bims-mibica 2025-03-09 papers

bims-mibica

Biomed News

on Mitochondrial bioenergetics in cancer

Issue of 2025–03–09
28 papers selected by
Kelsey Fisher-Wellman, Wake Forest University

Succinate Dehydrogenase loss causes cascading metabolic effects that impair pyrimidine biosynthesis.
Dodging mitochondrial mislocalization.
Mitochondria-enriched hematopoietic stem cells exhibit elevated self-renewal capabilities, thriving within the context of aged bone marrow.
Differential regulation of BAX and BAK apoptotic activity revealed by small molecules.
scMitoMut for calling mitochondrial lineage-related mutations in single cells.
PPTC7 acts as an essential co-factor of the SCFFBXL4 ubiquitin ligase complex to restrict BNIP3/3L-dependent mitophagy.
Cryptic mitochondrial DNA mutations coincide with mid-late life and are pathophysiologically informative in single cells across tissues and species.
The alternative oxidase reconfigures the larval mitochondrial electron transport system to accelerate growth and development in Drosophila melanogaster.
Pulling back the mitochondria's iron curtain.
Enhancing radiation-induced reactive oxygen species generation through mitochondrial transplantation in human glioblastoma.
De Novo Serine Synthesis is a Metabolic Vulnerability that can be Exploited to Overcome Sunitinib Resistance in Advanced Renal Cell Carcinoma.
NOX4 Suppresses Ferroptosis Through Regulation of the Pentose Phosphate Pathway in Colorectal Cancer.
Estrogen-related receptor alpha (ERRα) controls the stemness and cellular energetics of prostate cancer cells via its direct regulation of citrate metabolism and zinc transportation.
Structure of mitochondrial pyruvate carrier and its inhibition mechanism.
Aspirin prevents metastasis by limiting platelet TXA2 suppression of T cell immunity.
Realigned transsulfuration drives BRAF-V600E-targeted therapy resistance in melanoma.
Discovery of a novel alpha isoform of the long-known enzyme LDHA provides new insights into cancer research.
Cytoplasmic ribosomes on mitochondria alter the local membrane environment for protein import.
Regulation of mammalian cellular metabolism by endogenous cyanide production.
BCL-2 dependence is a favorable predictive marker of response to therapy for chronic lymphocytic leukemia.
ADSL-generated fumarate binds and inhibits STING to promote tumour immune evasion.
-----Targeting Acetyl-CoA Carboxylase Suppresses De Novo Lipogenesis and Tumor Cell Growth in Multiple Myeloma.
Lysine vitcylation is a vitamin C-derived protein modification that enhances STAT1-mediated immune response.
Proximity proteomics reveals a mechanism of fatty acid transfer at lipid droplet-mitochondria- endoplasmic reticulum contact sites.
Defined media reveals the essential role of lipid scavenging to support cancer cell proliferation.
Artificial intelligence-enabled automated analysis of transmission electron micrographs to evaluate chemotherapy impact on mitochondrial morphology in triple negative breast cancer.
Hematopoietic stem cells undergo bidirectional fate transitions in vivo.
Immunometabolite L-2-HG promotes epigenetic modification of exhausted T cells and improves anti-tumor immunity.

bioRxiv. 2025 Feb 19. pii: 2025.02.18.638948. [Epub ahead of print]

Succinate Dehydrogenase loss causes cascading metabolic effects that impair pyrimidine biosynthesis.

Madeleine L Hart, Kristian Davidsen, Serwah Danquah, Eric Zheng, David Sokolov, Lucas B Sullivan.

  Impaired availability of the amino acid aspartate can be a metabolic constraint of cell proliferation in diverse biological contexts. However, the kinetics of aspartate depletion, and its ramifications on downstream metabolism and cell proliferation, remain poorly understood. Here, we deploy the aspartate biosensor jAspSnFR3 with live cell imaging to resolve temporal relationships between aspartate and cell proliferation from genetic, pharmacological, and nutritional manipulations. In cells with impaired aspartate acquisition from mitochondrial complex I inhibition or constrained uptake in aspartate auxotrophs, we find that the proliferation defects lag changes in aspartate levels and only manifest once aspartate levels fall below a critical threshold, supporting the functional link between aspartate levels and cell proliferation in these contexts. In another context of aspartate synthesis inhibition, impairing succinate dehydrogenase (SDH), we find a more complex metabolic interaction, with initial aspartate depletion followed by a rebound of aspartate levels over time. We find that this aspartate rebound effect results from SDH inhibition disproportionately impairing pyrimidine synthesis by inhibiting aspartate transcarbamoylase (ATCase) through the dual effect of diminishing aspartate substrate availability while accumulating succinate, which functions as a competitive inhibitor of aspartate utilization. Finally, we uncover that the nucleotide imbalance from SDH inhibition causes replication stress and introduces a vulnerability to ATR kinase inhibition. Altogether, these findings identify a mechanistic role for succinate in modulating nucleotide synthesis and demonstrate how cascading metabolic interactions can unfold to impact cell function.

Keywords:  SDH; aspartate; biosensor; cancer; metabolism; metabolomics; proliferation; pyrimidines

DOI:  https://doi.org/10.1101/2025.02.18.638948
Nat Rev Mol Cell Biol. 2025 Mar 06.

Dodging mitochondrial mislocalization.

Lisa Heinke.

DOI: https://doi.org/10.1038/s41580-025-00840-5
Nat Aging. 2025 Mar 06.

Mitochondria-enriched hematopoietic stem cells exhibit elevated self-renewal capabilities, thriving within the context of aged bone marrow.

Haruhito Totani, Takayoshi Matsumura, Rui Yokomori, Terumasa Umemoto, Yuji Takihara, Chong Yang, Lee Hui Chua, Atsushi Watanabe, Takaomi Sanda, Toshio Suda.

The aging of hematopoietic stem cells (HSCs) substantially alters their characteristics. Mitochondria, essential for cellular metabolism, play a crucial role, and their dysfunction is a hallmark of aging-induced changes. The impact of mitochondrial mass on aged HSCs remains incompletely understood. Here we demonstrate that HSCs with high mitochondrial mass during aging are not merely cells that have accumulated damaged mitochondria and become exhausted. In addition, these HSCs retain a high regenerative capacity and remain in the aging bone marrow. Furthermore, we identified GPR183 as a distinct marker characterizing aged HSCs through single-cell analysis. HSCs marked by GPR183 were also enriched in aged HSCs with high mitochondrial mass, possessing a high capacity of self-renewal. These insights deepen understanding of HSC aging and provide additional perspectives on the assessment of aged HSCs, underscoring the importance of mitochondrial dynamics in aging.

