bims-camemi 2025-05-11 papers

bims-camemi

Biomed News

on Mitochondrial metabolism in cancer

Issue of 2025–05–11
forty papers selected by
Christian Frezza, Universität zu Köln

SIRT2-mediated ACSS2 K271 deacetylation suppresses lipogenesis under nutrient stress.
Annexin A5 controls VDAC1-dependent mitochondrial Ca2+ homeostasis and determines cellular susceptibility to apoptosis.
The role of mitochondrial mRNA translation in cellular communication.
Bacteria-derived nutrient recycling: How phagocytosed bacteria regulate macrophage metabolism.
Aneuploidy generates enhanced nucleotide dependency and sensitivity to metabolic perturbation.
mTORC1 cooperates with tRNA wobble modification to sustain the protein synthesis machinery.
A lipid in transit - the journey of cholesterol into the heart of mitochondrial research.
Functional mitochondrial respiration is essential for glioblastoma tumour growth.
Loss of RET-ROS at complex I induces diastolic dysfunction in mice that is reversed by aerobic exercise.
The Curated Cancer Cell Atlas provides a comprehensive characterization of tumors at single-cell resolution.
Lymphatic endothelial mTORC1 instructs metabolic and developmental signaling during lymphangiogenesis.
Metabolic reprogramming driven by Ant2 deficiency augments T Cell function and anti-tumor immunity in mice.
Lipid-degrading small molecule kills cancer cells by ferroptosis.
The oncoprotein SET promotes serine-derived one-carbon metabolism by regulating SHMT2 enzymatic activity.
Mitochondrial GCN5L1 coordinates with YME1L and MICOS to remodel mitochondrial cristae in white adipocytes and modulate obesity.
The rise of RAS: how gradual oncogene activation shapes the OIS spectrum.
Endoplasmic reticulum Nogo drives AgRP neuronal activation and feeding behavior.
CINs of the cytoplasm: dissecting dsRNA signaling in chromosomal instability.
The multilayered transcriptional architecture of glioblastoma ecosystems.
m6A/IGF2BP3-driven serine biosynthesis fuels AML stemness and metabolic vulnerability.
Activation of lysosomal iron triggers ferroptosis in cancer.
Induction of Fructose Mediated De Novo Lipogenesis Co-exists with the Upregulation of Mitochondrial Oxidative Function in Mice Liver.
PLA2G15 is a BMP hydrolase and its targeting ameliorates lysosomal disease.
Spatial and multiomics analysis of human and mouse lung adenocarcinoma precursors reveals TIM-3 as a putative target for precancer interception.
Cell Metabolism 20th anniversary Voices: Part 2 of 3.
The Integrated Stress Response Pathway Coordinates Translational Control of Multiple Immune Checkpoints in Lung Cancer.
The context-dependent epigenetic and organogenesis programs determine 3D vs. 2D cellular fitness of MYC-driven murine liver cancer cells.
Mitochondrial Respiratory Dysfunction Is Not Correlated With Mitochondrial Genotype in Premature Aging Mice.
Sestrin2 is a central regulator of mitochondrial stress responses in disease and aging.
Deciphering the longitudinal trajectories of glioblastoma ecosystems by integrative single-cell genomics.
LC-MS System for Collecting Time-Resolved Metabolomics Data of Cultured Cells.
Mechanism and application of thiol-disulfide redox biosensors with a fluorescence-lifetime readout.
Molecular basis of SIFI activity in the integrated stress response.
The Dissipation Theory of Aging: A Quantitative Analysis Using a Cellular Aging Map.
EGFR controls transcriptional and metabolic rewiring in KRASG12D colorectal cancer.
Endothelial cell metabolism in cardiovascular physiology and disease.
Bioenergetics and the Evolution of Cellular Traits.
Astrocytic GLUT1 deletion in adult mice enhances glucose metabolism and resilience to stroke.
Highlights of 2024: Tregs immunometabolism and how to counter inflammatory niches.
Uptake of lipids from ascites drives NK cell metabolic dysfunction in ovarian cancer.

Elife. 2025 May 07. pii: RP97019. [Epub ahead of print]13

SIRT2-mediated ACSS2 K271 deacetylation suppresses lipogenesis under nutrient stress.

Rezwana Karim, Wendi Teng, Cameron D Behram, Hening Lin.

  De novo lipogenesis is associated with the development of human diseases such as cancer, diabetes, and obesity. At the core of lipogenesis lies acetyl coenzyme A (CoA), a metabolite that plays a crucial role in fatty acid synthesis. One of the pathways contributing to the production of cytosolic acetyl-CoA is mediated by acetyl-CoA synthetase 2 (ACSS2). Here, we reveal that when cells encounter nutrient stress, particularly a deficiency in amino acids, Sirtuin 2 (SIRT2) catalyzes the deacetylation of ACSS2 at the lysine residue K271. This results in K271 ubiquitination and subsequently proteasomal degradation of ACSS2. Substitution of K271 leads to decreased ubiquitination of ACSS2, increased ACSS2 protein level, and thus increased lipogenesis. Our study uncovers a mechanism that cells employ to efficiently manage lipogenesis during periods of nutrient stress.

Keywords:  SIRT2; acetyl-CoA synthetase 2; acetylation; biochemistry; cell biology; chemical biology; human; lipogenesis; mouse; nutrient stress; ubiquitylation

DOI:  https://doi.org/10.7554/eLife.97019
EMBO J. 2025 May 09.

Annexin A5 controls VDAC1-dependent mitochondrial Ca2+ homeostasis and determines cellular susceptibility to apoptosis.

Furkan E Oflaz, Alexander I Bondarenko, Michael Trenker, Markus Waldeck-Weiermair, Benjamin Gottschalk, Eva Bernhart, Zhanat Koshenov, Snježana Radulović, Rene Rost, Martin Hirtl, Johannes Pilic, Aditya Karunanithi Nivedita, Adlet Sagintayev, Gerd Leitinger, Bent Brachvogel, Susanne Summerauer, Varda Shoshan-Barmatz, Roland Malli, Wolfgang F Graier.

  Annexin A5 (AnxA5) is a Ca2+-dependent phospholipid-binding protein associated with the regulation of intracellular Ca2+ homeostasis. However, the precise role of AnxA5 in controlling mitochondrial Ca2+ signaling remains elusive. Here, we introduce a novel function of AnxA5 in regulating mitochondrial Ca2+ signaling. Our investigation revealed that AnxA5 localizes at and in the mitochondria and orchestrates intermembrane space Ca2+ signaling upon high Ca2+ elevations induced by ER Ca2+ release. Proximity ligation assays and co-immunoprecipitation revealed a close association but no direct contact of AnxA5 with the voltage-dependent anion channel (VDAC1) in the outer mitochondrial membrane (OMM). In single-cell mitochondrial Ca2+ measurements and electrophysiological recordings, AnxA5 was found to enhance Ca2+ flux through the OMM by promoting the Ca2+-permeable state of VDAC1. By modulating intermembrane space Ca2+ signaling, AnxA5 shapes mitochondrial ultrastructure and influences the dynamicity of the mitochondrial Ca2+ uniporter. Furthermore, by controlling VDAC1's oligomeric state, AnxA5 is protective against cisplatin and selenite-induced apoptotic cell death. Our study uncovers AnxA5 as an integral regulator of VDAC1 in physiological and pathological conditions.

Keywords:  Annexin-A5; Apoptotic Cell Death; Intermembrane Space Ca2⁺ Signaling; VDAC1 Ca2+ Permeability

DOI:  https://doi.org/10.1038/s44318-025-00454-9
J Cell Sci. 2025 May 01. pii: jcs263753. [Epub ahead of print]138(9):

The role of mitochondrial mRNA translation in cellular communication.

Eleonora Zilio, Tim Schlegel, Marta Zaninello, Elena I Rugarli.

  Mitochondria are dynamic and heterogeneous organelles that rewire their network and metabolic functions in response to changing cellular needs. To this end, mitochondria integrate a plethora of incoming signals to influence cell fate and survival. A crucial and highly regulated node of cell-mitochondria communication is the translation of nuclear-encoded mitochondrial mRNAs. By controlling and monitoring the spatio-temporal translation of these mRNAs, cells can rapidly adjust mitochondrial function to meet metabolic demands, optimise ATP production and regulate organelle biogenesis and turnover. In this Review, we focus on how RNA-binding proteins that recognise nuclear-encoded mitochondrial mRNAs acutely modulate the rate of translation in response to nutrient availability. We further discuss the relevance of localised translation of these mRNAs for subsets of mitochondria in polarised cells. Finally, we highlight quality control mechanisms that monitor the translation process at the mitochondrial surface and their connections to mitophagy and stress responses. We propose that these processes collectively contribute to mitochondrial specialisation and signalling function.

