M Farinhas, Ana P Gomes, Parag Katira, Noemi Andor.

Glioblastoma (GBM) is the most aggressive form of primary brain tumor. The infiltrative nature of GBM makes complete surgical resection impossible. The selective forces that govern gliomagenesis are strong, shaping the composition of tumor cells during the initial progression to malignancy with late consequences for invasiveness and therapy response. Here, we developed a mathematical model that incorporates ploidy level and the nature of the brain tissue microenvironment to simulate the growth and invasion of GBM and used the model to make inferences about GBM initiation and response to standard-of-care treatment. The spatial distribution of resource access in the brain was approximated through integration of in silico modeling, multi-omics data, and image analysis of primary and recurrent GBM. The in silico results suggested that high ploidy cells transition faster from oxidative phosphorylation to glycolysis than low ploidy cells because they are more sensitive to hypoxia. Between surgeries, simulated tumors with different ploidy compositions progressed at different rates; however, whether higher ploidy predicted fast recurrence was a function of the brain microenvironment. Historical data supported the dependence on available resources in the brain, as shown by a significant correlation between the median oxygen levels in human tissues and the median ploidy of cancers that arise in the respective tissues. Taken together, these findings suggest that availability of metabolic substrates in the brain drives different cell fate decisions for cells with different ploidy, thereby modulating both gliomagenesis and GBM recurrence.

DOI: https://doi.org/10.1158/0008-5472.CAN-24-0401
Sci Adv. 2025 Feb 14. 11(7): eadu4034

Fluoxetine promotes IL-10-dependent metabolic defenses to protect from sepsis-induced lethality.

Robert M Gallant, Karina K Sanchez, Emeline Joulia, Jessica M Snyder, Christian M Metallo, Janelle S Ayres.

Selective serotonin reuptake inhibitors (SSRIs) are some of the most prescribed drugs in the world. While they are used for their ability to increase serotonergic signaling in the brain, SSRIs are also known to have a broad range of effects beyond the brain, including immune and metabolic effects. Recent studies have demonstrated that SSRIs are protective in animal models and humans against several infections, including sepsis and COVID-19; however, the mechanisms underlying this protection are largely unknown. Here, we mechanistically link two previously described effects of the SSRI fluoxetine in mediating protection against sepsis. We show that fluoxetine-mediated protection is independent of peripheral serotonin and instead increases levels of circulating interleukin-10 (IL-10). IL-10 is necessary for protection from sepsis-induced hypertriglyceridemia, preventing cardiac effects including impairment of glucose oxidation, ectopic lipid accumulation, ventricular stretch and possibly cardiac failure. Our work reveals a beneficial "off-target" effect of fluoxetine, and reveals a protective immunometabolic defense mechanism with therapeutic potential.

DOI: https://doi.org/10.1126/sciadv.adu4034