DOI: https://doi.org/10.1038/s43587-025-00828-y
Sci Adv. 2025 Mar 07. 11(10): eadr8146

Differential regulation of BAX and BAK apoptotic activity revealed by small molecules.

Kaiming Li, Yu Q Yap, Donia M Moujalled, Fransisca Sumardy, Yelena Khakham, Angela Georgiou, Michelle Jahja, Thomas E Lew, Melanie De Silva, Meng-Xiao Luo, Jia-Nan Gong, Zheng Yuan, Richard W Birkinshaw, Peter E Czabotar, Kym Lowes, David C S Huang, Benjamin T Kile, Andrew H Wei, Grant Dewson, Mark F van Delft, Guillaume Lessene.

Defective apoptosis mediated by B cell lymphoma 2 antagonist/killer (BAK) or B cell lymphoma 2-associated X protein (BAX) underlies various pathologies including autoimmune and degenerative conditions. On mitochondria, voltage-dependent anion channel 2 (VDAC2) interacts with BAK and BAX through a common interface to inhibit BAK or to facilitate BAX apoptotic activity. We identified a small molecule (WEHI-3773) that inhibits interaction between VDAC2 and BAK or BAX revealing contrasting effects on their apoptotic activity. WEHI-3773 inhibits apoptosis mediated by BAX by blocking VDAC2-mediated BAX recruitment to mitochondria. Conversely, WEHI-3773 promotes BAK-mediated apoptosis by limiting inhibitory sequestration by VDAC2. In cells expressing both pro-apoptotic proteins, apoptosis promotion by WEHI-3773 dominates, because activated BAK activates BAX through a feed-forward mechanism. Loss of BAX drives resistance to the BCL-2 inhibitor venetoclax in some leukemias. WEHI-3773 overcomes this resistance by promoting BAK-mediated killing. This work highlights the coordination of BAX and BAK apoptotic activity through interaction with VDAC2 that may be targeted therapeutically.

DOI: https://doi.org/10.1126/sciadv.adr8146
Brief Bioinform. 2024 Nov 22. pii: bbaf072. [Epub ahead of print]26(1):

scMitoMut for calling mitochondrial lineage-related mutations in single cells.

Wenjie Sun, Daphne van Ginneken, Leïla Perié.

  Tracing cell lineages has become a valuable tool for studying biological processes. Among the available tools for human data, mitochondrial DNA (mtDNA) has a high potential due to its ability to be used in conjunction with single-cell chromatin accessibility data, giving access to the cell phenotype. Nonetheless, the existing mutation calling tools are ill-equipped to deal with the polyploid nature of the mtDNA and lack a robust statistical framework. Here we introduce scMitoMut, an innovative R package that leverages statistical methodologies to accurately identify mitochondrial lineage-related mutations at the single-cell level. scMitoMut assigns a mutation quality q-value based on beta-binomial distribution to each mutation at each locus within individual cells, ensuring higher sensitivity and precision of lineage-related mutation calling in comparison to current methodologies. We tested scMitoMut using single-cell DNA sequencing, single-cell transposase-accessible chromatin (scATAC) sequencing, and 10× Genomics single-cell multiome datasets. Using a single-cell DNA sequencing dataset from a mixed population of cell lines, scMitoMut demonstrated superior sensitivity in identifying a small proportion of cancer cell line compared to existing methods. In a human colorectal cancer scATAC dataset, scMitoMut identified more mutations than state-of-the-art methods. Applied to 10× Genomics multiome datasets, scMitoMut effectively measured the lineage distance in cells from blood or brain tissues. Thus, the scMitoMut is a freely available, and well-engineered toolkit (https://www.bioconductor.org/packages/devel/bioc/html/scMitoMut.html) for mtDNA mutation calling with high memory and computational efficiency. Consequently, it will significantly advance the application of single-cell sequencing, facilitating the precise delineation of mitochondrial mutations for lineage-tracing purposes in development, tumour, and stem cell biology.

Keywords:  lineage tracing; mitochondrial mutation; single-cell sequencing

DOI:  https://doi.org/10.1093/bib/bbaf072
Cell Death Dis. 2025 Mar 01. 16(1): 145

PPTC7 acts as an essential co-factor of the SCFFBXL4 ubiquitin ligase complex to restrict BNIP3/3L-dependent mitophagy.

Xiayun Xu, Yingji Chen, Siqi Fei, Xinyue Jiang, Xiaoting Zhou, Yimeng Xue, Yao Li, Shi-Min Zhao, Yan Huang, Chenji Wang.

Mitophagy is a selective process that targets the damaged, dysfunctional, or superfluous mitochondria for degradation through autophagy. The SCFFBXL4 E3 ubiquitin ligase complex suppresses basal mitophagy by targeting BNIP3 and BNIP3L, two key mitophagy cargo receptors, for ubiquitin-proteasomal degradation. FBXL4 loss-of-function mutations lead to excessive BNIP3/3L-dependent mitophagy, thereby causing a devastating multi-system disorder called mitochondrial DNA depletion syndrome, type 13 (MTDPS13). PPTC7, a mitochondrial matrix phosphatase, is essential for proper mitochondrial function and biogenesis. Here, we show that a proportion of PPTC7 is located on the outer mitochondrial membrane, where it interacts with FBXL4 and BNIP3/3L. PPTC7 decreases BNIP3/3L protein stability in a protein phosphatase activity-independent manner. Using in vitro cell culture and Pptc7 knockout mouse model, we demonstrate that PPTC7 deficiency activates high levels of basal mitophagy in a BNIP3/3L-dependent manner. Mechanistically, PPTC7 facilitates SCFFBXL4-mediated ubiquitin-proteasomal degradation of BNIP3/3L. Overall, these findings establish PPTC7 as an essential co-factor of the SCFFBXL4 complex and a suppressor of BNIP3/3L-dependent mitophagy.

DOI: https://doi.org/10.1038/s41419-025-07463-w
Nat Commun. 2025 Mar 06. 16(1): 2250

Cryptic mitochondrial DNA mutations coincide with mid-late life and are pathophysiologically informative in single cells across tissues and species.

Alistair P Green, Florian Klimm, Aidan S Marshall, Rein Leetmaa, Juvid Aryaman, Aurora Gómez-Durán, Patrick F Chinnery, Nick S Jones.