Keywords:  Cell signalling; Mitochondria; RNA-binding proteins; Ribosome quality control; Translation; mRNA

DOI:  https://doi.org/10.1242/jcs.263753
Cell Metab. 2025 May 06. pii: S1550-4131(25)00210-4. [Epub ahead of print]37(5): 1046-1048

Bacteria-derived nutrient recycling: How phagocytosed bacteria regulate macrophage metabolism.

Andrea Riviello, Dirk Brenner.

Macrophages are responsible for sensing, phagocytosing, and destroying bacteria, yet the metabolic fate of these internalized microbes remains largely unexplored. A recent study published by Lesbats et al. in Nature1 uncovers how macrophages recycle some of the components from phagolysosomal degradation, using them as intermediates in various anabolic pathways and as fuel for oxidative phosphorylation.

DOI: https://doi.org/10.1016/j.cmet.2025.03.018
Genes Dev. 2025 May 05.

Aneuploidy generates enhanced nucleotide dependency and sensitivity to metabolic perturbation.

Rayna Y Magesh, Arshia N Kaur, Faith N Keller, Abdulrazak Frederick, Tenzin Tseyang, John A Haley, Alejandra M Rivera-Nieves, Anthony C Liang, David A Guertin, Jessica B Spinelli, Stephen J Elledge, Emma V Watson.

  Despite the general detriment of aneuploidy to cellular fitness, >90% of solid tumors carry an imbalanced karyotype. This existing paradox and the molecular responses to aneuploidy remain poorly understood. Here, we explore these cellular stresses and unique vulnerabilities of aneuploidy in human mammary epithelial cells (HMECs) enriched for breast cancer-associated copy number alterations (CNAs). To uncover the genetic dependencies specific to aneuploid cells, we conducted a comprehensive, genome-wide CRISPR knockout screen in isogenic aneuploid and diploid HMEC lines. Our study reveals that aneuploid HMECs exhibit an increased reliance on pyrimidine biosynthesis and mitochondrial oxidative phosphorylation genes and demonstrate heightened fitness advantages upon loss of tumor suppressor genes. Using an integrative multiomic analysis, we confirmed nucleotide pool insufficiency as a key contributor to widespread cellular dysfunction in aneuploid HMECs with net copy number gain. Although diploid cells can switch seamlessly between pyrimidine synthesis and salvage, cells with increased chromosomal content exhibit p53 activation and S-phase arrest when relying on salvage alone, alongside increased sensitivity to DNA-damaging chemotherapeutics. This work advances our understanding of the consequences of aneuploidy and uncovers potential avenues for patient stratification and therapeutic intervention based on tumor ploidy.

Keywords:  CRISPR; aneuploidy; cancer; genomics; metabolism

DOI:  https://doi.org/10.1101/gad.352512.124
Nat Commun. 2025 May 06. 16(1): 4201

mTORC1 cooperates with tRNA wobble modification to sustain the protein synthesis machinery.

Julia Hermann, Toman Borteçen, Robert Kalis, Alexander Kowar, Catarina Pechincha, Vivien Vogt, Martin Schneider, Dominic Helm, Jeroen Krijgsveld, Fabricio Loayza-Puch, Johannes Zuber, Wilhelm Palm.

Synthesizing the cellular proteome is a demanding process that is regulated by numerous signaling pathways and RNA modifications. How precisely these mechanisms control the protein synthesis machinery to generate specific proteome subsets remains unclear. Here, through genome-wide CRISPR screens we identify genes that enable mammalian cells to adapt to inactivation of the kinase mechanistic target of rapamycin complex 1 (mTORC1), the central driver of protein synthesis. When mTORC1 is inactive, enzymes that modify tRNAs at wobble uridines (U34-enzymes), Elongator and Ctu1/2, become critically essential for cell growth in vitro and in tumors. By integrating quantitative nascent proteomics, steady-state proteomics and ribosome profiling, we demonstrate that the loss of U34-enzymes particularly impairs the synthesis of ribosomal proteins. However, when mTORC1 is active, this biosynthetic defect only mildly affects steady-state protein abundance. By contrast, simultaneous suppression of mTORC1 and U34-enzymes depletes cells of ribosomal proteins, globally inhibiting translation. Thus, mTORC1 cooperates with tRNA U34-enzymes to sustain the protein synthesis machinery and support the high translational requirements of cell growth.

DOI: https://doi.org/10.1038/s41467-025-59185-4
J Cell Sci. 2025 May 01. pii: jcs263907. [Epub ahead of print]138(9):

A lipid in transit - the journey of cholesterol into the heart of mitochondrial research.

Thomas Simmen, Luca Pellegrini.

  Mitochondrial cholesterol biology in non-steroidogenic tissues remains understudied in cell science. Although detecting cholesterol in mitochondria is challenging due to isolation difficulties, studies using mitoplasts (mitochondria stripped of their outer membrane) and imaging approaches confirm its presence in the inner mitochondrial membrane. Through analysis of published evidence and first-principles reasoning, we advance a model of cholesterol trafficking into and out of mitochondria via phospholipids at mitochondria-associated membranes (MAMs), challenging the traditional view of protein-driven transport. In this model, cholesterol enters mitochondria alongside phosphatidylserine and exits with phosphatidylethanolamine - either unchanged or in a hydroxylated form after modification by the enzyme CYP27A1. Strong cholesterol-phospholipid binding energies, ∼17 kcal/mol (71.128 kJ/mol), support this lipid-mediated mechanism, suggesting it complements protein-based pathways. Future research should explore how these mechanisms collaborate to regulate mitochondrial cholesterol trafficking. By rethinking cholesterol dynamics, we raise the possibility that cholesterol plays a larger role in mitochondrial biology, influencing membrane-dependent functions like cristae structure, respiratory efficiency and inter-organelle communication. This Perspective also highlights the potential of mitochondria to regulate both dietary and endogenous cholesterol flux and homeostasis across the cell.

Keywords:  Lipid biology; Membrane trafficking; Organelles

DOI:  https://doi.org/10.1242/jcs.263907
Oncogene. 2025 May 05.

Functional mitochondrial respiration is essential for glioblastoma tumour growth.

Petra Brisudova, Dana Stojanovic, Jaromir Novak, Zuzana Nahacka, Gabriela Lopes Oliveira, Ondrej Vanatko, Sarka Dvorakova, Berwini Endaya, Jaroslav Truksa, Monika Kubiskova, Alice Foltynova, Daniel Jirak, Natalia Jirat-Ziolkowska, Lukas Kucera, Karel Chalupsky, Krystof Klima, Jan Prochazka, Radislav Sedlacek, Francesco Mengarelli, Patrick Orlando, Luca Tiano, Paulo Oliveira, Carole Grasso, Michael V Berridge, Renata Zobalova, Miroslava Anderova, Jiri Neuzil.

Horizontal transfer of mitochondria from the tumour microenvironment to cancer cells to support proliferation and enhance tumour progression has been shown for various types of cancer in recent years. Glioblastoma, the most aggressive adult brain tumour, has proven to be no exception when it comes to dynamic intercellular mitochondrial movement, as shown in this study using an orthotopic tumour model of respiration-deficient glioblastoma cells. Although confirmed mitochondrial transfer was shown to facilitate tumour progression in glioblastoma, we decided to investigate whether the related electron transport chain recovery is necessary for tumour formation in the brain. Based on experiments using time-resolved analysis of tumour formation by glioblastoma cells depleted of their mitochondrial DNA, we conclude that functional mitochondrial respiration is essential for glioblastoma growth in vivo, because it is needed to support coenzyme Q redox cycling for de novo pyrimidine biosynthesis controlled by respiration-linked dihydroorotate dehydrogenase enzyme activity. We also demonstrate here that astrocytes are key mitochondrial donors in this model.

DOI: https://doi.org/10.1038/s41388-025-03429-6
Am J Physiol Heart Circ Physiol. 2025 May 06.

Loss of RET-ROS at complex I induces diastolic dysfunction in mice that is reversed by aerobic exercise.

Ana Vujic, Amy Koo, Guillaume Bidault, Jan Lj Miljkovic, Andrew M James, Andreas Dannhorn, Xiaowen Duan, Lucy M Davis, Jiro Abe, Joyce Valadares, Jordan J Lee, Alexis Diaz-Vegas, Keira Turner, Richard Goodwin, Daniel J Fazakerley, Antonio Vidal Puig, Michael P Murphy, Thomas Krieg.

