bims-mibica Biomed News
on Mitochondrial bioenergetics in cancer
Issue of 2025–02–16
fourteen papers selected by
Kelsey Fisher-Wellman, Wake Forest University
  1. Diverse routes to mitophagy governed by ubiquitylation and mitochondrial import.
  2. Secretory mitophagy: an extracellular vesicle-mediated adaptive mechanism for cancer cell survival under oxidative stress.
  3. A microscopy-based screen identifies cellular kinases modulating mitochondrial translation.
  4. Mitochondrial potassium channels: New properties and functions.
  5. Metabolic Heterogeneity in Diffuse Large B-Cell Lymphoma Cells Reveals an Innovative Antimetabolic Combination Strategy.
  6. Intrinsic electrical activity drives small-cell lung cancer progression.
  7. Metformin Induces Apoptosis and Ferroptosis of Ovarian Cancer Cells Under Energy Stress Conditions.
  8. Mitochondrial carrier homolog 2 is important for mitochondrial functionality and non-small cell lung cancer cell growth.
  9. Intercellular mitochondrial transfer contributes to microenvironmental redirection of cancer cell fate.
  10. The Germline and Somatic Origins of Prostate Cancer Heterogeneity.
  11. Bone marrow mesenchymal stromal cells support translation in refractory acute myeloid leukemia.
  12. Serine starvation suppresses the progression of esophageal cancer by regulating the synthesis of purine nucleotides and NADPH.
  13. Lactate controls cancer stemness and plasticity through epigenetic regulation.
  14. Mitochondrial succinate feeds T cell exhaustion in cancer.
  1. 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
  2. Front Cell Dev Biol. 2024 ;12 1490902
    Secretory mitophagy: an extracellular vesicle-mediated adaptive mechanism for cancer cell survival under oxidative stress.
    Purva V Gade, Angela Victoria Rojas Rivera, Layla Hasanzadah, Sofie Strompf, Thomas Raymond Philipson, Matthew Gadziala, Atharva Tyagi, Arnav Bandam, Rithvik Gabbireddy, Fatah Kashanchi, Amanda Haymond, Lance A Liotta, Marissa A Howard.
      Mitophagy is a critically important survival mechanism in which toxic, aged, or defective mitochondria are segregated into mitophagosomes, which shuttle the damaged mitochondrial segments to the lysosome and proteasome for destruction. Cancer cells rely on mitophagy under conditions of high oxidative stress or increased energy demand. Oxidative stress can generate a large volume of damaged mitochondria, overwhelming lysosomal removal. Accumulated damaged mitochondria are toxic and their proper removal is crucial for maintaining mitochondrial health. We propose a new cancer cell mechanism for survival that is activated when the demand for segregating and eliminating damaged mitochondria exceeds the capacity of the lysosome or proteasome. Specifically, we show that tumor cells subjected to oxidative stress by carbonyl cyanide-3-chlorophenylhdrazone (CCCP) eliminate damaged mitochondria segments by bypassing the lysosome to export them outside the cell via extracellular vesicles (EVs), a process termed "secretory mitophagy". PINK1, the initiator of mitophagy, remains associated with the damaged mitochondria that exported in EVs. Using several types of cancer cells, we show that tumor cells treated with CCCP can be induced to switch over to secretory mitophagy by treatment with Bafilomycin A1, which blocks the fusion of mitophagosomes with lysosomes. Under these conditions, an increased number of PINK1 + EVs are exported. This is associated with greater cell survival by a given CCCP dose, enhanced mitochondrial ATP production, and reduced mitochondrial oxidative damage (membrane depolarization). Our data supports the hypothesis that secretory mitophagy is a previously unexplored process by which cancer cells adapt to survive therapeutic or hypoxic stress. Ultimately, our findings may inform new prevention strategies targeting pre-malignant lesions and therapeutic approaches designed to sensitize tumor cells to oxidative stress-inducing therapies.
    Keywords:  PINK1; cancer progression; cell survival; extracellular vesicles; mitophagy; oxidative stress
    DOI:  https://doi.org/10.3389/fcell.2024.1490902
  3. 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
  4. Biochim Biophys Acta Bioenerg. 2025 Feb 09. pii: S0005-2728(25)00012-X. [Epub ahead of print] 149546
    Mitochondrial potassium channels: New properties and functions.
    Adam Szewczyk, Piotr Bednarczyk, Bogusz Kulawiak, Monika Żochowska, Barbara Kalenik, Joanna Lewandowska, Karolina Pytlak, Shur Gałecka, Antoni Wrzosek, Piotr Koprowski.