Ageing is associated with a range of chronic diseases and has diverse hallmarks. Mitochondrial dysfunction is implicated in ageing, and mouse-models with artificially enhanced mitochondrial DNA mutation rates show accelerated ageing. A scarcely studied aspect of ageing, because it is invisible in aggregate analyses, is the accumulation of somatic mitochondrial DNA mutations which are unique to single cells (cryptic mutations). We find evidence of cryptic mitochondrial DNA mutations from diverse single-cell datasets, from three species, and discover: cryptic mutations constitute the vast majority of mitochondrial DNA mutations in aged post-mitotic tissues, that they can avoid selection, that their accumulation is consonant with theory we develop, hitting high levels coinciding with species specific mid-late life, and that their presence covaries with a majority of the hallmarks of ageing including protein misfolding and endoplasmic reticulum stress. We identify mechanistic links to endoplasmic reticulum stress experimentally and further give an indication that aged brain cells with high levels of cryptic mutations show markers of neurodegeneration and that calorie restriction slows the accumulation of cryptic mutations.

DOI: https://doi.org/10.1038/s41467-025-57286-8
bioRxiv. 2025 Feb 21. pii: 2025.02.20.639223. [Epub ahead of print]

The alternative oxidase reconfigures the larval mitochondrial electron transport system to accelerate growth and development in Drosophila melanogaster.

Geovana S Garcia, Murilo F Othonicar, Antonio Thiago P Campos, Eric A Kilbourn, Kenia C Bicego, Johannes Lerchner, Jason M Tennessen, Marcos T Oliveira.

The alternative oxidase (AOX) is naturally present in the mitochondrial electron transfer system (ETS) of many organisms but absent in vertebrates and most insects. AOX oxidizes coenzyme Q and reduces O 2 in H 2 O, partially replacing the ETS cytochrome c segment and alleviating the oxidative stress caused by ETS overload. As successfully demonstrated in animal models, AOX shows potential in mitigating mitochondrial diseases. However, its non-proton-pumping nature may uncouple mitochondria, leading to excessive heat generation and interference with normal metabolism and physiology. Here we show that AOX from the tunicate Ciona intestinalis accelerates development of Drosophila melanogaster , elevating larval biomass accumulation (primarily due to increased fat), mobility and food intake, without increasing body heat production. AOX intensifies Leak respiration and lowers oxidative phosphorylation efficiency through functional interactions with the mitochondrial glycerol-3-phosphate dehydrogenase (mGPDH). This is associated with increased complex I (CI)-driven respiration and supercomplex formation, higher cellular NAD+/NADH ratios, and an enhanced flux through the central carbon metabolism. Chemical uncouplers and rotenone confirm the roles of mitochondrial uncoupling and CI in the development of AOX-expressing larvae. Thus, AOX appears to be promoting increased growth by reinforcing the larval proliferative metabolic program via an intricate mechanism that reconfigures the larval ETS.

DOI: https://doi.org/10.1101/2025.02.20.639223
NPJ Metab Health Dis. 2025 ;3(1): 6

Pulling back the mitochondria's iron curtain.

Shani Ben Zichri-David, Liraz Shkuri, Tslil Ast.

  Mitochondrial functionality and cellular iron homeostasis are closely intertwined. Mitochondria are biosynthetic hubs for essential iron cofactors such as iron-sulfur (Fe-S) clusters and heme. These cofactors, in turn, enable key mitochondrial pathways, such as energy and metabolite production. Mishandling of mitochondrial iron is associated with a spectrum of human pathologies ranging from rare genetic disorders to common conditions. Here, we review mitochondrial iron utilization and its intersection with disease.

Keywords:  Biochemistry; Cell biology; Metabolic pathways

DOI:  https://doi.org/10.1038/s44324-024-00045-y
Sci Rep. 2025 Mar 04. 15(1): 7618

Enhancing radiation-induced reactive oxygen species generation through mitochondrial transplantation in human glioblastoma.

Kent L Marshall, Murugesan Velayutham, Valery V Khramtsov, Alan Mizener, Christopher P Cifarelli.

  Glioblastoma (GBM) is the most aggressive primary brain malignancy in adults, with high recurrence rates and resistance to standard therapies. This study explores mitochondrial transplantation as a novel method to enhance the radiobiological effect (RBE) of ionizing radiation (IR) by increasing mitochondrial density in GBM cells, potentially boosting reactive oxygen species (ROS) production and promoting radiation-induced cell death. Using cell-penetrating peptides (CPPs), mitochondria were transplanted into GBM cell lines U3035 and U3046. Transplanted mitochondria were successfully incorporated into recipient cells, increasing mitochondrial density significantly. Mitochondrial chimeric cells demonstrated enhanced ROS generation post-irradiation, as evidenced by increased electron paramagnetic resonance (EPR) signal intensity and fluorescent ROS assays. The transplanted mitochondria retained functionality and viability for up to 14 days, with mitochondrial DNA (mtDNA) sequencing confirming high transfection and retention rates. Notably, mitochondrial transplantation was feasible in radiation-resistant GBM cells, suggesting potential clinical applicability. These findings support mitochondrial transplantation as a promising strategy to overcome therapeutic resistance in GBM by amplifying ROS-mediated cytotoxicity, warranting further investigation into its efficacy and mechanisms in vivo.

Keywords:  Cell-penetrating peptide; EPR; Glioblastoma; Mitochondria; RBE; ROS; Radiation

DOI:  https://doi.org/10.1038/s41598-025-91331-2
Cancer Res. 2025 Mar 03.

De Novo Serine Synthesis is a Metabolic Vulnerability that can be Exploited to Overcome Sunitinib Resistance in Advanced Renal Cell Carcinoma.

Manon Teisseire, Umakant Sahu, Julien Parola, Meng-Chen Tsai, Valérie Vial, Jérôme Durivault, Renaud Grépin, Yann Cormerais, Clément Molina, Arthur Gouraud, Gilles Pagès, Issam Ben-Sahra, Sandy Giuliano.

Sunitinib is an oral tyrosine kinase inhibitor used in treating advanced renal cell carcinoma (RCC) that exhibits significant efficacy but faces resistance in 30% of patients. Identifying the molecular mechanisms underlying resistance could enable the development of strategies to enhance sunitinib sensitivity. Here, we showed that sunitinib induces a metabolic shift leading to increased serine synthesis in RCC cells. Activation of the GCN2-ATF4 stress response pathway was identified as the mechanistic link between sunitinib treatment and elevated serine production. The increased serine biosynthesis supported nucleotide synthesis and sustained cell proliferation, migration, and invasion following sunitinib treatment. Inhibiting key enzymes in the serine synthesis pathway, such as PHGDH and PSAT1, enhanced the sensitivity of resistant cells to sunitinib. Beyond RCC, similar activation of serine synthesis following sunitinib treatment occurred in a variety of other cancer types, suggesting a shared adaptive response to sunitinib therapy. Together, this study identifies the de novo serine synthesis pathway as a potential target to overcome sunitinib resistance, offering insights into therapeutic strategies applicable across diverse cancer contexts.