  Central to the development of heart failure with preserved ejection fraction (HFpEF) is the redox disruption of metabolic processes, however, the underlying mechanisms are not fully understood. This study utilized a murine model (ND6) carrying a homoplasmic mitochondrial DNA point mutation (ND6 G13997A), which maintains functional NADH oxidation but lacks the site-specific reactive oxygen species (ROS) generation via reverse electron transport (RET). We demonstrate that mice with RET-ROS deficiency have reduced exercise capacity despite higher lean body mass, impaired resilience to high-fat/high-sucrose dietary stress, and cardiac hypertrophy with diastolic dysfunction. Importantly, dobutamine-induced stress elevated succinate levels in the heart, accompanied by RET-ROS production in WT but not in ND6 mice. Furthermore, ND6 mice showed perturbation in metabolite profiles following dobutamine stress. Mechanistically, the ND6 heart had an upregulated expression of fatty acid transport, oxidation, and synthesis genes (CD36, Cpt1b, Acly, Fas, Elovl6 and Scd1) and increased protein levels of lipid metabolism regulators (acetyl-CoA carboxylase and perilipin 2). Interestingly, 8 weeks of forced treadmill running increased acetyl-CoA abundance, alleviated metabolic stress, and improved diastolic function in RET-ROS mutant hearts. In summary, these findings reveal a critical role for RET-ROS in regulating exercise capacity and cardiometabolic health, identifying it as a potentially selective target for modulating cardiac metabolism.

Keywords:  HFpEF; RET-ROS; exercise; lipid metabolism; mitochondria

DOI:  https://doi.org/10.1152/ajpheart.00482.2024
Nat Cancer. 2025 May 08.

The Curated Cancer Cell Atlas provides a comprehensive characterization of tumors at single-cell resolution.

Michael Tyler, Avishai Gavish, Chaya Barbolin, Roi Tschernichovsky, Rouven Hoefflin, Michael Mints, Sidharth V Puram, Itay Tirosh.

Recent years have seen a rapid proliferation of single-cell cancer studies, yet most of these studies profiled few tumors, limiting their statistical power. Combining data and results across studies holds great promise but also involves various challenges. We recently began to address these challenges by curating a large collection of cancer single-cell RNA-sequencing datasets, leveraging it for systematic analyses of tumor heterogeneity. Here we greatly extend this repository to 124 datasets for over 40 cancer types, together comprising 2,836 samples, with improved data annotations, visualizations and exploration. Using this vast cohort, we generate an updated map of recurrent expression programs in malignant cells and systematically quantify context-dependent gene expression and cell-cycle patterns across cell types and cancer types. These data, annotations and analysis results are all freely available for exploration and download through the Curated Cancer Cell Atlas, a central community resource that opens new avenues in cancer research.

DOI: https://doi.org/10.1038/s43018-025-00957-8
Dev Cell. 2025 May 02. pii: S1534-5807(25)00250-3. [Epub ahead of print]

Lymphatic endothelial mTORC1 instructs metabolic and developmental signaling during lymphangiogenesis.

Fei Han, Summer Simeroth, Jie Zhu, Irma Gryniuk, Atul Pranay, Weiqing Chen, Yuan Wang, Yuanyuan Cai, Zhiyuan Shen, Guangyu Wang, Courtney T Griffin, Lijun Xia, Pengchun Yu.

  The lymphatic vasculature comprises lymphatic capillaries and collecting vessels. To support lymphatic development, lymphatic endothelial cells (LECs) utilize nutrients to fuel lymphangiogenic processes. Meanwhile, LECs maintain constant prospero homeobox 1 (PROX1) expression critical for lymphatic specification. However, molecular mechanisms orchestrating nutrient metabolism while sustaining PROX1 levels in LECs remain unclear. Here, we show that loss of RAPTOR, an indispensable mechanistic target of rapamycin complex 1 (mTORC1) component, downregulates PROX1 and impairs lymphatic capillary growth and differentiation of collecting lymphatics in mice. Mechanistically, mTORC1 inhibition in mouse and human LECs causes Myc reduction, which decreases hexokinase 2 (HK2) and glutaminase (GLS), inhibiting glycolysis and glutaminolysis. Myc or HK2/GLS ablation impedes lymphatic capillary and collecting vessel formation. Interestingly, mTORC1 regulation of PROX1 is independent of Myc-HK2/GLS signaling. Moreover, genetic interaction analysis indicates that Myc and PROX1 play crucial roles in mTORC1-regulated lymphatic development. Collectively, our findings identify mTORC1 as a key regulator of metabolic programs and PROX1 expression during lymphangiogenesis.

Keywords:  Myc; PROX1; glutaminase; glutaminolysis; glycolysis; hexokinase 2; lymphangiogenesis; lymphatic endothelial cell; lymphatic vessel; mTORC1

DOI:  https://doi.org/10.1016/j.devcel.2025.04.012
Nat Commun. 2025 May 08. 16(1): 4292

Metabolic reprogramming driven by Ant2 deficiency augments T Cell function and anti-tumor immunity in mice.

Omri Yosef, Leonor Cohen-Daniel, Oded Shamriz, Zahala Bar-On, Wajeeh Salaymeh, Amijai Saragovi, Ifat Abramovich, Bella Agranovich, Veronika Lutz, Joseph Tam, Anna Permyakova, Eyal Gottlieb, Magdalena Huber, Michael Berger.

T cell activation requires a substantial increase in NAD+ production, often exceeding the capacity of oxidative phosphorylation (OXPHOS). To investigate how T cells adapt to this metabolic challenge, we generate T cell-specific ADP/ATP translocase-2 knockout (Ant2-/-) mice. Loss of Ant2, a crucial protein mediating ADP/ATP exchange between mitochondria and cytoplasm, induces OXPHOS restriction by limiting ATP synthase activity, thereby impeding NAD+ regeneration. Interestingly, Ant2-/- naïve T cells exhibit enhanced activation, proliferation and effector functions compared to wild-type controls. Metabolic profiling reveals that these T cells adopt an activated-like metabolic program with increased mitobiogenesis and anabolism. Lastly, pharmacological inhibition of ANT in wild-type T cells recapitulates the Ant2-/- phenotype and improves adoptive T cell therapy of cancer in mouse models. Our findings thus suggest that Ant2-deficient T cells bypass the typical metabolic reprogramming required for activation, leading to enhanced T cell function and highlighting the therapeutic potential of targeting ANT for immune modulation.

DOI: https://doi.org/10.1038/s41467-025-59310-3
Nature. 2025 May 07.

Lipid-degrading small molecule kills cancer cells by ferroptosis.

Mike Lange, James A Olzmann.



Keywords:  Cancer; Cell biology

DOI:  https://doi.org/10.1038/d41586-025-01337-z
Proc Natl Acad Sci U S A. 2025 May 13. 122(19): e2412854122

The oncoprotein SET promotes serine-derived one-carbon metabolism by regulating SHMT2 enzymatic activity.

Zishan Jiao, Mi Zhang, Jingyuan Ning, Han Yao, Xiaojun Yan, Zhen Wu, Dexuan Wu, Yajing Liu, Meng Zhang, Lin Wang, Donglai Wang.

  Cancer cells frequently reprogram one-carbon metabolic pathways to fulfill their vigorous demands of biosynthesis and antioxidant defense for survival and proliferation. Dysfunction of oncogenes or tumor suppressor genes is critically involved in this process, but the precise mechanisms by which cancer cells actively trigger one-carbon metabolic alterations remain incompletely elucidated. Here, by using untargeted metabolomic analysis, we identify the oncoprotein SE translocation (SET) as a key regulator of one-carbon metabolism in cancer cells. SET physically interacts with mitochondrial SHMT2 and facilitates SHMT2 enzymatic activity. Loss of SET profoundly suppresses serine-derived one-carbon metabolic flux, whereas reexpression of ectopic SET leads to the opposite effect. Notably, although the presence of SHMT2 is critical for SET-mediated one-carbon metabolic alterations, the depletion of SHMT2 alone is insufficient to antagonize SET-induced tumor growth, probably due to functional compensation by its cytosolic isozyme SHMT1 upon SHMT2 knockdown. Instead, pharmacological targeting of cellular SHMT (including both SHMT1 and SHMT2) activity results in dramatic suppression of SET-induced tumor growth. Moreover, by using a Kras/Lkb1 mutation-driven lung tumor mouse model, we demonstrate that the loss of SET compromises both tumor formation and intratumoral SHMT2 enzymatic activity. Clinically, the overexpression of SET and SHMT2 is observed in lung tumors, both of which correlate with poor prognosis. Our study reveals a SET-SHMT2 axis in regulating serine-derived one-carbon metabolism and uncovers one-carbon metabolic reprogramming as a mechanism for SET-driven tumorigenesis.

Keywords:  SET; SHMT2; enzymatic activity; one-carbon metabolism; tumor

DOI:  https://doi.org/10.1073/pnas.2412854122
Cell Rep. 2025 May 07. pii: S2211-1247(25)00453-X. [Epub ahead of print]44(5): 115682

Mitochondrial GCN5L1 coordinates with YME1L and MICOS to remodel mitochondrial cristae in white adipocytes and modulate obesity.

