bims-camemi 2025-05-25 papers

bims-camemi

Biomed News

on Mitochondrial metabolism in cancer

Issue of 2025–05–25
37 papers selected by
Christian Frezza, Universität zu Köln

De novo serine biosynthesis is protective in mitochondrial disease.
Cell-intrinsic metabolic phenotypes identified in patients with glioblastoma, using mass spectrometry imaging of 13C-labelled glucose metabolism.
Dual Ribosome Profiling reveals metabolic limitations of cancer and stromal cells in the tumor microenvironment.
Age-associated nicotinamide adenine dinucleotide decline drives CAR-T cell failure.
Unravelling cysteine-deficiency-associated rapid weight loss.
Silencing mitochondrial gene expression in living cells.
Early immune evasion in colorectal cancer: interplay between stem cells and the tumor microenvironment.
Clonal tracing with somatic epimutations reveals dynamics of blood ageing.
Isocitrate dehydrogenase 1 primes group-3 medulloblastomas for cuproptosis.
Lactate dehydrogenase A-coupled NAD+ regeneration is critical for acute myeloid leukemia cell survival.
S-adenosylmethionine metabolism shapes CD8+ T cell functions in colorectal cancer.
Liver as a nexus of daily metabolic cross talk.
MULTIPLE, REDUNDANT CARBOXYLIC ACID TRANSPORTERS SUPPORT MITOCHONDRIAL METABOLISM IN PLASMODIUM FALCIPARUM.
Modelling POLG mutations in mice unravels a critical role of POLγΒ in regulating phenotypic severity.
BTK Inhibition in Systemic Sclerosis: A Promising New B Cell Therapy.
Dynamic single-cell metabolomics reveals cell-cell interaction between tumor cells and macrophages.
Emerging interactions between circadian rhythms and extracellular vesicles.
Hepatic glutamic-oxaloacetic transaminase (GOT2) promotes mitochondrial respiration energized at complex II and alters whole body metabolism.
A ketogenic diet halts malaria parasite growth.
Metabolomics biomarkers of frailty: a longitudinal study of aging female and male mice.
Glutamine catabolism supports amino acid biosynthesis and suppresses the integrated stress response to promote photoreceptor survival.
Cholesterol metabolism and intrabacterial potassium homeostasis are intrinsically related in Mycobacterium tuberculosis.
Image-guided targeting of mitochondrial metabolism sensitizes pediatric malignant rhabdoid tumors to low-dose radiotherapy.
PCSK9 drives sterol-dependent metastatic organ choice in pancreatic cancer.
Mechanistic insights into Bcs1-mediated mitochondrial membrane translocation of the folded Rieske protein.
Novel metabolic routes to cancer immune evasion.
Paired mutation calling and spatial transcriptomics identify cellular neighbourhoods dictating the neoplastic outcome of colitis.
Cholinergic regulation of thymocyte negative selection.
Abiotic lipid metabolism enables membrane plasticity in artificial cells.
A lncRNA-mediated metabolic rewiring of cell senescence.
Pex30-dependent membrane contact sites maintain ER lipid homeostasis.
Deconvoluting clonal and cellular architecture in IDH-mutant acute myeloid leukemia.
Dietary lipids are largely deposited in skin and rapidly affect insulating properties.
Translational control of leukemic metabolism and disease progression.
Genomic landscape of multiple myeloma and its precursor conditions.
Interplay of kinetochores and catalysts drives rapid assembly of the mitotic checkpoint complex.
Glioblastoma-instructed astrocytes suppress tumour-specific T cell immunity.

Cell Rep. 2025 May 15. pii: S2211-1247(25)00481-4. [Epub ahead of print]44(5): 115710

De novo serine biosynthesis is protective in mitochondrial disease.

Christopher B Jackson, Anastasiia Marmyleva, Geoffray Monteuuis, Ryan Awadhpersad, Takayuki Mito, Nicola Zamboni, Takashi Tatsuta, Amy E Vincent, Liya Wang, Nahid A Khan, Thomas Langer, Christopher J Carroll, Anu Suomalainen.