DOI: https://doi.org/10.1158/0008-5472.CAN-24-1393
Curr Med Sci. 2025 Mar 03.

NOX4 Suppresses Ferroptosis Through Regulation of the Pentose Phosphate Pathway in Colorectal Cancer.

Jing Zhu, Chao Jiang, Fan Wang, Ming-Yue Tao, Hai-Xiao Wang, Yuan Sun, Hong-Xia Hui.

   OBJECTIVE: Nicotinamide adenine dinucleotide phosphate (NADPH) oxidases (NOXs) are known as major sources of reactive oxygen species (ROS), yet their role in regulating cellular antioxidative metabolism and ferroptosis is unclear. This study assessed the expression and clinical relevance of NOXs across pan-cancer and investigated the role of NOX4 in colorectal cancer progression METHODS: We analyzed transcriptomic and survival data from The Cancer Genome Atlas (TCGA) for NOXs across 22 types of solid tumors. A CRISPR library targeting NOXs was developed for potential therapeutic target screening in colorectal cancer cells (CRCs). Techniques such as CRISPR-knockout cell lines, 1,2-13C-glucose tracing, PI staining, BrdU assays, and coimmunoprecipitation were employed to elucidate the function of NOX4 in CRCs.
RESULTS: NOX4 emerged as a key therapeutic target for colorectal cancer from TCGA data. CRISPR screening highlighted its essential role in CRC survival, with functional experiments confirming that NOX4 upregulation promotes cell survival and proliferation. The interaction of NOX4 with glucose‑6‑phosphate dehydrogenase (G6PD) was found to enhance the pentose phosphate pathway (PPP), facilitating ROS clearance and protecting CRCs against ferroptosis.
CONCLUSIONS: This study identified NOX4 as a novel ferroptosis suppressor and a therapeutic target for the treatment of colorectal cancer. The findings suggest that a coupling between NADPH oxidase enzyme NOX4 and the PPP regulates ferroptosis and reveal an accompanying metabolic vulnerability for therapeutic targeting in colorectal cancer.

Keywords:  Colorectal cancer; Ferroptosis; Oxidative stress; Pentose phosphate pathway

DOI:  https://doi.org/10.1007/s11596-025-00013-7
Cell Death Dis. 2025 Mar 05. 16(1): 154

Estrogen-related receptor alpha (ERRα) controls the stemness and cellular energetics of prostate cancer cells via its direct regulation of citrate metabolism and zinc transportation.

Taiyang Ma, Wenjuan Xie, Zhenyu Xu, Weijie Gao, Jianfu Zhou, Yuliang Wang, Franky Leung Chan.

Compared to most tumors that are more glycolytic, primary prostate cancer is less glycolytic but more dependent on TCA cycle coupled with OXPHOS for its energy demand. This unique metabolic energetic feature is attributed to activation of mitochondrial m-aconitase in TCA caused by decreased cellular Zn level. Evidence suggests that a small subpopulation of cancer cells within prostate tumors, designated as prostate cancer stem cells (PCSCs), play significant roles in advanced prostate cancer progression. However, their cellular energetics status is still poorly understood. Nuclear receptor ERRα (ESRRA) is a key regulator of energy metabolism. Previous studies characterize that ERRα exhibits an upregulation in prostate cancer and can perform multiple oncogenic functions. Here, we demonstrate a novel role of ERRα in the control of stemness and energetics metabolism in PCSCs via a mechanism of combined transrepression of Zn transporter ZIP1 in reducing intracellular Zn uptake and transactivation of ACO2 (m-aconitase) in completion of TCA cycle. Results also showed that restoration of Zn accumulation by treatment with a Zn ionophore Clioquinol could significantly suppress both in vitro growth of PCSCs and also their in vivo tumorigenicity, implicating that enhanced cellular Zn uptake could be a potential therapeutic approach for targeting PCSCs in advanced prostate cancer.

DOI: https://doi.org/10.1038/s41419-025-07460-z
Nature. 2025 Mar 05.

Structure of mitochondrial pyruvate carrier and its inhibition mechanism.

Zheng He, Jianxiu Zhang, Yan Xu, Eve J Fine, Carl-Mikael Suomivuori, Ron O Dror, Liang Feng.

The mitochondrial pyruvate carrier (MPC) governs the entry of pyruvate-a central metabolite that bridges cytosolic glycolysis with mitochondrial oxidative phosphorylation-into the mitochondrial matrix1-5. It thus serves as a pivotal metabolic gatekeeper and has fundamental roles in cellular metabolism. Moreover, MPC is a key target for drugs aimed at managing diabetes, non-alcoholic steatohepatitis and neurodegenerative diseases4-6. However, despite MPC's critical roles in both physiology and medicine, the molecular mechanisms underlying its transport function and how it is inhibited by drugs have remained largely unclear. Here our structural findings on human MPC define the architecture of this vital transporter, delineate its substrate-binding site and translocation pathway, and reveal its major conformational states. Furthermore, we explain the binding and inhibition mechanisms of MPC inhibitors. Our findings provide the molecular basis for understanding MPC's function and pave the way for the development of more-effective therapeutic reagents that target MPC.

DOI: https://doi.org/10.1038/s41586-025-08667-y
Nature. 2025 Mar 05.

Aspirin prevents metastasis by limiting platelet TXA2 suppression of T cell immunity.

Jie Yang, Yumi Yamashita-Kanemaru, Benjamin I Morris, Annalisa Contursi, Daniel Trajkovski, Jingru Xu, Ilinca Patrascan, Jayme Benson, Alexander C Evans, Alberto G Conti, Aws Al-Deka, Layla Dahmani, Adnan Avdic-Belltheus, Baojie Zhang, Hanneke Okkenhaug, Sarah K Whiteside, Charlotte J Imianowski, Alexander J Wesolowski, Louise V Webb, Simone Puccio, Stefania Tacconelli, Annalisa Bruno, Sara Di Berardino, Alessandra De Michele, Heidi C E Welch, I-Shing Yu, Shu-Wha Lin, Suman Mitra, Enrico Lugli, Louise van der Weyden, Klaus Okkenhaug, Kourosh Saeb-Parsy, Paola Patrignani, David J Adams, Rahul Roychoudhuri.