Juan Xu, Qiqi Zhang, Xinyu Yang, Qiqi Tang, Yitong Han, Jiahui Meng, Jiaqi Zhang, Xin Lu, Danni Wang, Jing Liu, Bo Shan, Xue Bai, Kai Zhang, Longhao Sun, Lingdi Wang, Lu Zhu.

  The relationship between mitochondrial architecture and energy homeostasis in adipose tissues is not well understood. In this study, we utilized GCN5L1-knockout mice in white (AKO) and brown (BKO) adipose tissues to examine mitochondrial homeostasis in adipose tissues. GCN5L1, a regulator of mitochondrial metabolism and dynamics, influences resistance to high-fat-diet-induced obesity in AKO but not BKO mice. This resistance is mediated by an increase in mitochondrial cristae that stabilizes oxidative phosphorylation (OXPHOS) complexes and enhances energy expenditure. Our protein-interactome analysis reveals that GCN5L1 is associated with the mitochondrial crista complex MICOS (MIC13) and the protease YME1L, facilitating the degradation of MICOS and disassembly of cristae during obesity. This interaction results in decreased OXPHOS levels and subsequent adipocyte expansion. Accumulation of GCN5L1 in the mitochondrial intermembrane space is triggered by a high-fat diet. Our findings highlight a regulatory pathway involving YME1L/GCN5L1/MIC13 that remodels mitochondrial cristae in WAT in response to overnutrition-induced obesity.

Keywords:  CP: Cell biology; CP: Metabolism; MICOS; OXPHOS; YME1L; beige; mitochondria; mitochondrial crista remodeling; white adipose tissue

DOI:  https://doi.org/10.1016/j.celrep.2025.115682
Genes Dev. 2025 May 05.

The rise of RAS: how gradual oncogene activation shapes the OIS spectrum.

Haoran Zhu, Adelyne Sue Li Chan, Masashi Narita.

  Excessive levels of oncogenic RAS expression in normal cells trigger reactive cellular senescence, known as oncogene-induced senescence (OIS)-a putative autonomous tumor-suppressive mechanism. However, the monoallelic expression of oncogenic RAS from the endogenous locus often fails to induce senescence, at least in the short term. Consequently, whether robust senescence characterizes the preneoplasia driven by oncogenic RAS under physiological conditions has been debated. A key challenge is the highly heterogeneous nature of senescence at both the population and single-cell levels. Notably, increasing evidence suggests that RAS levels are gradually upregulated during the development of tumors driven by oncogenic RAS. To address the complex relationship between diverse oncogenic responses, including senescence and tumor initiation, we introduce the concept of an OIS spectrum, where oncogenic dosage-dependent cellular states lie between normal cells and full senescence. Intermediate "sub-OIS" states may play a critical role in tumor initiation, potentially providing one explanation for the ongoing debate.

Keywords:  RAS; liver cancer; oncogene-induced senescence; tumor-initiating cells

DOI:  https://doi.org/10.1101/gad.352761.125
Cell Metab. 2025 Apr 30. pii: S1550-4131(25)00215-3. [Epub ahead of print]

Endoplasmic reticulum Nogo drives AgRP neuronal activation and feeding behavior.

Sungho Jin, Nal Ae Yoon, Mian Wei, Tilla Worgall, Luisa Rubinelli, Tamas L Horvath, Wei Min, Nadia Diano, Annarita di Lorenzo, Sabrina Diano.

  Lipid sensing in the hypothalamus contributes to the control of feeding and whole-body metabolism. However, the mechanism responsible for this nutrient-sensing process is ill-defined. Here, we show that Nogo-A, encoded by reticulon 4 (Rtn4) gene and associated with brain development and synaptic plasticity, regulates feeding and energy metabolism by controlling lipid metabolism in Agouti-related protein (AgRP) neurons. Nogo-A expression was upregulated in AgRP neurons of fasted mice and was associated with a significant downregulation of enzymes involved in sphingolipid de novo biosynthesis and the upregulation of key enzymes in intracellular lipid transport and fatty acid oxidation. Deletion of Rtn4 in AgRP neurons reduced body weight, ghrelin-induced AgRP activity and food intake, and fasting-induced AgRP activation, together with an increase in ceramide levels. Finally, high-fat-diet-induced obesity induced a significant downregulation of Rtn4 and increased ceramide levels in AgRP neurons, suggesting a role for Nogo in AgRP dysregulation in obesity. Taken together, our data reveal that Nogo-A drives AgRP neuronal activity and associated feeding behavior by controlling mitochondrial function and cellular lipid metabolism.

Keywords:  AgRP; ceramides; endoplasmic reticulum; feeding behavior; hypothalamus; lipid metabolism; mitochondria

DOI:  https://doi.org/10.1016/j.cmet.2025.04.005
Mol Oncol. 2025 May 07.

CINs of the cytoplasm: dissecting dsRNA signaling in chromosomal instability.

Aglaia Skolariki, Rose L Jady-Clark, Eileen E Parkes.

  Chromosomal instability (CIN), a pervasive feature of cancer, promotes tumor evolution and inflammatory signaling, yet its influence on innate immune sensing remains incompletely understood. Ruptured micronuclei, a direct byproduct of CIN arising from missegregated chromosomes, expose out-of-context double-stranded DNA that engages the cGAS-STING pathway. In their recent study, Sasaki et al. show that micronuclei are also a source of immunogenic double-stranded RNA (dsRNA), triggering MAVS-dependent type I interferon responses independently of STING. The authors show that micronuclei undergo aberrant transcription, producing dsRNA from nonexonic, transcriptionally accessible loci, with many species localizing near interferon-stimulated genes. This work suggests a feedforward loop in which type I interferon signaling reinforces its own activation through transcriptional dysregulation. Using MPS1 inhibition to induce acute CIN, the authors show that MAVS signaling promotes MHC Class I expression and immune cell recruitment. These findings reposition CIN as a dual trigger of innate immunity through cytoplasmic DNA and RNA sensing. Future work should define how these pathways integrate in the context of chronic CIN and evaluate strategies to target DNA and RNA sensing in immune-edited tumors.

Keywords:  MAVS; RNA sensing; chromosomal instability; dsRNA; innate immunity; micronuclei

DOI:  https://doi.org/10.1002/1878-0261.70047
Nat Genet. 2025 May 09.

The multilayered transcriptional architecture of glioblastoma ecosystems.

Masashi Nomura, Avishay Spitzer, Kevin C Johnson, Luciano Garofano, Djamel Nehar-Belaid, Noam Galili Darnell, Alissa C Greenwald, Lillian Bussema, Young Taek Oh, Frederick S Varn, Fulvio D'Angelo, Simon Gritsch, Kevin J Anderson, Simona Migliozzi, L Nicolas Gonzalez Castro, Tamrin ChowdhFury, Nicolas Robine, Catherine Reeves, Jong Bae Park, Anuja Lipsa, Frank Hertel, Anna Golebiewska, Simone P Niclou, Labeeba Nusrat, Sorcha Kellet, Sunit Das, Hyo Eun Moon, Sun Ha Paek, Franck Bielle, Alice Laurenge, Anna Luisa Di Stefano, Bertrand Mathon, Alberto Picca, Marc Sanson, Shota Tanaka, Nobuhito Saito, David M Ashley, Stephen T Keir, Keith L Ligon, Jason T Huse, W K Alfred Yung, Anna Lasorella, Roel G W Verhaak, Antonio Iavarone, Mario L Suvà, Itay Tirosh.

In isocitrate dehydrogenase wildtype glioblastoma (GBM), cellular heterogeneity across and within tumors may drive therapeutic resistance. Here we analyzed 121 primary and recurrent GBM samples from 59 patients using single-nucleus RNA sequencing and bulk tumor DNA sequencing to characterize GBM transcriptional heterogeneity. First, GBMs can be classified by their broad cellular composition, encompassing malignant and nonmalignant cell types. Second, in each cell type we describe the diversity of cellular states and their pathway activation, particularly an expanded set of malignant cell states, including glial progenitor cell-like, neuronal-like and cilia-like. Third, the remaining variation between GBMs highlights three baseline gene expression programs. These three layers of heterogeneity are interrelated and partially associated with specific genetic aberrations, thereby defining three stereotypic GBM ecosystems. This work provides an unparalleled view of the multilayered transcriptional architecture of GBM. How this architecture evolves during disease progression is addressed in the companion manuscript by Spitzer et al.

DOI: https://doi.org/10.1038/s41588-025-02167-5
Nat Commun. 2025 May 06. 16(1): 4214

m6A/IGF2BP3-driven serine biosynthesis fuels AML stemness and metabolic vulnerability.

Feng Huang, Yushuai Wang, Xiuxin Zhang, Weiwei Gao, Jingwen Li, Ying Yang, Hongjie Mo, Emily Prince, Yifei Long, Jiacheng Hu, Chuang Jiang, Yalin Kang, Zhenhua Chen, Yueh-Chiang Hu, Chengwu Zeng, Lu Yang, Chun-Wei Chen, Jianjun Chen, Huilin Huang, Hengyou Weng.