  The importance of serine as a metabolic regulator is well known for tumors and is also gaining attention in degenerative diseases. Recent data indicate that de novo serine biosynthesis is an integral component of the metabolic response to mitochondrial disease, but the roles of the response have remained unknown. Here, we report that glucose-driven de novo serine biosynthesis maintains metabolic homeostasis in energetic stress. Pharmacological inhibition of the rate-limiting enzyme, phosphoglycerate dehydrogenase (PHGDH), aggravated mitochondrial muscle disease, suppressed oxidative phosphorylation and mitochondrial translation, altered whole-cell lipid profiles, and enhanced the mitochondrial integrated stress response (ISRmt) in vivo in skeletal muscle and in cultured cells. Our evidence indicates that de novo serine biosynthesis is essential to maintain mitochondrial respiration, redox balance, and cellular lipid homeostasis in skeletal muscle with mitochondrial dysfunction. Our evidence implies that interventions activating de novo serine synthesis may protect against mitochondrial failure in skeletal muscle.

Keywords:  CP: Metabolism; de novo serine synthesis; mitochondrial disease; mitochondrial integrated stress response; mitochondrial translation; tissue specificity; treatment

DOI:  https://doi.org/10.1016/j.celrep.2025.115710
Nat Metab. 2025 May 19.

Cell-intrinsic metabolic phenotypes identified in patients with glioblastoma, using mass spectrometry imaging of 13C-labelled glucose metabolism.

CRUK Rosetta Grand Challenge Consortium

Transcriptomic studies have attempted to classify glioblastoma (GB) into subtypes that predict survival and have different therapeutic vulnerabilities1-3. Here we identified three metabolic subtypes: glycolytic, oxidative and a mix of glycolytic and oxidative, using mass spectrometry imaging of rapidly excised tumour sections from two patients with GB who were infused with [U-13C]glucose and from spatial transcriptomic analysis of contiguous sections. The phenotypes are not correlated with microenvironmental features, including proliferation rate, immune cell infiltration and vascularization, are retained when patient-derived cells are grown in vitro or as orthotopically implanted xenografts and are robust to changes in oxygen concentration, demonstrating their cell-intrinsic nature. The spatial extent of the regions occupied by cells displaying these distinct metabolic phenotypes is large enough to be detected using clinically applicable metabolic imaging techniques. A limitation of the study is that it is based on only two patient tumours, albeit on multiple sections, and therefore represents a proof-of-concept study.

DOI: https://doi.org/10.1038/s42255-025-01293-y
Nat Commun. 2025 May 19. 16(1): 4652

Dual Ribosome Profiling reveals metabolic limitations of cancer and stromal cells in the tumor microenvironment.

Daniela Aviles-Huerta, Rossella Del Pizzo, Alexander Kowar, Ali Hyder Baig, Giuliana Palazzo, Ekaterina Stepanova, Cinthia Claudia Amaya Ramirez, Sara D'Agostino, Edoardo Ratto, Catarina Pechincha, Nora Siefert, Helena Engel, Shangce Du, Silvia Cadenas-De Miguel, Beiping Miao, Victor M Cruz-Vilchez, Karin Müller-Decker, Ilaria Elia, Chong Sun, Wilhelm Palm, Fabricio Loayza-Puch.

The tumor microenvironment (TME) influences cancer cell metabolism and survival. However, how immune and stromal cells respond to metabolic stress in vivo, and how nutrient limitations affect therapy, remains poorly understood. Here, we introduce Dual Ribosome Profiling (DualRP) to simultaneously monitor translation and ribosome stalling in multiple tumor cell populations. DualRP reveals that cancer-fibroblast interactions trigger an inflammatory program that reduces amino acid shortages during glucose starvation. In immunocompetent mice, we show that serine and glycine are essential for optimal T cell function and that their deficiency impairs T cell fitness. Importantly, immune checkpoint blockade therapy imposes amino acid restrictions specifically in T cells, demonstrating that therapies create distinct metabolic demands across TME cell types. By mapping codon-resolved ribosome stalling in a cell‑type‑specific manner, DualRP uncovers metabolic crosstalk that shapes translational programs. DualRP thus offers a powerful, innovative approach for dissecting tumor cell metabolic interplay and guiding combined metabolic-immunotherapeutic strategies.

DOI: https://doi.org/10.1038/s41467-025-59986-7
Nat Cancer. 2025 May 20.

Age-associated nicotinamide adenine dinucleotide decline drives CAR-T cell failure.

Helen Carrasco Hope, Jana de Sostoa, Pierpaolo Ginefra, Massimo Andreatta, Yi-Hsuan Chiang, Catherine Ronet, Christine Pich-Bavastro, Jesús Corria Osorio, François Kuonen, Johan Auwerx, Patrizia D'Amelio, Ping-Chih Ho, Santiago J Carmona, George Coukos, Denis Migliorini, Nicola Vannini.