Metastasis is the spread of cancer cells from primary tumours to distant organs and is the cause of 90% of cancer deaths globally1,2. Metastasizing cancer cells are uniquely vulnerable to immune attack, as they are initially deprived of the immunosuppressive microenvironment found within established tumours3. There is interest in therapeutically exploiting this immune vulnerability to prevent recurrence in patients with early cancer at risk of metastasis. Here we show that inhibitors of cyclooxygenase 1 (COX-1), including aspirin, enhance immunity to cancer metastasis by releasing T cells from suppression by platelet-derived thromboxane A2 (TXA2). TXA2 acts on T cells to trigger an immunosuppressive pathway that is dependent on the guanine exchange factor ARHGEF1, suppressing T cell receptor-driven kinase signalling, proliferation and effector functions. T cell-specific conditional deletion of Arhgef1 in mice increases T cell activation at the metastatic site, provoking immune-mediated rejection of lung and liver metastases. Consequently, restricting the availability of TXA2 using aspirin, selective COX-1 inhibitors or platelet-specific deletion of COX-1 reduces the rate of metastasis in a manner that is dependent on T cell-intrinsic expression of ARHGEF1 and signalling by TXA2 in vivo. These findings reveal a novel immunosuppressive pathway that limits T cell immunity to cancer metastasis, providing mechanistic insights into the anti-metastatic activity of aspirin and paving the way for more effective anti-metastatic immunotherapies.

DOI: https://doi.org/10.1038/s41586-025-08626-7
Cell Metab. 2025 Feb 28. pii: S1550-4131(25)00021-X. [Epub ahead of print]

Realigned transsulfuration drives BRAF-V600E-targeted therapy resistance in melanoma.

Klaudia Borbényi-Galambos, Katalin Erdélyi, Tamás Ditrói, Eszter Petra Jurányi, Noémi Szántó, Réka Szatmári, Ágnes Czikora, Edward E Schmidt, Dorottya Garai, Mihály Cserepes, Gabriella Liszkay, Erika Tóth, József Tóvári, Péter Nagy.

  BRAF V600E-inhibition effectively treats melanoma, but acquired resistance rapidly develops. Protein expression profiles, mitochondrial energetics, metabolomics and fluxomics data in cell line, xenograft, and patient-derived xenograft systems revealed that concerted reprogramming of metabolic pathways (including glutaminolysis, glycolysis, TCA cycle, electron transport chain [ETC], and transsulfuration), along with an immediate cytoprotective response to drug-induced oxidative stress, underpins drug-tolerant persister cancer cell survival. Realignment of cysteine (Cys) metabolism, in particular an immediate upregulation of cystathionine-γ-lyase (CSE), was vital in persister cells. The oxidative cellular environment, drug-induced elevated cystine uptake and oxidative Cys catabolism, increased intracellular cystine/Cys ratios, thereby favoring cystine as a CSE substrate. This produces persulfides and hydrogen sulfide to protect protein thiols and support elevated energy demand in persister cells. Combining BRAF V600E inhibitors with CSE inhibitors effectively diminished proliferative relapse in culture models and increased progression-free survival of xenografted mice. This, together with induced CSE expression in patient samples under BRAF-V600E-inhibition, reveals an approach to increase BRAF-V600E-targeted therapeutic efficacy.

Keywords:  BRAF V600E targeted therapy resistance; cystathionine γ-lyase; cysteine metabolism; fluxomics of metabolic reprogramming; hydrogen sulfide; melanoma; persister cells; persulfide; redox regulation; transsulfuration

DOI:  https://doi.org/10.1016/j.cmet.2025.01.021
FEBS J. 2025 Mar 06.

Discovery of a novel alpha isoform of the long-known enzyme LDHA provides new insights into cancer research.

Wonyoung Park, Shibo Wei, Dongryeol Ryu, Ki-Tae Ha.

  Lactate dehydrogenase A is a key enzyme in energy metabolism, with significant roles in cancer progression. Huang et al. identified LDHAα, a novel LDHA isoform derived from an alternative transcript initiated at AUG198, producing a protein 3 kDa larger than canonical LDHA. LDHAα exhibits enhanced glycolytic activity and promotes glucose uptake, lactate production, and tumor growth more effectively than LDHA. Regulated by c-MYC and FOXM1, LDHAα is mainly cytoplasmic and serves as a potential cancer biomarker and therapeutic target. These findings highlight LDHAα's unique role in cancer metabolism and its potential for advancing targeted cancer therapies.

Keywords:  FOXM1; LDHA; LDHAα; c‐MYC; glycolysis

DOI:  https://doi.org/10.1111/febs.70058
J Cell Biol. 2025 Apr 07. pii: e202407110. [Epub ahead of print]224(4):

Cytoplasmic ribosomes on mitochondria alter the local membrane environment for protein import.

Ya-Ting Chang, Benjamin A Barad, Juliette Hamid, Hamidreza Rahmani, Brian M Zid, Danielle A Grotjahn.

Most of the mitochondria proteome is nuclear-encoded, synthesized by cytoplasmic ribosomes, and targeted to the mitochondria posttranslationally. However, a subset of mitochondrial-targeted proteins is imported co-translationally, although the molecular mechanisms governing this process remain unclear. We employ cellular cryo-electron tomography to visualize interactions between cytoplasmic ribosomes and mitochondria in Saccharomyces cerevisiae. We use surface morphometrics tools to identify a subset of ribosomes optimally oriented on mitochondrial membranes for protein import. This allows us to establish the first subtomogram average structure of a cytoplasmic ribosome at the mitochondrial surface in the native cellular context, which showed three distinct connections with the outer mitochondrial membrane surrounding the peptide exit tunnel. Further, this analysis demonstrated that cytoplasmic ribosomes primed for mitochondrial protein import cluster on the outer mitochondrial membrane at sites of local constrictions of the outer and inner mitochondrial membranes. Overall, our study reveals the architecture and the spatial organization of cytoplasmic ribosomes at the mitochondrial surface, providing a native cellular context to define the mechanisms that mediate efficient mitochondrial co-translational protein import.

DOI: https://doi.org/10.1083/jcb.202407110
Nat Metab. 2025 Mar 03.

Regulation of mammalian cellular metabolism by endogenous cyanide production.

Karim Zuhra, Maria Petrosino, Lucia Janickova, Jovan Petric, Kelly Ascenção, Thibaut Vignane, Moustafa Khalaf, Thilo M Philipp, Stella Ravani, Abhishek Anand, Vanessa Martins, Sidneia Santos, Serkan Erdemir, Sait Malkondu, Barbara Sitek, Taha Kelestemur, Anna Kieronska-Rudek, Tomas Majtan, Luis Filgueira, Darko Maric, Stefan Chlopicki, David Hoogewijs, György Haskó, Andreas Papapetropoulos, Brian A Logue, Gerry R Boss, Milos R Filipovic, Csaba Szabo.