Metabolic reprogramming of amino acids represents a vulnerability in cancer cells, yet the mechanisms underlying serine metabolism in acute myeloid leukemia (AML) and leukemia stem/initiating cells (LSCs/LICs) remain unclear. Here, we identify RNA N6-methyladenosine (m6A) modification as a key regulator of serine biosynthesis in AML. Using a CRISPR/Cas9 screen, we find that depletion of m6A regulators IGF2BP3 or METTL14 sensitizes AML cells to serine and glycine (SG) deprivation. IGF2BP3 recognizies m6A on mRNAs of key serine synthesis pathway (SSP) genes (e.g., ATF4, PHGDH, PSAT1), stabilizing these transcripts and sustaining serine production to meet the high metabolic demand of AML cells and LSCs/LICs. IGF2BP3 silencing combined with dietary SG restriction potently inhibits AML in vitro and in vivo, while its deletion spares normal hematopoiesis. Our findings reveal the critical role of m6A modification in the serine metabolic vulnerability of AML and highlight the IGF2BP3/m6A/SSP axis as a promising therapeutic target.

DOI: https://doi.org/10.1038/s41467-025-58966-1
Nature. 2025 May 07.

Activation of lysosomal iron triggers ferroptosis in cancer.

Tatiana Cañeque, Leeroy Baron, Sebastian Müller, Alanis Carmona, Ludovic Colombeau, Antoine Versini, Stéphanie Solier, Christine Gaillet, Fabien Sindikubwabo, Julio L Sampaio, Marie Sabatier, Eikan Mishima, Armel Picard-Bernes, Laurène Syx, Nicolas Servant, Bérangère Lombard, Damarys Loew, Jiashuo Zheng, Bettina Proneth, Leishemba K Thoidingjam, Laurence Grimaud, Cameron S Fraser, Krystina J Szylo, Emma Der Kazarian, Caroline Bonnet, Emmanuelle Charafe-Jauffret, Christophe Ginestier, Patricia Santofimia-Castaño, Matias Estaras, Nelson Dusetti, Juan Lucio Iovanna, Antonio Sa Cunha, Gabriella Pittau, Pascal Hammel, Dimitri Tzanis, Sylvie Bonvalot, Sarah Watson, Vincent Gandon, Aditya Upadhyay, Derek A Pratt, Florêncio Porto Freitas, José Pedro Friedmann Angeli, Brent R Stockwell, Marcus Conrad, Jessalyn M Ubellacker, Raphaël Rodriguez.

Iron catalyses the oxidation of lipids in biological membranes and promotes a form of cell death called ferroptosis1. Defining where this chemistry occurs in the cell can inform the design of drugs capable of inducing or inhibiting ferroptosis in various disease-relevant settings. Genetic approaches have revealed suppressors of ferroptosis2-4; by contrast, small molecules can provide spatiotemporal control of the chemistry at work5. Here we show that the ferroptosis inhibitor liproxstatin-1 exerts cytoprotective effects by inactivating iron in lysosomes. We also show that the ferroptosis inducer RSL3 initiates membrane lipid oxidation in lysosomes. We designed a small-molecule activator of lysosomal iron-fentomycin-1-to induce the oxidative degradation of phospholipids and ultimately ferroptosis. Fentomycin-1 is able to kill iron-rich CD44high primary sarcoma and pancreatic ductal adenocarcinoma cells, which can promote metastasis and fuel drug tolerance. In such cells, iron regulates cell adaptation6,7 while conferring vulnerability to ferroptosis8,9. Sarcoma cells exposed to sublethal doses of fentomycin-1 acquire a ferroptosis-resistant cell state characterized by the downregulation of mesenchymal markers and the activation of a membrane-damage response. This phospholipid degrader can eradicate drug-tolerant persister cancer cells in vitro and reduces intranodal tumour growth in a mouse model of breast cancer metastasis. Together, these results show that control of iron reactivity confers therapeutic benefits, establish lysosomal iron as a druggable target and highlight the value of targeting cell states10.

DOI: https://doi.org/10.1038/s41586-025-08974-4
J Nutr. 2025 May 05. pii: S0022-3166(25)00276-7. [Epub ahead of print]

Induction of Fructose Mediated De Novo Lipogenesis Co-exists with the Upregulation of Mitochondrial Oxidative Function in Mice Liver.

Parama Bhattacharjee, Ayeesha Fadlaoui, Caitlin E Ryan, Courtney B Carlson, Daoning Zhang, Nishanth E Sunny.

   BACKGROUND: Dysfunctional mitochondrial metabolism and sustained de novo lipogenesis (DNL) are characteristics of metabolic dysfunction-associated steatotic liver disease (MASLD), a comorbidity of obesity and type 2 diabetes. Fructose, a common sweetener and a potent inducer of lipogenesis, contributes to the etiology of MASLD.
OBJECTIVES: Our goal was to determine whether higher rates of DNL, through its biochemical relationships with mitochondria, can contribute to dysfunctional induction of oxidative networks in the liver.
METHODS: Male C57BL/6JN mice were given a low-fat (LF; 10% fat Kcal, 49.9% corn starch Kcal), high-fat (HF; 60% fat Kcal), or HF/ high-fructose diet (HF/HFr; 25% fat Kcal, 34.9% fructose Kcal) for 24-wks. In a follow-up study, mice on normal chow were provided either 30% fructose in drinking water (FW) to induce hepatic DNL or regular water (NW) for 14 days. Hepatic mitochondria and liver tissue were used to determine oxygen consumption, reactive oxygen species (ROS) generation, tricarboxylic acid (TCA) cycle activity and gene/protein expression profiles.
RESULTS: Hepatic steatosis remained similar between HF and HF/HFr fed mice livers. However, lipogenic and lipid oxidation gene expression profiles and the induction of TCA cycle metabolism were all higher (P ≤ 0.05) in HF/HFr livers. Under fed conditions, the upregulation of DNL in FW livers occurred in concert with higher mitochondrial oxygen consumption (basal; 1.7±0.21 vs. 3.3±0.14 nmoles/min, P ≤ 0.05), higher ROS (0.87±0.09 vs. 1.25±0.12 μM, P ≤ 0.05) and higher flux through TCA cycle components P ≤ 0.05. Further, TCA cycle activity and lipid oxidation remained higher during fasting in the FW livers P ≤ 0.05.
CONCLUSIONS: Our results show that fructose administration to mice led to the concurrent induction of mitochondrial oxidative networks and DNL in the liver. Sustained induction of both de novo lipogenesis and mitochondrial oxidative function could accelerate cellular stress and metabolic dysfunction during MASLD.

Keywords:  De novo lipogenesis; fructose; ketogenesis; lipid oxidation; liver; mitochondrial metabolism; tri-carboxylic acid cycle

DOI:  https://doi.org/10.1016/j.tjnut.2025.04.030
Nature. 2025 May 07.

PLA2G15 is a BMP hydrolase and its targeting ameliorates lysosomal disease.

Kwamina Nyame, Jian Xiong, Hisham N Alsohybe, Arthur P H de Jong, Isabelle V Peña, Ricardo de Miguel, Thijn R Brummelkamp, Guido Hartmann, Sebastian M B Nijman, Matthijs Raaben, Judith A Simcox, Vincent A Blomen, Monther Abu-Remaileh.

Lysosomes catabolize lipids and other biological molecules, maintaining cellular and organismal homeostasis. Bis(monoacylglycero)phosphate (BMP), a major lipid constituent of intralysosomal vesicles, stimulates lipid-degrading enzymes and is altered in various human conditions, including neurodegenerative diseases1,2. Although lysosomal BMP synthase was recently discovered3, the enzymes mediating BMP turnover remain elusive. Here we show that lysosomal phospholipase PLA2G15 is a physiological BMP hydrolase. We further demonstrate that the resistance of BMP to lysosomal hydrolysis arises from its unique sn2, sn2' esterification position and stereochemistry, as neither feature alone confers resistance. Purified PLA2G15 catabolizes most BMP species derived from cell and tissue lysosomes. Furthermore, PLA2G15 efficiently hydrolyses synthesized BMP stereoisomers with primary esters, challenging the long-held thought that BMP stereochemistry alone ensures resistance to acid phospholipases. Conversely, BMP with secondary esters and S,S stereoconfiguration is stable in vitro and requires acyl migration for hydrolysis in lysosomes. Consistent with our biochemical data, PLA2G15-deficient cells and tissues accumulate several BMP species, a phenotype reversible by supplementing wild-type PLA2G15 but not its inactive mutant. Targeting PLA2G15 reduces the cholesterol accumulation in fibroblasts of patients with Niemann-Pick disease type C1 and significantly ameliorates disease pathologies in Niemann-Pick disease type C1-deficient mice, leading to an extended lifespan. Our findings established the rules governing BMP stability in lysosomes and identified PLA2G15 as a lysosomal BMP hydrolase and a potential target for therapeutic intervention in neurodegenerative diseases.