      Mitochondria are recently implicated in phenomena such as cytoprotection, cellular senescence, tumor metabolism, and inflammation. The basis of these processes relies on biochemical functions of mitochondria such as the synthesis of reactive oxygen species or biophysical properties such as the integrity of the inner mitochondrial membrane. The transport of potassium cations plays an important role in all these events. The K+ influx is mediated by potassium channels present in the inner mitochondrial membrane. In this article, we present an overview of our new findings on the properties of mitochondrial large-conductance calcium-activated and mitochondrial ATP-regulated potassium channels. This concerns the role of mitochondrial potassium channels in cellular senescence, and interactions with other mitochondrial proteins or small molecules such as quercetin, hemin, and hydrogen sulfide. We also discuss the prospects of research on potassium channels present in mitochondria.
    Keywords:  Hemin; Hydrogen sulfide; Kinases; Mitochondria; Potassium channels; Quercetin; ROS; Senescence
    DOI:  https://doi.org/10.1016/j.bbabio.2025.149546
  5. Cancers (Basel). 2025 Jan 24. pii: 394. [Epub ahead of print]17(3):
    Metabolic Heterogeneity in Diffuse Large B-Cell Lymphoma Cells Reveals an Innovative Antimetabolic Combination Strategy.
    Leonardo Lordello, Stéphanie Nuan-Aliman, Karoline Kielbassa-Elkadi, Aurélie Montagne, Konstantina Kotta, Isabelle Martins, Eva Pinto Jurado, Cédric Caradeuc, Jacqueline Lehmann-Che, José Ángel Martínez-Climent, Véronique Meignin, Nicolas Giraud, Guido Kroemer, Gildas Bertho, Catherine Thieblemont, Véronique Baud.
      Background/Objectives: Diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin lymphoma, characterized by aggressive and heterogeneous tumors originating from B-cells. Especially in patients with relapsed or refractory (R/R) disease, DLBCL remains a challenging cancer to treat. Metabolic reprogramming is a hallmark of malignant cells. Our research focuses on developing strategies to enhance clinical outcomes for R/R DLBCL patients by targeting metabolic vulnerabilities. Methods: We investigated the effects of combining metformin and L-asparaginase, two FDA-approved antimetabolic drugs, on DLBCL cell metabolism and survival. Nuclear magnetic resonance (NMR) spectroscopy was employed to assess metabolic disturbances induced by the drug combination. The impact on lipid metabolism, glycolysis, glutaminolysis, the tricarboxylic acid (TCA) cycle, and antioxidant responses was examined. Induction of apoptosis was evaluated by FACS analysis. Results: The combination of metformin and L-asparaginase strongly sensitized DLBCL cells to apoptosis, independently of their oxidative phosphorylation (OxPhos) or BCR/glycolytic status. NMR spectroscopy revealed that this combination induces broader metabolic disturbances than either drug alone. It disrupts lipid metabolism by altering levels of phospholipids, cholesterol, and fatty acids. Additionally, it counteracts the pro-glycolytic effect of metformin, decreases glycolysis, and reduces glutaminolysis. It also affects the TCA cycle and antioxidant responses, critical for cellular energy production and redox balance. Furthermore, this combination interferes with two key cancer survival pathways, mTORC1 and MAPK signaling. Importantly, proof of principle for its beneficial effect was demonstrated in DLBCL patients. Conclusions: Combining metformin and L-asparaginase affects DLBCL cell survival by targeting multiple metabolic pathways and may represent a novel therapeutic approach for R/R DLBCL patients.
    Keywords:  B-cell lymphoma; apoptosis; cell death; combination of antimetabolic drugs; diffuse large B-cell lymphoma (DLBCL); metabolism; oncogenic pathways
    DOI:  https://doi.org/10.3390/cancers17030394
  6. 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
  7. Cells. 2025 Feb 02. pii: 213. [Epub ahead of print]14(3):
    Metformin Induces Apoptosis and Ferroptosis of Ovarian Cancer Cells Under Energy Stress Conditions.
    Yulun Wu, Ziying Zhang, Minhui Ren, Yao Chen, Jingying Zhang, Jiarui Li, Feng Gao, Yongli Bao, Yanxin Huang, Xiaoguang Yang, Zhenbo Song.