Chimeric antigen receptor (CAR) T cell therapy is one of the most promising cancer treatments. However, different hurdles are limiting its application and efficacy. In this context, how aging influences CAR-T cell outcomes is largely unknown. Here we show that CAR-T cells generated from aged female mice present a mitochondrial dysfunction derived from nicotinamide adenine dinucleotide (NAD) depletion that leads to poor stem-like properties and limited functionality in vivo. Moreover, human data analysis revealed that both age and NAD metabolism determine the responsiveness to CAR-T cell therapy. Targeting NAD pathways, we were able to recover the mitochondrial fitness and functionality of CAR-T cells derived from older adults. Altogether, our study demonstrates that aging is a limiting factor to successful CAR-T cell responses. Repairing metabolic and functional obstacles derived from age, such as NAD decline, is a promising strategy to improve current and future CAR-T cell therapies.

DOI: https://doi.org/10.1038/s43018-025-00982-7
Nature. 2025 May 21.

Unravelling cysteine-deficiency-associated rapid weight loss.

Alan Varghese, Ivan Gusarov, Begoña Gamallo-Lana, Daria Dolgonos, Yatin Mankan, Ilya Shamovsky, Mydia Phan, Rebecca Jones, Maria Gomez-Jenkins, Eileen White, Rui Wang, Drew R Jones, Thales Papagiannakopoulos, Michael E Pacold, Adam C Mar, Dan R Littman, Evgeny Nudler.

Around 40% of the US population and 1 in 6 individuals worldwide have obesity, with the incidence surging globally1,2. Various dietary interventions, including carbohydrate, fat and, more recently, amino acid restriction, have been explored to combat this epidemic3-6. Here we investigated the impact of removing individual amino acids on the weight profiles of mice. We show that conditional cysteine restriction resulted in the most substantial weight loss when compared to essential amino acid restriction, amounting to 30% within 1 week, which was readily reversed. We found that cysteine deficiency activated the integrated stress response and oxidative stress response, which amplify each other, leading to the induction of GDF15 and FGF21, partly explaining the phenotype7-9. Notably, we observed lower levels of tissue coenzyme A (CoA), which has been considered to be extremely stable10, resulting in reduced mitochondrial functionality and metabolic rewiring. This results in energetically inefficient anaerobic glycolysis and defective tricarboxylic acid cycle, with sustained urinary excretion of pyruvate, orotate, citrate, α-ketoglutarate, nitrogen-rich compounds and amino acids. In summary, our investigation reveals that cysteine restriction, by depleting GSH and CoA, exerts a maximal impact on weight loss, metabolism and stress signalling compared with other amino acid restrictions. These findings suggest strategies for addressing a range of metabolic diseases and the growing obesity crisis.

DOI: https://doi.org/10.1038/s41586-025-08996-y
Science. 2025 May 22. eadr3498

Silencing mitochondrial gene expression in living cells.

Luis Daniel Cruz-Zaragoza, Drishan Dahal, Mats Koschel, Angela Boshnakovska, Aiturgan Zheenbekova, Mehmet Yilmaz, Marcel Morgenstern, Jan-Niklas Dohrke, Julian Bender, Anusha Valpadashi, Kristine A Henningfeld, Silke Oeljeklaus, Laura Sophie Kremer, Mirjam Breuer, Oliver Urbach, Sven Dennerlein, Michael Lidschreiber, Stefan Jakobs, Bettina Warscheid, Peter Rehling.

Mitochondria fulfill central functions in metabolism and energy supply. They express their own genome, which encodes key subunits of the oxidative phosphorylation system. However, central mechanisms underlying mitochondrial gene expression remain enigmatic. A lack of suitable technologies to target mitochondrial protein synthesis in cells has limited experimental access. Here, we silenced the translation of specific mitochondrial mRNAs in living human cells by delivering synthetic peptide-morpholino chimeras. This approach allowed us to perform a comprehensive temporal monitoring of cellular responses. Our study provides insights into mitochondrial translation, its integration into cellular physiology, and provides a strategy to address mitochondrial gene expression in living cells. The approach can potentially be used to analyze mechanisms and pathophysiology of mitochondrial gene expression in a range of cellular model systems.