DOI: https://doi.org/10.1038/s41586-025-08942-y
Cancer Cell. 2025 May 02. pii: S1535-6108(25)00162-X. [Epub ahead of print]

Spatial and multiomics analysis of human and mouse lung adenocarcinoma precursors reveals TIM-3 as a putative target for precancer interception.

Bo Zhu, Pingjun Chen, Muhammad Aminu, Jian-Rong Li, Junya Fujimoto, Yanhua Tian, Lingzhi Hong, Hong Chen, Xin Hu, Chenyang Li, Natalie Vokes, Andre L Moreira, Don L Gibbons, Luisa M Solis Soto, Edwin Roger Parra Cuentas, Ou Shi, Songhui Diao, Jie Ye, Frank R Rojas, Eduardo Vilar, Anirban Maitra, Ken Chen, Nicolas Navin, Monique Nilsson, Beibei Huang, Simon Heeke, Jianhua Zhang, Cara L Haymaker, Vamsidhar Velcheti, Daniel H Sterman, Veena Kochat, William I Padron, Ludmil B Alexandrov, Zhubo Wei, Xiuning Le, Linghua Wang, Junya Fukuoka, J Jack Lee, Ignacio I Wistuba, Harvey I Pass, Mark Davis, Samir Hannash, Chao Cheng, Steven Dubinett, Avrum Spira, Kunal Rai, Scott M Lippman, P Andrew Futreal, John V Heymach, Alexandre Reuben, Jia Wu, Jianjun Zhang.

  How tumor microenvironment shapes lung adenocarcinoma (LUAD) precancer evolution remains poorly understood. Spatial immune profiling of 114 human LUAD and LUAD precursors reveals a progressive increase of adaptive response and a relative decrease of innate immune response as LUAD precursors progress. The immune evasion features align the immune response patterns at various stages. TIM-3-high features are enriched in LUAD precancers, which decrease in later stages. Furthermore, single-cell RNA sequencing (scRNA-seq) and spatial immune and transcriptomics profiling of LUAD and LUAD precursor specimens from 5 mouse models validate high TIM-3 features in LUAD precancers. In vivo TIM-3 blockade at precancer stage, but not at advanced cancer stage, decreases tumor burden. Anti-TIM-3 treatment is associated with enhanced antigen presentation, T cell activation, and increased M1/M2 macrophage ratio. These results highlight the coordination of innate and adaptive immune response/evasion during LUAD precancer evolution and suggest TIM-3 as a potential target for LUAD precancer interception.

Keywords:  TIM-3; cancer prevention; imaging mass cytometry; immune landscape; lung adenocarcinoma evolution; precancer; spatial single cell; stage dependent

DOI:  https://doi.org/10.1016/j.ccell.2025.04.003
Cell Metab. 2025 May 06. pii: S1550-4131(25)00214-1. [Epub ahead of print]37(5): 1039-1042

Cell Metabolism 20th anniversary Voices: Part 2 of 3.

Shingo Kajimura, Cristina García-Cáceres, Lawrence Kazak, Edward B Thorp, Katrin J Svensson, Ling Yang.

This year, Cell Metabolism is celebrating its 20th anniversary! We are taking this opportunity to highlight authors that have published with us as they developed, and keep developing, their research careers. In 2005, Cell Metabolism was just starting an exciting journey to become a reference forum for interdisciplinary, high-quality metabolism studies. Throughout these years, it has been an honor to feature in our issues articles from these investigators and their labs that have contributed to both consolidating and expanding the metabolism field.

DOI: https://doi.org/10.1016/j.cmet.2025.04.004
Cancer Res. 2025 May 06.

The Integrated Stress Response Pathway Coordinates Translational Control of Multiple Immune Checkpoints in Lung Cancer.

Shayna Thomas-Jardin, Shruthy Suresh, Ariana Arce, Nicole Novaresi, Qing Deng, Emily Stein, Lisa Thomas, Cheryl Lewis, Chul Ahn, Bret M Evers, Esra A Akbay, Maria E Salvatierra, Wei Lu, Khaja Khan, Luisa M Solis Soto, Ignacio I Wistuba, John D Minna, Kathryn A O'Donnell.

The integrated stress response (ISR) is an adaptive pathway hijacked by cancer cells to survive cellular stresses in the tumor microenvironment. ISR activation potently induces PD-L1, leading to suppression of anti-tumor immunity. Here, we sought to uncover additional immune checkpoint proteins regulated by the ISR to elucidate mechanisms of tumor immune escape. ISR coordinately induced CD155 and PD-L1, enhancing translation of both immune checkpoint proteins through bypass of inhibitory upstream open reading frames in their 5' UTRs. Analysis of primary human lung tumors identified a significant correlation between expression of PD-L1 and CD155. ISR activation accelerated tumorigenesis and inhibited T cell function, which could be overcome by combining PD-1 and TIGIT blockade with the ISR inhibitor ISRIB. This study uncovers a mechanism by which two immune checkpoint proteins are coordinately regulated and suggests a therapeutic strategy for lung cancer patients.

DOI: https://doi.org/10.1158/0008-5472.CAN-24-3844
Elife. 2025 May 06. pii: RP101299. [Epub ahead of print]14

The context-dependent epigenetic and organogenesis programs determine 3D vs. 2D cellular fitness of MYC-driven murine liver cancer cells.

Jie Fang, Shivendra Singh, Brennan Wells, Qiong Wu, Hongjian Jin, Laura J Janke, Shibiao Wan, Jacob A Steele, Jon P Connelly, Andrew J Murphy, Ruoning Wang, Andrew Davidoff, Margaret Ashcroft, Shondra M Pruett-Miller, Jun Yang.

  3D cellular-specific epigenetic and transcriptomic reprogramming is critical to organogenesis and tumorigenesis. Here, we dissect the distinct cell fitness in 2D (normoxia vs. chronic hypoxia) vs 3D (normoxia) culture conditions for an MYC-driven murine liver cancer model. We identify over 600 shared essential genes and additional context-specific fitness genes and pathways. Knockout of the VHL-HIF1 pathway results in incompatible fitness defects under normoxia vs. 1% oxygen or 3D culture conditions. Moreover, deletion of each of the mitochondrial respiratory electron transport chain complex has distinct fitness outcomes. Notably, multicellular organogenesis signaling pathways including TGFβ-SMAD, which is upregulated in 3D culture, specifically constrict the uncontrolled cell proliferation in 3D while inactivation of epigenetic modifiers (Bcor, Kmt2d, Mettl3, and Mettl14) has opposite outcomes in 2D vs. 3D. We further identify a 3D-dependent synthetic lethality with partial loss of Prmt5 due to a reduction of Mtap expression resulting from 3D-specific epigenetic reprogramming. Our study highlights unique epigenetic, metabolic, and organogenesis signaling dependencies under different cellular settings.

Keywords:  3-dimensional; CRISPR; MYC; cancer biology; fitness; human; hypoxia; liver cancer; mouse

DOI:  https://doi.org/10.7554/eLife.101299
Aging Cell. 2025 May 02. e70085

Mitochondrial Respiratory Dysfunction Is Not Correlated With Mitochondrial Genotype in Premature Aging Mice.

Hiroaki Tamashiro, Kaori Ishikawa, Koichi Sadotomo, Emi Ogasawara, Kazuto Nakada.

  mtDNA mutator mice (Polgmut/mut mice) have reinforced the mitochondrial theory of aging. These mice accumulate multiple mutations in mtDNA with age due to a homozygous proofreading-deficient mutation in mtDNA polymerase gamma (Polg), resulting in mitochondrial respiratory dysfunction and premature aging phenotypes. However, whether the accumulation of multiple mutations in Polgmut/mut mice induces mitochondrial respiratory dysfunction remains unclear. Here, we determined the accurate mtDNA genotype, including the frequency of total mutations and the number of non-synonymous substitutions and pathogenic mutations, using next-generation sequencing in the progeny of all three genotypes obtained from the mating of heterozygous mtDNA mutator mice (Polg+/mut mice) and examined their correlation with mitochondrial respiratory activity. Although Polg+/mut mice showed equivalent mtDNA genotype to Polg+/+ (wild-type) mice, the mitochondrial respiratory activity in the Polg+/mut mice was mildly reduced. To further investigate the causal relationship between mtDNA genotype and mitochondrial respiratory activity, we experimentally varied the mtDNA genotype in Polg mice. However, mitochondrial respiratory activity was mildly reduced in Polg+/mut mice and severely reduced in Polgmut/mut mice, regardless of the mtDNA genotype. Moreover, by varying the mtDNA genotype, some Polg+/+ mice showed mtDNA genotype equivalent to those of Polgmut/mut mice, but mitochondrial respiratory activity in Polg+/+ mice was normal. These results indicate that the mitochondrial respiratory dysfunction observed in mice with proofreading-deficient mutation in Polg is correlated with the nuclear genotype of Polg rather than the mtDNA genotype. Thus, the mitochondrial theory of aging in Polgmut/mut mice needs further re-examination.