      As ovarian cancer progresses, increased glucose use causes a glucose shortage in the tumor microenvironment. Therefore, it is crucial to find drugs that can effectively kill cancer cells in this energy stress setting. Here, we propose an effective therapeutic strategy that combines nutrient restriction with metformin to combat tumors. This study investigated the effects of metformin on ovarian cancer cells under energy stress conditions, mimicking the nutrient-deprived tumor microenvironment. We revealed that Metformin (10 mM) significantly reduced cell viability and proliferation under glucose deprivation conditions. Furthermore, it enhanced apoptosis and ferroptosis, as demonstrated by alterations in apoptotic protein expression and elevated levels of lipid reactive oxygen species (ROS), malondialdehyde (MDA), lipid peroxidation (LPO), and Fe2+. Transcriptional profiling revealed significant alterations in genes related to iron homeostasis and oxidative phosphorylation. Moreover, Metformin was found to induce mitochondrial dysfunction without affecting mitochondrial DNA or the expression of enzymes in the tricarboxylic acid (TCA) cycle, resulting in decreased ATP production and compromised activities of the respiratory chain complexes. The direct interaction between metformin and the NDUFB4 subunit in mitochondrial complex I was corroborated through the application of cellular thermal shift assay (CETSA) and drug affinity responsive target stability (DARTS) assays. In vivo, the combination of metformin and fasting cycles significantly inhibited SKOV3 cell-derived xenograft tumors in immunodeficient mice. Altogether, we have demonstrated that Metformin potentiates apoptosis and ferroptosis in ovarian cancer cells under energy stress conditions by targeting the NDUFB4 subunit of mitochondrial complex I, thus laying the groundwork for clinical testing. This study, though limited to cellular and animal levels, provides valuable insights into the therapeutic potential of metformin in ovarian cancer treatment.
    Keywords:  NDUFB4; apoptosis; ferroptosis; metformin; ovarian cancer
    DOI:  https://doi.org/10.3390/cells14030213
  8. Cell Death Dis. 2025 Feb 13. 16(1): 95
    Mitochondrial carrier homolog 2 is important for mitochondrial functionality and non-small cell lung cancer cell growth.
    Yong Zhao, Siyang Wu, Guohong Cao, Peidong Song, Chang-Gong Lan, Lin Zhang, Yong-Hua Sang.
      Discovering new molecular targets for non-small cell lung cancer (NSCLC) is critically important. Enhanced mitochondrial function can promote NSCLC progression by enabling metabolic reprogramming, resistance to apoptosis, and increased cell proliferation. Mitochondrial carrier homolog 2 (MTCH2), located in the outer mitochondrial membrane, is pivotal in regulating mitochondrial activities. This study examines MTCH2 expression and its functional role in NSCLC. Bioinformatic analysis showed that MTCH2 is overexpressed in NSCLC tissues, correlating with poor prognosis and other key clinical parameters of the patients. In addition, single-cell sequencing data revealed higher MTCH2 expression levels in cancer cells of NSCLC tumor mass. Moreover, MTCH2 is also upregulated in locally-treated NSCLC tissues and multiple primary/established human NSCLC cells. In various NSCLC cells, silencing MTCH2 via targeted shRNA or knockout (KO) using the CRISPR/Cas9 method significantly hindered cell proliferation, migration and invasion, while inducing apoptosis. MTCH2 knockdown or KO robustly impaired mitochondrial function, as indicated by reduced mitochondrial respiration, decreased complex I activity, lower ATP levels, lower mitochondrial membrane potential (mitochondrial depolarization), and increased reactive oxygen species (ROS) production. Conversely, ectopic overexpression of MTCH2 in primary NSCLC cells enhanced mitochondrial complex I activity and ATP production, promoting cell proliferation and migration. In vivo, the intratumoral injection of MTCH2 shRNA adeno-associated virus (aav) impeded the growth of subcutaneous xenografts of primary NSCLC cells in nude mice. In MTCH2 shRNA aav-injected NSCLC xenograft tissues, there was decreases in MTCH2 expression, mitochondrial complex I activity, ATP content, and the glutathione (GSH)/glutathione disulfide (GSSG) ratio, but increase in thiobarbituric acid reactive substances (TBAR) activity. Additionally, MTCH2 silencing led to reduced Ki-67 staining but increased apoptosis in NSCLC xenografts. Collectively, these findings demonstrate that overexpressed MTCH2 promotes NSCLC cell growth potentially through the maintenance of mitochondrial hyper-function, highlighting MTCH2 as a novel and promising therapeutic target for treating this disease.
    DOI:  https://doi.org/10.1038/s41419-025-07419-0
  9. 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
  10. Cancer Discov. 2025 Feb 13.
    The Germline and Somatic Origins of Prostate Cancer Heterogeneity.