DOI: https://doi.org/10.1126/science.adr3498
Trends Cancer. 2025 May 16. pii: S2405-8033(25)00112-8. [Epub ahead of print]

Early immune evasion in colorectal cancer: interplay between stem cells and the tumor microenvironment.

Norihiro Goto, Judith Agudo, Ömer H Yilmaz.

  Most colorectal cancers (CRCs) are characterized by a low mutational burden and an immune-cold microenvironment, limiting the efficacy of immune checkpoint blockade (ICB) therapies. While advanced tumors exhibit diverse immune evasion mechanisms, emerging evidence suggests that aspects of immune escape arise much earlier, within precancerous lesions. In this review, we discuss how early driver mutations and epigenetic alterations contribute to the establishment of an immunosuppressive microenvironment in CRC. We also highlight the dynamic crosstalk between cancer cells, stromal niche cells, and immune cells driving immune evasion and liver metastasis. A deeper understanding of these early events may guide the development of more effective preventive and therapeutic strategies for CRC.

Keywords:  colorectal cancer; immune evasion; niche cell; stem cell

DOI:  https://doi.org/10.1016/j.trecan.2025.04.016
Nature. 2025 May 21.

Clonal tracing with somatic epimutations reveals dynamics of blood ageing.

Michael Scherer, Indranil Singh, Martina Maria Braun, Chelsea Szu-Tu, Pedro Sanchez Sanchez, Dominik Lindenhofer, Niels Asger Jakobsen, Verena Körber, Michael Kardorff, Lena Nitsch, Pauline Kautz, Julia Rühle, Agostina Bianchi, Luca Cozzuto, Robert Frömel, Sergi Beneyto-Calabuig, Caleb Lareau, Ansuman T Satpathy, Renée Beekman, Lars M Steinmetz, Simon Raffel, Leif S Ludwig, Paresh Vyas, Alejo Rodriguez-Fraticelli, Lars Velten.

Current approaches used to track stem cell clones through differentiation require genetic engineering1,2 or rely on sparse somatic DNA variants3,4, which limits their wide application. Here we discover that DNA methylation of a subset of CpG sites reflects cellular differentiation, whereas another subset undergoes stochastic epimutations and can serve as digital barcodes of clonal identity. We demonstrate that targeted single-cell profiling of DNA methylation5 at single-CpG resolution can accurately extract both layers of information. To that end, we develop EPI-Clone, a method for transgene-free lineage tracing at scale. Applied to mouse and human haematopoiesis, we capture hundreds of clonal differentiation trajectories across tens of individuals and 230,358 single cells. In mouse ageing, we demonstrate that myeloid bias and low output of old haematopoietic stem cells6 are restricted to a small number of expanded clones, whereas many functionally young-like clones persist in old age. In human ageing, clones with and without known driver mutations of clonal haematopoieis7 are part of a spectrum of age-related clonal expansions that display similar lineage biases. EPI-Clone enables accurate and transgene-free single-cell lineage tracing on hematopoietic cell state landscapes at scale.

DOI: https://doi.org/10.1038/s41586-025-09041-8
Cancer Cell. 2025 May 12. pii: S1535-6108(25)00172-2. [Epub ahead of print]

Isocitrate dehydrogenase 1 primes group-3 medulloblastomas for cuproptosis.

Derek Dang, Akash Deogharkar, John McKolay, Kyle S Smith, Pooja Panwalkar, Simon Hoffman, Wentao Tian, Sunjong Ji, Ana P Azambuja, Siva Kumar Natarajan, Joanna Lum, Jill Bayliss, Katie Manzeck, Stefan R Sweha, Erin Hamanishi, Matthew Pun, Diya Patel, Sagar Rau, Olamide Animasahun, Abhinav Achreja, Martin P Ogrodzinski, Jutta Diessl, Jennifer Cotter, Debra Hawes, Fusheng Yang, Robert Doherty, Andrea T Franson, Allison R Hanaford, Charles G Eberhart, Eric H Raabe, Brent A Orr, Robert J Wechsler-Reya, Brandon Chen, Costas A Lyssiotis, Yatrik M Shah, Sophia Y Lunt, Ruma Banerjee, Alexander R Judkins, John R Prensner, Carl Koschmann, Sebastian M Waszak, Deepak Nagrath, Marcos Simoes-Costa, Paul A Northcott, Sriram Venneti.