Small, gaseous molecules such as nitric oxide, carbon monoxide and hydrogen sulfide are produced as signalling molecules in mammalian cells. Here, we show that low concentrations of cyanide are generated endogenously in various mammalian tissues and cells. We detect cyanide in several cellular compartments of human cells and in various tissues and the blood of mice. Cyanide production is stimulated by glycine, occurs at the low pH of lysosomes and requires peroxidase activity. When generated at a specific rate, cyanide exerts stimulatory effects on mitochondrial bioenergetics, cell metabolism and cell proliferation, but impairs cellular bioenergetics at high concentrations. Cyanide can modify cysteine residues via protein S-cyanylation, which is detectable basally in cells and mice, and increases in response to glycine. Low-dose cyanide supplementation exhibits cytoprotective effects in hypoxia and reoxygenation models in vitro and in vivo. Conversely, pathologically elevated cyanide production in nonketotic hyperglycinaemia is detrimental to cells. Our findings indicate that cyanide should be considered part of the same group of endogenous mammalian regulatory gasotransmitters as nitric oxide, carbon monoxide and hydrogen sulfide.

DOI: https://doi.org/10.1038/s42255-025-01225-w
Mol Cancer. 2025 Mar 03. 24(1): 62

BCL-2 dependence is a favorable predictive marker of response to therapy for chronic lymphocytic leukemia.

Stephen Jun Fei Chong, Junyan Lu, Rebecca Valentin, Timothy Z Lehmberg, Jie Qing Eu, Jing Wang, Fen Zhu, Li Ren Kong, Stacey M Fernandes, Jeremy Zhang, Charles Herbaux, Boon Cher Goh, Jennifer R Brown, Carsten U Niemann, Wolfgang Huber, Thorsten Zenz, Matthew S Davids.

BACKGROUND: Established genetic biomarkers in chronic lymphocytic leukemia (CLL) have been useful in predicting response to chemoimmunotherapy but are less predictive of response to targeted therapies. With several such targeted therapies now approved for CLL, identifying novel, non-genetic predictive biomarkers of response may help to select the optimal therapy for individual patients.
METHODS: We coupled data from a functional precision medicine technique called BH3-profiling, which assesses cellular cytochrome c loss levels as indicators for survival dependence on anti-apoptotic proteins, with multi-omics data consisting of targeted and whole-exome sequencing, genome-wide DNA methylation profiles, RNA-sequencing, protein and functional analyses, to identify biomarkers for treatment response in CLL patients.
RESULTS: We initially studied 73 CLL patients from a discovery cohort. We found that greater dependence on the anti-apoptotic BCL-2 protein was associated with prognostically favorable genetic biomarkers. Furthermore, BCL-2 dependence was strongly associated with gene expression patterns and signaling pathways that suggest a more targeted drug-sensitive milieu and was predictive of drug responses. We subsequently demonstrated that these associations were causal in cell lines and additional CLL patient samples. To validate the findings from our discovery cohort and in vitro studies, we utilized primary CLL cells from 54 additional patients treated on a prospective, phase-2 clinical trial of the BTK inhibitor ibrutinib given in combination with chemoimmunotherapy (fludarabine, cyclophosphamide, rituximab) and confirmed in this independent dataset that higher BCL-2 dependence predicted favorable clinical response, independent of the genetic background of the CLL cells.
CONCLUSION: We comprehensively defined BCL-2 dependence as a potential functional and predictive biomarker of treatment response in CLL, underscoring the importance of characterizing apoptotic signaling in CLL to stratify patients beyond genetic markers and identifying novel combinations to exploit BCL-2 dependence therapeutically. Our approach has the potential to help optimize targeted therapy combinations for CLL patients.

DOI: https://doi.org/10.1186/s12943-025-02260-7
Nat Cell Biol. 2025 Mar 03.

ADSL-generated fumarate binds and inhibits STING to promote tumour immune evasion.

Yuran Duan, Zhiqiang Hu, Peng Han, Bo Lei, Shuo Wang, Zheng Wang, Yueru Hou, Yanni Lin, Min Li, Liwei Xiao, Qingang Wu, Ying Meng, Guijun Liu, Shenghan Lou, Laishou Yang, Xueli Bai, Shengzhong Duan, Peng Zhan, Tong Liu, Zhimin Lu, Daqian Xu.

Highly aggressive tumours have evolved to restrain the cGAS-STING pathway for immune evasion, and the mechanisms underlying this hijacking remain unknown. Here we demonstrate that hypoxia induces robust STING activation in normal mammary epithelial cells but not in breast cancer cells. Mechanistically, adenylosuccinate lyase (ADSL), a key metabolic enzyme in de novo purine synthesis, is highly expressed in breast cancer tissues and is phosphorylated at T350 by hypoxia-activated IKKβ. Phosphorylated ADSL interacts with STING at the endoplasmic reticulum, where ADSL-produced fumarate binds to STING, leading to the inhibition of cGAMP binding to STING, STING activation and subsequent IRF3-dependent cytokine gene expression. Disrupting the ADSL-STING association promotes STING activation and blunts tumour growth. Notably, a combination treatment with ADSL endoplasmic reticulum translocation-blocking peptide and anti-PD-1 antibody induces an additive inhibitory effect on tumour growth accompanying a substantially increased immune response. Notably, ADSL T350 phosphorylation levels are inversely correlated with levels of STING activation and predicate poor prognosis in patients with breast cancer. These findings highlight a pivotal role of the metabolite fumarate in inhibiting STING activation and uncover new strategies to improve immune-checkpoint therapy by targeting ADSL-moonlighting function-mediated STING inhibition.

DOI: https://doi.org/10.1038/s41556-025-01627-8
Clin Cancer Res. 2025 Mar 07.

-----Targeting Acetyl-CoA Carboxylase Suppresses De Novo Lipogenesis and Tumor Cell Growth in Multiple Myeloma.

Eugenio Morelli, Caroline Fidalgo Ribeiro, Silvia D Rodrigues, Claire Gao, Fabio Socciarelli, Domenico Maisano, Vanessa Favasuli, Na Liu, Katia Todoerti, Chandraditya Chakraborty, Yao Yao, Mariateresa Fulciniti, Mehmet Samur, Anil Aktas-Samur, Nicola Amodio, Marcello Turi, Francesca Barello, Johany Penailillo, Cesarina Giallongo, Alessandra Romano, Annamaria Gulla, Kenneth C Anderson, Giorgio Inghirami, Nikhil C Munshi, Massimo Loda.