    Takafumi N Yamaguchi, Kathleen E Houlahan, Helen Zhu, Natalie Kurganovs, Julie Livingstone, Natalie S Fox, Jiapei Yuan, Jocelyn Sietsma Penington, Chol-Hee Jung, Tommer Schwarz, Weerachai Jaratlerdsiri, Job van Riet, Peter Georgeson, Stefano Mangiola, Kodi Taraszka, Robert Lesurf, Jue Jiang, Ken Chow, Lawrence E Heisler, Yu-Jia Shiah, Susmita G Ramanand, Michael J Clarkson, Anne Nguyen, Shadrielle Melijah G Espiritu, Ryan Stuchbery, Richard Jovelin, Vincent Huang, Connor Bell, Edward O'Connor, Patrick J McCoy, Christopher M Lalansingh, Marek Cmero, Adriana Salcedo, Eva K F Chan, Lydia Y Liu, Phillip D Stricker, Vinayak Bhandari, Riana M S Bornman, Dorota Hs Sendorek, Andrew Lonie, Stephenie D Prokopec, Michael Fraser, Justin S Peters, Adrien Foucal, Shingai B A Mutambirwa, Lachlan Mcintosh, Michèle Orain, Matthew Wakefield, Valérie Picard, Daniel J Park, Hélène Hovington, Michael Kerger, Alain Bergeron, Veronica Sabelnykova, Ji-Heui Seo, Mark M Pomerantz, Noah Zaitlen, Sebastian M Waszak, Alexander Gusev, Louis Lacombe, Yves Fradet, Andrew Ryan, Amar U Kishan, Martijn P Lolkema, Joachim Weischenfeldt, Bernard Têtu, Anthony J Costello, Vanessa M Hayes, Rayjean J Hung, Housheng H He, John D McPherson, Bogdan Pasaniuc, Theodorus van der Kwast, Anthony T Papenfuss, Matthew L Freedman, Bernard J Pope, Robert G Bristow, Ram S Mani, Niall M Corcoran, Jüri Reimand, Christopher M Hovens, Paul C Boutros.
      Newly diagnosed prostate cancers differ dramatically in mutational composition and lethality. The most accurate clinical predictor of lethality is tumor tissue architecture, quantified as tumor grade. To interrogate the evolutionary origins of prostate cancer heterogeneity, we analyzed 666 prostate tumor whole genomes. We identified a compendium of 223 recurrently mutated driver regions, most influencing downstream mutational processes and gene expression. We identified and validated individual germline variants that predispose tumors to acquire specific somatic driver mutations: these explain heterogeneity in disease presentation and ancestry differences. High-grade tumors have a superset of the drivers in lower-grade tumors, including increased frequency of BRCA2 and MYC mutations. Grade-associated driver mutations occur early in tumor evolution, and their earlier occurrence strongly predicts cancer relapse and metastasis. Our data suggest high- and low-grade prostate tumors both emerge from a common pre-malignant field, influenced by germline genomic context and stochastic mutation-timing.
    DOI:  https://doi.org/10.1158/2159-8290.CD-23-0882
  11. Cell Rep. 2025 Jan 28. pii: S2211-1247(24)01502-X. [Epub ahead of print]44(1): 115151
    Bone marrow mesenchymal stromal cells support translation in refractory acute myeloid leukemia.
    Livia E Lisi-Vega, Alice Pievani, María García-Fernández, Dorian Forte, Tim L Williams, Marta Serafini, Simón Méndez-Ferrer.
      In acute myeloid leukemia (AML), malignant cells surviving chemotherapy rely on high mRNA translation and their microenvironmental metabolic support to drive relapse. However, the role of translational reprogramming in the niche is unclear. Here, we found that relapsing AML cells increase translation in their bone marrow (BM) niches, where BM mesenchymal stromal cells (BMSCs) become a source of eIF4A-cap-dependent translation machinery that is transferred to AML cells via extracellular vesicles (EVs) to meet their translational demands. In two independent models of highly chemo-resistant AML driven by MLL-AF9 or FLT3-ITD (internal tandem duplication) and nucleophosmin (NPMc) mutations, protein synthesis levels increase in refractory AML dependent on nestin+ BMSCs. Inhibiting cap-dependent translation in BMSCs abolishes their chemoprotective ability, while EVs from BMSCs carrying eIF4A boost AML cell translation and survival. Consequently, eIF4A inhibition synergizes with conventional chemotherapy. Together, these results suggest that AML cells rely on BMSCs to maintain an oncogenic translational program required for relapse.
    Keywords:  CP: Cancer; acute myeloid leukemia; bone marrow mesenchymal stromal cells; chemotherapy; extracellular vesicles; microenvironment; niche; protein synthesis; refractory; relapse; translation
    DOI:  https://doi.org/10.1016/j.celrep.2024.115151
  12. 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
  13. 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
  14. 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
This page is being maintained by Thomas Krichel. It was last updated on 2025‒02‒16 at 14:40.