Keywords:  aging; mitochondria; mitochondrial DNA

DOI:  https://doi.org/10.1111/acel.70085
Ageing Res Rev. 2025 May 02. pii: S1568-1637(25)00108-4. [Epub ahead of print]109 102762

Sestrin2 is a central regulator of mitochondrial stress responses in disease and aging.

Ivo F Machado, Carlos M Palmeira, Anabela P Rolo.

  Mitochondria supply most of the energy for cellular functions and coordinate numerous cellular pathways. Their dynamic nature allows them to adjust to stress and cellular metabolic demands, thus ensuring the preservation of cellular homeostasis. Loss of normal mitochondrial function compromises cell survival and has been implicated in the development of many diseases and in aging. Although exposure to continuous or severe stress has adverse effects on cells, mild mitochondrial stress enhances mitochondrial function and potentially extends health span through mitochondrial adaptive responses. Over the past few decades, sestrin2 (SESN2) has emerged as a pivotal regulator of stress responses. For instance, SESN2 responds to genotoxic, oxidative, and metabolic stress, promoting cellular defense against stress-associated damage. Here, we focus on recent findings that establish SESN2 as an orchestrator of mitochondrial stress adaptation, which is supported by its involvement in the integrated stress response, mitochondrial biogenesis, and mitophagy. Additionally, we discuss the integral role of SESN2 in mediating the health benefits of exercise as well as its impact on skeletal muscle, liver and heart injury, and aging.

Keywords:  Aging; Liver; Mitochondria; Mitohormesis; Muscle; Sestrin2

DOI:  https://doi.org/10.1016/j.arr.2025.102762
Nat Genet. 2025 May 09.

Deciphering the longitudinal trajectories of glioblastoma ecosystems by integrative single-cell genomics.

Avishay Spitzer, Kevin C Johnson, Masashi Nomura, Luciano Garofano, Djamel Nehar-Belaid, Noam Galili Darnell, Alissa C Greenwald, Lillian Bussema, Young Taek Oh, Frederick S Varn, Fulvio D'Angelo, Simon Gritsch, Kevin J Anderson, Simona Migliozzi, L Nicolas Gonzalez Castro, Tamrin Chowdhury, Nicolas Robine, Catherine Reeves, Jong Bae Park, Anuja Lipsa, Frank Hertel, Anna Golebiewska, Simone P Niclou, Labeeba Nusrat, Sorcha Kellet, Sunit Das, Hyo-Eun Moon, Sun Ha Paek, Franck Bielle, Alice Laurenge, Anna Luisa Di Stefano, Bertrand Mathon, Alberto Picca, Marc Sanson, Shota Tanaka, Nobuhito Saito, David M Ashley, Stephen T Keir, Keith L Ligon, Jason T Huse, W K Alfred Yung, Anna Lasorella, Antonio Iavarone, Roel G W Verhaak, Itay Tirosh, Mario L Suvà.

The evolution of isocitrate dehydrogenase (IDH)-wildtype glioblastoma (GBM) after standard-of-care therapy remains poorly understood. Here we analyzed matched primary and recurrent GBMs from 59 patients using single-nucleus RNA sequencing and bulk DNA sequencing, assessing the longitudinal evolution of the GBM ecosystem across layers of cellular and molecular heterogeneity. The most consistent change was a lower malignant cell fraction at recurrence and a reciprocal increase in glial and neuronal cell types in the tumor microenvironment (TME). The predominant malignant cell state differed between most matched pairs, but no states were exclusive or highly enriched in either time point, nor was there a consistent longitudinal trajectory across the cohort. Nevertheless, specific trajectories were enriched in subsets of patients. Changes in malignant state abundances mirrored changes in TME composition and baseline profiles, reflecting the co-evolution of the GBM ecosystem. Our study provides a blueprint of GBM's diverse longitudinal trajectories and highlights the treatment and TME modifiers that shape them.

DOI: https://doi.org/10.1038/s41588-025-02168-4
Anal Chem. 2025 May 08.

LC-MS System for Collecting Time-Resolved Metabolomics Data of Cultured Cells.

Carly C Y Chan, Ryan A Groves, Raied Aburashed, Thomas Rydzak, Ian A Lewis.

Temporal metabolic dynamics are difficult to capture but are critical to understanding biology. We developed an automated liquid chromatography-mass spectrometry system that collects time-resolved metabolomics data from cultured cells, enabling sub-minute sequential sampling, broad metabolite coverage, robust metabolite identification, and parallel monitoring of up to 72 experimental conditions. Using this system, we identified temporal metabolic phenotypes of Escherichia coli and Proteus mirabilis that could not be captured from single time points.

DOI: https://doi.org/10.1021/acs.analchem.4c06697
Proc Natl Acad Sci U S A. 2025 May 13. 122(19): e2503978122

Mechanism and application of thiol-disulfide redox biosensors with a fluorescence-lifetime readout.

Paul C Rosen, Andrew Glaser, Juan R Martínez-François, Daniel C Lim, Daniel J Brooks, Panhui Fu, Erica Kim, Dorothee Kern, Gary Yellen.

  Genetically encoded biosensors with changes in fluorescence lifetime (as opposed to fluorescence intensity) can quantify small molecules in complex contexts, even in vivo. However, lifetime-readout sensors are poorly understood at a molecular level, complicating their development. Although there are many sensors that have fluorescence-intensity changes, there are currently only a few with fluorescence-lifetime changes. Here, we optimized two biosensors for thiol-disulfide redox (RoTq-Off and RoTq-On) with opposite changes in fluorescence lifetime in response to oxidation. Using biophysical approaches, we showed that the high-lifetime states of these sensors lock the chromophore more firmly in place than their low-lifetime states do. Two-photon fluorescence lifetime imaging of RoTq-On fused to a glutaredoxin (Grx1) enabled robust, straightforward monitoring of cytosolic glutathione redox state in acute mouse brain slices. The motional mechanism described here is probably common and may inform the design of other lifetime-readout sensors; the Grx1-RoTq-On fusion sensor will be useful for studying glutathione redox in physiology.

Keywords:  conformational change; fluorescence lifetime; genetically encoded fluorescent biosensor; glutathione redox

DOI:  https://doi.org/10.1073/pnas.2503978122
Nature. 2025 May 06.

Molecular basis of SIFI activity in the integrated stress response.

Zhi Yang, Diane L Haakonsen, Michael Heider, Samuel R Witus, Alex Zelter, Tobias Beschauner, Michael J MacCoss, Michael Rapé.

Chronic stress response activation impairs cell survival and causes devastating degenerative di-seases 1-3. Organisms accordingly deploy silencing factors, such as the E3 ubiquitin ligase SIFI, to terminate stress response signaling and ensure cellular homeostasis 4. How a silencing factor can sense stress across cellular scales to elicit timely stress response inactivation is poorly understood. Here, we combine cryo-electron microscopy of endogenous SIFI with AlphaFold modeling and biochemical analyses to report the structural and mechanistic basis of integrated stress response silencing. SIFI detects both stress-indicators and stress response components through flexible domains within an easily accessible scaffold, before building linkage-specific ubiquitin chains at separate, sterically restricted elongation modules. Ubiquitin handover by a ubiquitin-like domain couples versatile substrate modification to linkage-specific ubiquitin polymer formation. Stress response silencing therefore exploits a catalytic mechanism that is geared towards processing many diverse proteins and hence allows a single enzyme to monitor and, if needed, modulate a complex cellular state.

DOI: https://doi.org/10.1038/s41586-025-09074-z
ArXiv. 2025 Apr 17. pii: arXiv:2504.13044v1. [Epub ahead of print]

The Dissipation Theory of Aging: A Quantitative Analysis Using a Cellular Aging Map.

Farhan Khodaee, Rohola Zandie, Yufan Xia, Elazer R Edelman.

We propose a new theory for aging based on dynamical systems and provide a data-driven computational method to quantify the changes at the cellular level. We use ergodic theory to decompose the dynamics of changes during aging and show that aging is fundamentally a dissipative process within biological systems, akin to dynamical systems where dissipation occurs due to non-conservative forces. To quantify the dissipation dynamics, we employ a transformer-based machine learning algorithm to analyze gene expression data, incorporating age as a token to assess how age-related dissipation is reflected in the embedding space. By evaluating the dynamics of gene and age embeddings, we provide a cellular aging map (CAM) and identify patterns indicative of divergence in gene embedding space, nonlinear transitions, and entropy variations during aging for various tissues and cell types. Our results provide a novel perspective on aging as a dissipative process and introduce a computational framework that enables measuring age-related changes with molecular resolution.
EMBO Mol Med. 2025 May 06.