  MYC-driven group-3 medulloblastomas (MBs) are malignant pediatric brain cancers without cures. To define actionable metabolic dependencies, we identify upregulation of dihydrolipoyl transacetylase (DLAT), the E2-subunit of pyruvate dehydrogenase complex (PDC) in a subset of group-3 MB with poor prognosis. DLAT is induced by c-MYC and targeting DLAT lowers TCA cycle metabolism and glutathione synthesis. We also note upregulation of isocitrate dehydrogenase 1 (IDH1) gene expression in group-3 MB patient tumors and suppression of IDH1 epigenetically reduces c-MYC and downstream DLAT levels in multiple c-MYC amplified cancers. DLAT is a central regulator of cuproptosis (copper-dependent cell death) induced by the copper ionophore elesclomol. DLAT expression in group-3 MB cells correlates with increased sensitivity to cuproptosis. Elesclomol is brain-penetrant and suppresses tumor growth in vivo in multiple group-3 MB animal models. Our data uncover an IDH1/c-MYC dependent vulnerability that regulates DLAT levels and can be targeted to kill group-3 MB by cuproptosis.

Keywords:  cancer metabolism; cell death; copper; cuproptosis; elesclomol; epigenetics; pediatric brain tumor; protein lipoylation

DOI:  https://doi.org/10.1016/j.ccell.2025.04.013
Cancer Metab. 2025 May 19. 13(1): 22

Lactate dehydrogenase A-coupled NAD+ regeneration is critical for acute myeloid leukemia cell survival.

Ayşegül Erdem, Séléna Kaye, Francesco Caligiore, Manuel Johanns, Fleur Leguay, Jan Jacob Schuringa, Keisuke Ito, Guido Bommer, Nick van Gastel.

   BACKGROUND: Enhanced glycolysis plays a pivotal role in fueling the aberrant proliferation, survival and therapy resistance of acute myeloid leukemia (AML) cells. Here, we aimed to elucidate the extent of glycolysis dependence in AML by focusing on the role of lactate dehydrogenase A (LDHA), a key glycolytic enzyme converting pyruvate to lactate coupled with the recycling of NAD+.
METHODS: We compared the glycolytic activity of primary AML patient samples to protein levels of metabolic enzymes involved in central carbon metabolism including glycolysis, glutaminolysis and the tricarboxylic acid cycle. To evaluate the therapeutic potential of targeting glycolysis in AML, we treated AML primary patient samples and cell lines with pharmacological inhibitors of LDHA and monitored cell viability. Glycolytic activity and mitochondrial oxygen consumption were analyzed in AML patient samples and cell lines post-LDHA inhibition. Perturbations in global metabolite levels and redox balance upon LDHA inhibition in AML cells were determined by mass spectrometry, and ROS levels were measured by flow cytometry.
RESULTS: Among metabolic enzymes, we found that LDHA protein levels had the strongest positive correlation with glycolysis in AML patient cells. Blocking LDHA activity resulted in a strong growth inhibition and cell death induction in AML cell lines and primary patient samples, while healthy hematopoietic stem and progenitor cells remained unaffected. Investigation of the underlying mechanisms showed that LDHA inhibition reduces glycolytic activity, lowers levels of glycolytic intermediates, decreases the cellular NAD+ pool, boosts OXPHOS activity and increases ROS levels. This increase in ROS levels was however not linked to the observed AML cell death. Instead, we found that LDHA is essential to maintain a correct NAD+/NADH ratio in AML cells. Continuous intracellular NAD+ supplementation via overexpression of water-forming NADH oxidase from Lactobacillus brevis in AML cells effectively increased viable cell counts and prevented cell death upon LDHA inhibition.
CONCLUSIONS: Collectively, our results demonstrate that AML cells critically depend on LDHA to maintain an adequate NAD+/NADH balance in support of their abnormal glycolytic activity and biosynthetic demands, which cannot be compensated for by other cellular NAD+ recycling systems. These findings also highlight LDHA inhibition as a promising metabolic strategy to eradicate leukemic cells.

Keywords:  Acute myeloid leukemia; Cancer metabolism; Glycolysis; Lactate dehydrogenase A; NAD+ ; Redox balance

DOI:  https://doi.org/10.1186/s40170-025-00392-4
Cancer Metab. 2025 May 19. 13(1): 23

S-adenosylmethionine metabolism shapes CD8+ T cell functions in colorectal cancer.

Xiaohua Yang, Tianzhang Kou, Hongmiao Wang, Ji Zhu, Zheng-Jiang Zhu, Yuping Cai.