PURPOSE: In multiple myeloma (MM), tumor cells reprogram metabolic pathways to sustain growth and monoclonal immunoglobulin production. This study examines acetyl-CoA carboxylase 1 (ACC1), the enzyme driving the rate-limiting step in de novo lipogenesis (DNL), in MM metabolic reprogramming, particularly in c-MYC (MYC)-driven subtypes.
EXPERIMENTAL DESIGN: ACC1 expression was evaluated across MM genetic subgroups, focusing on MYC translocations. Functional studies using ACC1 inhibitors and genetic knockdown assessed MM cell growth, lipid synthesis, and metabolic homeostasis in vitro and in vivo. The role of MYC overexpression in ACC1 sensitivity was examined, with palmitate rescue experiments. Lipidomic analysis and assessments of ER stress, protein translation, and oxidative damage elucidated underlying mechanisms.
RESULTS: ACC1 was overexpressed in MYC-translocated MM. Its inhibition or knockdown reduced MM cell growth in vitro and in vivo, particularly in MYC-overexpressing cells. ACC1 knockdown suppressed de novo lipid synthesis, partially rescued by palmitate. Lipidomic disruptions increased cholesterol ester desaturation and altered phospholipid ratios, inducing ER stress, impaired translation, protein carbonylation, oxidative damage, and apoptosis.
CONCLUSIONS: ACC1 is a metabolic vulnerability in MYC-driven MM. Inhibiting ACC1 disrupts lipid homeostasis, induces ER stress, and causes oxidative damage, impairing cell survival. Targeting lipid synthesis pathways, especially in MYC-dependent subtypes, offers a promising therapeutic strategy for MM.

DOI: https://doi.org/10.1158/1078-0432.CCR-24-2000
Cell. 2025 Feb 27. pii: S0092-8674(25)00145-X. [Epub ahead of print]

Lysine vitcylation is a vitamin C-derived protein modification that enhances STAT1-mediated immune response.

Xiadi He, Qiwei Wang, Xin Cheng, Weihua Wang, Yutong Li, Yabing Nan, Jiang Wu, Bingqiu Xiu, Tao Jiang, Johann S Bergholz, Hao Gu, Fuhui Chen, Guangjian Fan, Lianhui Sun, Shaozhen Xie, Junjie Zou, Sheng Lin, Yun Wei, James Lee, John M Asara, Ke Zhang, Lewis C Cantley, Jean J Zhao.

  Vitamin C (vitC) is essential for health and shows promise in treating diseases like cancer, yet its mechanisms remain elusive. Here, we report that vitC directly modifies lysine residues to form "vitcyl-lysine"-a process termed vitcylation. Vitcylation occurs in a dose-, pH-, and sequence-dependent manner in both cell-free systems and living cells. Mechanistically, vitC vitcylates signal transducer and activator of transcription-1 (STAT1)- lysine-298 (K298), impairing its interaction with T cell protein-tyrosine phosphatase (TCPTP) and preventing STAT1-Y701 dephosphorylation. This leads to enhanced STAT1-mediated interferon (IFN) signaling in tumor cells, increased major histocompatibility complex (MHC)/human leukocyte antigen (HLA) class I expression, and activation of anti-tumor immunity in vitro and in vivo. The discovery of vitcylation as a distinctive post-translational modification provides significant insights into vitC's cellular function and therapeutic potential, opening avenues for understanding its biological effects and applications in disease treatment.

Keywords:  STAT1; immune response; protein modification; vitamin C; vitcylation

DOI:  https://doi.org/10.1016/j.cell.2025.01.043
Nat Commun. 2025 Mar 03. 16(1): 2135

Proximity proteomics reveals a mechanism of fatty acid transfer at lipid droplet-mitochondria- endoplasmic reticulum contact sites.

Ayenachew Bezawork-Geleta, Camille J Devereux, Stacey N Keenan, Jieqiong Lou, Ellie Cho, Shuai Nie, David P De Souza, Vinod K Narayana, Nicole A Siddall, Carlos H M Rodrigues, Stephanie Portelli, Tenghao Zheng, Hieu T Nim, Mirana Ramialison, Gary R Hime, Garron T Dodd, Elizabeth Hinde, David B Ascher, David A Stroud, Matthew J Watt.

Membrane contact sites between organelles are critical for the transfer of biomolecules. Lipid droplets store fatty acids and form contacts with mitochondria, which regulate fatty acid oxidation and adenosine triphosphate production. Protein compartmentalization at lipid droplet-mitochondria contact sites and their effects on biological processes are poorly described. Using proximity-dependent biotinylation methods, we identify 71 proteins at lipid droplet-mitochondria contact sites, including a multimeric complex containing extended synaptotagmin (ESYT) 1, ESYT2, and VAMP Associated Protein B and C (VAPB). High resolution imaging confirms localization of this complex at the interface of lipid droplet-mitochondria-endoplasmic reticulum where it likely transfers fatty acids to enable β-oxidation. Deletion of ESYT1, ESYT2 or VAPB limits lipid droplet-derived fatty acid oxidation, resulting in depletion of tricarboxylic acid cycle metabolites, remodeling of the cellular lipidome, and induction of lipotoxic stress. These findings were recapitulated in Esyt1 and Esyt2 deficient mice. Our study uncovers a fundamental mechanism that is required for lipid droplet-derived fatty acid oxidation and cellular lipid homeostasis, with implications for metabolic diseases and survival.

DOI: https://doi.org/10.1038/s41467-025-57405-5
bioRxiv. 2025 Feb 17. pii: 2025.02.12.637975. [Epub ahead of print]

Defined media reveals the essential role of lipid scavenging to support cancer cell proliferation.

Oliver J Newsom, Lucas B Sullivan.

Fetal bovine serum (FBS) is a nearly ubiquitous, yet undefined additive in mammalian cell culture media whose functional contributions to promoting cell proliferation remain poorly understood. Efforts to replace serum supplementation in culture media have been hindered by an incomplete understanding of the environmental requirements fulfilled by FBS in culture. Here, we use a combination of live-cell imaging and liquid chromatography-mass spectrometry to elucidate the role of serum in supporting proliferation. We show that serum provides consumed factors that enable proliferation and demonstrate that the serum metal and lipid components are crucial to sustaining proliferation in culture. Importantly, despite access to a wide range of lipid classes, albumin-bound lipids are the primary species consumed during cancer cell proliferation. Furthermore, we find that combinations of the additive ITS, containing necessary metals, and albumin-associated lipid classes are sufficient to replace FBS in culture media. We show that serum-free media enables sensitive quantification of lipid consumption dynamics during cell proliferation, which indicate that fatty acids (FA) are consumed through a mass-action mechanism, with minimal competition from other lipid classes. Finally, we find that pharmacologic disruption of FA activation and incorporation into the cellular lipidome reduces uptake from the environment and impairs cell proliferation. This work therefore identifies metabolic contributions of serum in cell culture settings and provides a framework for building cell culture systems that sustain cell proliferation without the variable and undefined contributions of FBS.