EGFR controls transcriptional and metabolic rewiring in KRASG12D colorectal cancer.

Dana Krauß, Veronica Moreno-Viedma, Emi Adachi-Fernandez, Cristiano de Sá Fernandes, Jakob-Wendelin Genger, Ourania Fari, Bernadette Blauensteiner, Dominik Kirchhofer, Nikolina Bradaric, Valeriya Gushchina, Georgios Fotakis, Thomas Mohr, Ifat Abramovich, Inbal Mor, Martin Holcmann, Andreas Bergthaler, Arvand Haschemi, Zlatko Trajanoski, Juliane Winkler, Eyal Gottlieb, Maria Sibilia.

  Inhibition of the epidermal growth factor receptor (EGFR) shows clinical benefit in metastatic colorectal cancer (CRC) patients, but KRAS-mutations are known to confer resistance. However, recent reports highlight EGFR as a crucial target to be co-inhibited with RAS inhibitors for effective treatment of KRAS mutant CRC. Here, we investigated the tumor cell-intrinsic contribution of EGFR in KRASG12D tumors by establishing murine CRC organoids with key CRC mutations (KRAS, APC, TP53) and inducible EGFR deletion. Metabolomic, transcriptomic, and scRNA-analyses revealed that EGFR deletion in KRAS-mutant organoids reduced their phenotypic heterogeneity and activated a distinct cancer-stem-cell/WNT signature associated with reduced cell size and downregulation of major signaling cascades like MAPK, PI3K, and ErbB. This was accompanied by metabolic rewiring with a decrease in glycolytic routing and increased anaplerotic glutaminolysis. Mechanistically, following EGFR loss, Smoc2 was identified as a key upregulated target mediating these phenotypes that could be rescued upon additional Smoc2 deletion. Validation in patient-datasets revealed that the identified signature is associated with better overall survival of RAS mutant CRC patients possibly allowing to predict therapy responses in patients.

Keywords:  CRC-organoids; EGFR; KRAS; Metabolism; Stemness-WNT

DOI:  https://doi.org/10.1038/s44321-025-00240-4
Nat Rev Cardiol. 2025 May 09.

Endothelial cell metabolism in cardiovascular physiology and disease.

Alessandra Pasut, Eleonora Lama, Amaryllis H Van Craenenbroeck, Jeffrey Kroon, Peter Carmeliet.

Endothelial cells are multifunctional cells that form the inner layer of blood vessels and have a crucial role in vasoreactivity, angiogenesis, immunomodulation, nutrient uptake and coagulation. Endothelial cells have unique metabolism and are metabolically heterogeneous. The microenvironment and metabolism of endothelial cells contribute to endothelial cell heterogeneity and metabolic specialization. Endothelial cell dysfunction is an early event in the development of several cardiovascular diseases and has been shown, at least to some extent, to be driven by metabolic changes preceding the manifestation of clinical symptoms. Diabetes mellitus, hypertension, obesity and chronic kidney disease are all risk factors for cardiovascular disease. Changes in endothelial cell metabolism induced by these cardiometabolic stressors accelerate the accumulation of dysfunctional endothelial cells in tissues and the development of cardiovascular disease. In this Review, we discuss the diversity of metabolic programmes that control endothelial cell function in the cardiovascular system and how these metabolic programmes are perturbed in different cardiovascular diseases in a disease-specific manner. Finally, we discuss the potential and challenges of targeting endothelial cell metabolism for the treatment of cardiovascular diseases.

DOI: https://doi.org/10.1038/s41569-025-01162-x
Annu Rev Biophys. 2025 May;54(1): 81-99

Bioenergetics and the Evolution of Cellular Traits.

Paul E Schavemaker, Michael Lynch.

  Evolutionary processes have transformed simple cellular life into a great diversity of forms, ranging from the ubiquitous eukaryotic cell design to the more specific cellular forms of spirochetes, cyanobacteria, ciliates, heliozoans, amoeba, and many others. The cellular traits that constitute these forms require an evolutionary explanation. Ultimately, the persistence of a cellular trait depends on its net contribution to fitness, a quantitative measure. Independent of any positive effects, a cellular trait exhibits a baseline energetic cost that needs to be accounted for when quantitatively examining its net fitness effect. Here, we explore how the energetic burden introduced by a cellular trait quantitatively affects cellular fitness, describe methods for determining cell energy budgets, summarize the costs of cellular traits across the tree of life, and examine how the fitness impacts of these energetic costs compare to other evolutionary forces and trait benefits.

Keywords:  cell biology; energetics; evolution; fitness

DOI:  https://doi.org/10.1146/annurev-biophys-070524-090334
Nat Commun. 2025 May 06. 16(1): 4190

Astrocytic GLUT1 deletion in adult mice enhances glucose metabolism and resilience to stroke.

Laetitia Thieren, Henri S Zanker, Jeanne Droux, Urvashi Dalvi, Matthias T Wyss, Rebecca Waag, Pierre-Luc Germain, Lukas M von Ziegler, Zoe J Looser, Ladina Hösli, Luca Ravotto, E Dale Abel, Johannes Bohacek, Susanne Wegener, L Felipe Barros, Mohamad El Amki, Bruno Weber, Aiman S Saab.

Brain activity relies on a steady supply of blood glucose. Astrocytes express glucose transporter 1 (GLUT1), considered their primary route for glucose uptake to sustain metabolic and antioxidant support for neurons. While GLUT1 deficiency causes severe developmental impairments, its role in adult astrocytes remains unclear. Here, we show that astrocytes and neurons tolerate the inducible, astrocyte-specific deletion of GLUT1 in adulthood. Sensorimotor and memory functions remain intact in male GLUT1 cKO mice, indicating that GLUT1 loss does not impair behavior. Despite GLUT1 loss, two-photon glucose sensor imaging reveals that astrocytes maintain normal resting glucose levels but exhibit a more than two-fold increase in glucose consumption, indicating enhanced metabolic activity. Notably, male GLUT1 cKO mice display reduced infarct volumes following stroke, suggesting a neuroprotective effect of increased astrocytic glucose metabolism. Our findings reveal metabolic adaptability in astrocytes, ensuring glucose uptake and neuronal support despite the absence of their primary transporter.

DOI: https://doi.org/10.1038/s41467-025-59400-2
Immunol Cell Biol. 2025 May 04.

Highlights of 2024: Tregs immunometabolism and how to counter inflammatory niches.

Nicolas Valentini, Christopher J Requejo Cier, Caroline Lamarche.

  In this article for the Highlights of 2024 Series, we discuss recent discoveries in Treg immunometabolism, which reveal how inflammatory niches alter Treg fate and function through distinct metabolic cues. Key findings include IL-21-driven mitochondrial dysfunction, lactate-enhanced OXPHOS via MGAT1, sphingolipid-dependent Treg differentiation in tumors, ferroptosis susceptibility under high-fat diets, and sex-specific adipose Treg subsets modulating glucose homeostasis. Together, these insights highlight potential metabolic targets to restore Treg function in inflammatory diseases and cancer.

Keywords:  Tregs; glycolysis; immunometabolism; mitochondria; oxidative phosphorylation

DOI:  https://doi.org/10.1111/imcb.70027
Sci Immunol. 2025 May 09. 10(107): eadr4795

Uptake of lipids from ascites drives NK cell metabolic dysfunction in ovarian cancer.

Karen Slattery, Cong-Hui Yao, Eimear Mylod, John Scanlan, Barry Scott, Joseph Patrick Crowley, Orla McGowan, Gavin McManus, Martin Brennan, Katie O'Brien, Kate Glennon, Edward Corry, Ann Treacy, Rafael J Argüello, Clair M Gardiner, Marcia C Haigis, Donal J Brennan, Lydia Lynch.

High-grade serous ovarian cancer (HGSOC) remains an urgent unmet clinical need, with more than 70% of patients presenting with metastatic disease. Many patients develop large volumes of ascites, which promotes metastasis and is associated with poor therapeutic response and survival. Immunotherapy trials have shown limited success, highlighting the need to better understand HGSOC immunology. Here, we analyzed cytotoxic lymphocytes [natural killer (NK), T, and innate T cells] from patients with HGSOC and observed widespread dysfunction across primary and metastatic sites. Although nutrient rich, ascites was immunosuppressive for all lymphocyte subsets. NK cell dysfunction was driven by uptake of polar lipids, with associated dysregulation in lipid storage. Phosphatidylcholine was a key immunosuppressive metabolite, disrupting NK cell membrane order and cytotoxicity. Blocking lipid uptake through SR-B1 protected NK cell antitumor functions in ascites. These findings offer insights into immune suppression in HGSOC and have important implications for the design of future immunotherapies.

DOI: https://doi.org/10.1126/sciimmunol.adr4795