  Metabolite nutrients within the tumor microenvironment shape both tumor progression and immune cell functionality. It remains elusive how the metabolic interaction between T cells and tumor cells results in different anti-cancer immunotherapeutic responses. Here, we use untargeted metabolomics to investigate the metabolic heterogeneity in patients with colorectal cancer (CRC). Our analysis reveals enhanced S-adenosylmethionine (SAM) and S-adenosylhomocysteine (SAH) metabolism in microsatellite stable (MSS) CRC, a subtype known for its resistance to immunotherapy. Functional studies reveal that SAM and SAH enhance the initial activation and effector functions of CD8+ T cells. Instead, cancer cells outcompete CD8+ T cells for SAM and SAH availability to impair T cell survival. In vivo, SAM supplementation promotes T cell proliferation and reduces exhaustion of the tumor-infiltrating CD8+ T cells, thus suppressing tumor growth in tumor-bearing mice. This study uncovers the metabolic crosstalk between T cells and tumor cells, which drives the development of tumors resistant to immunotherapy.

Keywords:  CD8+ T cell function; Metabolite nutrients; Metabolomics; Microsatellite stable colorectal cancer; S-adenosylmethionine (SAM) and S-adenosylhomocysteine (SAH) metabolism

DOI:  https://doi.org/10.1186/s40170-025-00394-2
Int Rev Cell Mol Biol. 2025 ;pii: S1937-6448(24)00089-3. [Epub ahead of print]393 95-139

Liver as a nexus of daily metabolic cross talk.

Christopher Litwin, Kevin B Koronowski.

  Over the course of a day, the circadian clock promotes a homeostatic balance between energy intake and energy expenditure by aligning metabolism with nutrient availability. In mammals, this process is driven by central clocks in the brain that control feeding behavior, the peripheral nervous system, and humoral outputs, as well as by peripheral clocks in non-brain tissues that regulate gene expression locally. Circadian organization of metabolism is critical, as circadian disruption is associated with increased risk of metabolic disease. Emerging evidence shows that circadian metabolism hinges upon inter-organ cross talk involving the liver, a metabolic hub that integrates many facets of systemic energy homeostasis. Here, we review spatiotemporal interactions, mainly metabolite exchange, signaling factors, and hormonal control, between the liver and skeletal muscle, pancreas, gut, microbiome, and adipose tissue. Modern society presents the challenge of circadian disturbances from rotating shift work to social jet lag and 24/7 food availability. Thus, it is important to better understand the mechanisms by which the clock system controls metabolic homeostasis and work toward targeted therapies.

Keywords:  Circadian clock; Circadian rhythm; Hepatic metabolism; Inter-organ cross talk; Liver; Molecular clock; Systems biology

DOI:  https://doi.org/10.1016/bs.ircmb.2024.06.001
J Biol Chem. 2025 May 19. pii: S0021-9258(25)02098-8. [Epub ahead of print] 110248

MULTIPLE, REDUNDANT CARBOXYLIC ACID TRANSPORTERS SUPPORT MITOCHONDRIAL METABOLISM IN PLASMODIUM FALCIPARUM.

Krithika Rajaram, Gabriel W Rangel, Justin T Munro, Sethu C Nair, Rubayet Elahi, Manuel Llinás, Sean T Prigge.

The mitochondrion of the deadliest human malaria parasite, Plasmodium falciparum, is an essential source of cellular acetyl-CoA during the asexual blood-stage of the parasite life cycle. Blocking mitochondrial acetyl-CoA synthesis leads to a hypoacetylated proteome and parasite death. We previously determined that mitochondrial acetyl-CoA is primarily synthesized from glucose-derived pyruvate by α-ketoacid dehydrogenases. Here, we asked if inhibiting the import of glycolytic pyruvate across the mitochondrial inner membrane would affect acetyl-CoA production and, thus, could be a potential target for antimalarial drug development. We selected the two predicted mitochondrial pyruvate carrier proteins, PfMPC1 (PF3D7_1340800) and PfMPC2 (PF3D7_1470400), for genetic knockout and isotopic metabolite tracing via HPLC-MS metabolomic analysis. Surprisingly, we observed that asexual blood-stage parasites could survive the loss of either or both PfMPCs with only minor growth defects, despite a substantial reduction in the amount of glucose-derived isotopic labelling into acetyl-CoA. Furthermore, genetic deletion of two additional mitochondrial carboxylic acid transporters - DTC (PF3D7_0823900, di/tricarboxylic acid carrier) and YHM2 (PF3D7_1223800, a putative citrate/α-ketoglutarate carrier protein) - only mildly affected blood-stage replication, even in the context of PfMPC deficiency. Although we observed no added impact on the incorporation of glucose carbon into acetyl-CoA in these quadruple knockout mutants, we noted a large decrease in glutamine-derived label in tricarboxylic acid cycle metabolites, suggesting that DTC and YHM2 both import glutamine derivatives into the mitochondrion. Altogether, our results demonstrate that redundant routes are used to fuel the blood-stage malaria parasite mitochondrion with imported carbon from two major sources - glucose and glutamine.