DOI: https://doi.org/10.1101/2025.02.12.637975
bioRxiv. 2025 Feb 23. pii: 2025.02.19.635300. [Epub ahead of print]

Artificial intelligence-enabled automated analysis of transmission electron micrographs to evaluate chemotherapy impact on mitochondrial morphology in triple negative breast cancer.

Argenis Arriojas, Lily M Baek, Mariah J Berner, Alexander Zhurkevich, Antentor Othrell Hinton, Matthew D Meyer, Lacey E Dobrolecki, Michael T Lewis, Kourosh Zarringhalam, Gloria V Echeverria.

Advancements in transmission electron microscopy (TEM) have enabled in-depth studies of biological specimens, offering new avenues to large-scale imaging experiments with subcellular resolution. Mitochondrial structure is of growing interest in cancer biology due to its crucial role in regulating the multi-faceted functions of mitochondria. We and others have established the crucial role of mitochondria in triple-negative breast cancer (TNBC), an aggressive subtype of breast cancer with limited therapeutic options. Building upon our previous work demonstrating the regulatory role of mitochondrial structure dynamics in metabolic adaptation and survival of chemotherapy-refractory TNBC cells, we sought to extend those findings to a large-scale analysis of transmission electron micrographs. Here we present a UNet artificial intelligence (AI) model for automatic annotation and assessment of mitochondrial morphology and feature quantification. Our model is trained on 11,039 manually annotated mitochondria across 125 micrographs derived from a variety of orthotopic patient-derived xenograft (PDX) mouse model tumors and adherent cell cultures. The model achieves an F1 score of 0.85 on test micrographs at the pixel level. To validate the ability of our model to detect expected mitochondrial structural features, we utilized micrographs from mouse primary skeletal muscle cells genetically modified to lack Dynamin-related protein 1 (Drp1). The algorithm successfully detected a significant increase in mitochondrial elongation, in alignment with the well-established role of Drp1 as a driver of mitochondrial fission. Further, we subjected in vitro and in vivo TNBC models to conventional chemotherapy treatments commonly used for clinical management of TNBC, including doxorubicin, carboplatin, paclitaxel, and docetaxel (DTX). We found substantial within-sample heterogeneity of mitochondrial structure in both in vitro and in vivo TNBC models and observed a consistent reduction in mitochondrial elongation in DTX-treated specimens. We went on to compare mammary tumors and matched lung metastases in a highly metastatic PDX model of TNBC, uncovering significant reduction in mitochondrial length in metastatic lesions. Our large, curated dataset provides high statistical power to detect frequent chemotherapy-induced shifts in mitochondrial shapes and sizes in residual cells left behind after treatment. The successful application of our AI model to capture mitochondrial structure marks a step forward in high-throughput analysis of mitochondrial structures, enhancing our understanding of how morphological changes may relate to chemotherapy efficacy and mechanism of action. Finally, our large, manually curated electron micrograph dataset - now publicly available - serves as a unique gold-standard resource for developing, benchmarking, and applying computational models, while further advancing investigations into mitochondrial morphology and its impact on cancer biology.

DOI: https://doi.org/10.1101/2025.02.19.635300
bioRxiv. 2025 Feb 26. pii: 2025.02.23.639689. [Epub ahead of print]

Hematopoietic stem cells undergo bidirectional fate transitions in vivo.

Tsuyoshi Fukushima, Trine Ahn Kristiansen, Lai Ping Wong, Samuel Keyes, Yosuke Tanaka, Michael Mazzola, Ting Zhao, Lingli He, Masaki Yagi, Konrad Hochedlinger, Satoshi Yamazaki, Ruslan I Sadreyev, David T Scadden.

Transitions between subsets of differentiating hematopoietic cells are widely regarded as unidirectional in vivo. Here, we introduce clonal phylogenetic tracer (CP-tracer) that sequentially introduces genetic barcodes, enabling high-resolution analysis of ~100,000 subclones derived from ~500 individual hematopoietic stem cells (HSC). This revealed previously uncharacterized HSC functional subsets and identified bidirectional fate transitions between myeloid-biased and lineage-balanced HSC. Contrary to the prevailing view that the more self-renewing My-HSCs unidirectionally transition to balanced-HSCs, phylogenetic tracing revealed durable lineage bidirectionality with the transition favoring My-HSC accumulation over time1,2. Further, balanced-HSCs mature through distinct intermediates My-HSCs and lymphoid-biased-HSCs with lymphoid competence here shown by CRISPR/Cas9 screening to be dependent on the homeobox gene, Hhex. Hhex enables Ly-HSC differentiation, but its expression declines with age. These findings establish HSC plasticity and Hhex as a determinant of myeloid-lymphoid balance with each changing over time to favor the age-related myeloid bias of the elderly.

DOI: https://doi.org/10.1101/2025.02.23.639689
JCI Insight. 2025 Mar 04. pii: e174600. [Epub ahead of print]

Immunometabolite L-2-HG promotes epigenetic modification of exhausted T cells and improves anti-tumor immunity.

Yanying Yang, Xiaoyan Li, Fangming Liu, Mingyue Ma, Ying Yang, Chengchao Ruan, Yan Lu, Xiaoyang Li, Xiangdong Wang, Yinghong Shi, Zheng Zhang, Hua Wang, Zhouli Cheng, Duojiao Wu.

  This study aimed to explore the potential correlation between the metabolic intermediate L-2-hydroxyglutarate (L-2-HG) and T cell exhaustion, as well as the underlying mechanisms involved. In this study, we investigated the presence of exhausted T cells (Tex) in patients under certain conditions: HIV infection, chronic leukemia, and hepatocellular carcinoma. To gain insights into the epigenetic signatures and transcriptome alterations in Tex, we employed a combination of RNA-seq and ATAC-seq analyses. To evaluate the impact of L-2-HG on mitochondrial function, differentiation, and anti-tumor capacity of Tex, we utilized in vitro cell culture experiments and animal tumor models. We observed mitochondrial depolarization and metabolic dysfunction in Tex, accompanied by a significant reduction in the metabolic intermediate L-2-HG level. Moreover, altered epigenetic characteristics was observed in Tex, including a substantial increase in H3K27me3 abundance. Culturing Tex with L-2-HG demonstrated improved mitochondrial metabolism, reduced H3K27me3 abundance, and enhanced memory T cell differentiation. In the mouse melanoma tumor model, L-2-HG-treated CD8+T cells for adoptive therapy led to significantly reduced tumor volume and significantly enhanced effector function of T cells. The study revealed L-2-HG acted as an immune metabolite through epigenetic modifications of Tex.

Keywords:  Cancer immunotherapy; Immunology; Metabolism; T cells

DOI:  https://doi.org/10.1172/jci.insight.174600