DOI: https://doi.org/10.1016/j.jbc.2025.110248
Nat Commun. 2025 May 23. 16(1): 4782

Modelling POLG mutations in mice unravels a critical role of POLγΒ in regulating phenotypic severity.

Samantha Corrà, Alessandro Zuppardo, Sebastian Valenzuela, Louise Jenninger, Raffaele Cerutti, Sirelin Sillamaa, Emily Hoberg, Katarina A S Johansson, Urska Rovsnik, Sara Volta, Pedro Silva-Pinheiro, Hannah Davis, Aleksandra Trifunovic, Michal Minczuk, Claes M Gustafsson, Anu Suomalainen, Massimo Zeviani, Bertil Macao, Xuefeng Zhu, Maria Falkenberg, Carlo Viscomi.

DNA polymerase γ (POLγ), responsible for mitochondrial DNA replication, consists of a catalytic POLγA subunit and two accessory POLγB subunits. Mutations in POLG, which encodes POLγA, lead to various mitochondrial diseases. We investigated the most common POLG mutations (A467T, W748S, G848S, Y955C) by characterizing human and mouse POLγ variants. Our data reveal that these mutations significantly impair POLγ activities, with mouse variants exhibiting milder defects. Cryogenic electron microscopy highlighted structural differences between human and mouse POLγ, particularly in the POLγB subunit, which may explain the higher activity of mouse POLγ and the reduced severity of mutations in mice. We further generated a panel of mouse models mirroring common human POLG mutations, providing crucial insights into the pathogenesis of POLG-related disorders and establishing robust models for therapeutic development. Our findings emphasize the importance of POLγB in modulating the severity of POLG mutations.

DOI: https://doi.org/10.1038/s41467-025-60059-y
Br J Dermatol. 2025 May 23. pii: ljaf202. [Epub ahead of print]

BTK Inhibition in Systemic Sclerosis: A Promising New B Cell Therapy.

Taiki Ando, Hirotsugu Oda.

DOI: https://doi.org/10.1093/bjd/ljaf202
Nat Commun. 2025 May 16. 16(1): 4582

Dynamic single-cell metabolomics reveals cell-cell interaction between tumor cells and macrophages.

Yi Zhang, Mingying Shi, Mingxuan Li, Shaojie Qin, Daiyu Miao, Yu Bai.

Single-cell metabolomics reveals cell heterogeneity and elucidates intracellular molecular mechanisms. However, general concentration measurement of metabolites can only provide a static delineation of metabolomics, lacking the metabolic activity information of biological pathways. Herein, we develop a universal system for dynamic metabolomics by stable isotope tracing at the single-cell level. This system comprises a high-throughput single-cell data acquisition platform and an untargeted isotope tracing data processing platform, providing an integrated workflow for dynamic metabolomics of single cells. This system enables the global activity profiling and flow analysis of interlaced metabolic networks at the single-cell level and reveals heterogeneous metabolic activities among single cells. The significance of activity profiling is underscored by a 2-deoxyglucose inhibition model, demonstrating delicate metabolic alteration within single cells which cannot reflected by concentration analysis. Significantly, the system combined with a neural network model enables the metabolomic profiling of direct co-cultured tumor cells and macrophages. This reveals intricate cell-cell interaction mechanisms within the tumor microenvironment and firstly identifies versatile polarization subtypes of tumor-associated macrophages based on their metabolic signatures, which is in line with the renewed diversity atlas of macrophages from single-cell RNA-sequencing. The developed system facilitates a comprehensive understanding single-cell metabolomics from both static and dynamic perspectives.

DOI: https://doi.org/10.1038/s41467-025-59878-w
Int Rev Cell Mol Biol. 2025 ;pii: S1937-6448(24)00159-X. [Epub ahead of print]393 73-93

Emerging interactions between circadian rhythms and extracellular vesicles.

Jacob G Smith.

  Circadian rhythms are present across species, tuning internal processes to daily changes in the environment. Driven by genetically encoded circadian clocks present throughout the body, and modulated by external inputs, the circadian system is a key player in metabolic control. However, the molecular mediators underlying coordination between cells and tissues are not well known. Extracellular vesicles (EVs) have emerged over recent years as important players in cell-cell and organ-organ communication, however the influence of circadian rhythms on EVs is not yet understood. Research into this area is still scarce, yet already offers glimpses into the potential impact of circadian rhythms on EV biology. In this review, recent discoveries that reveal, directly or indirectly, a potential role for circadian rhythms in EV abundance, properties, cargo and signalling functions are first discussed. Next, the feedback of EV signalling on circadian clocks is considered. Last, unanswered questions regarding the interaction between circadian rhythms and EVs are examined alongside potential approaches to address them. Overall, the circadian impact on EV signalling is an exciting yet understudied aspect that warrants further investigation.

Keywords:  Cell-cell communication; Circadian clocks; Circadian rhythms; Exosomes; Extracellular vesicles; Inter-organ crosstalk

DOI:  https://doi.org/10.1016/bs.ircmb.2024.11.001
J Biol Chem. 2025 May 21. pii: S0021-9258(25)02111-8. [Epub ahead of print] 110261

Hepatic glutamic-oxaloacetic transaminase (GOT2) promotes mitochondrial respiration energized at complex II and alters whole body metabolism.

Brian D Fink, Ritu Som, Adam J Rauckhorst, Eric B Taylor, Liping Yu, William I Sivitz.

  The mitochondrial enzyme, glutamic-oxaloacetic transaminase (GOT2), catalyzes the reaction between oxaloacetate and glutamate generating aspartate and alpha-ketoglutarate (α-KG). Glutamate can also be directly converted to α-KG by glutamate dehydrogenase. We investigated mitochondrial and systemic effects of an inducible liver specific-mouse GOT2 knockout (KO). We observed no differences in body mass or percent fat mass in KO mice, however, KO mice had lower fasting glucose and liver tissue contained more fat. Respiration by liver mitochondria energized at complex II by succinate + glutamate was decreased in KO compared to wildtype (WT) mice at low inner membrane potential (ΔΨ) as induced by titration with ADP. Metabolite studies by NMR showed that at low versus high ΔΨ, GOT2KO mitochondria energized by succinate + glutamate generated more oxaloacetate (a potent inhibitor of succinate dehydrogenase, SDH) and less aspartate. Respiration and mitochondrial metabolites energized by pyruvate + malate or palmitoyl-carnitine + malate did not differ between KO and WT mice. Respiration by GOT2KO mitochondria energized by glutamate + malate was decreased at all levels of ΔΨ. Pathway analysis of LC-MS profile data in liver tissue of KO versus WT mice revealed differential enrichment of the malate aspartate shuttle, TCA cycle, aspartate metabolism, glutamate metabolism, and gluconeogenesis. In summary, GOT2KO impaired potential-dependent complex II energized O2 flux likely due at least in part to oxaloacetate inhibition of SDH.

Keywords:  Mitochondria; glutamic-oxaloacetic transaminase-2; liver; mitochondrial complex II; mitochondrial inner membrane potential; oxaloacetate; respiration; succinate dehydrogenase

DOI:  https://doi.org/10.1016/j.jbc.2025.110261
Nat Metab. 2025 May 23.

A ketogenic diet halts malaria parasite growth.

Temitope W Ademolue, Lena Pernas.

DOI: https://doi.org/10.1038/s42255-025-01310-0
NPJ Aging. 2025 May 23. 11(1): 40

Metabolomics biomarkers of frailty: a longitudinal study of aging female and male mice.

Dantong Zhu, Judy Z Wu, Patrick T Griffin, Brady A Samuelson, David A Sinclair, Alice E Kane.

Frailty is an age-related geriatric syndrome. We performed a longitudinal study of aging female (n = 40) and male (n = 47) C57BL/6NIA mice, measured frailty index and derived metabolomics data from plasma. We identify age-related differentially abundant metabolites, determine frailty-related metabolites, and generate frailty features, both in the whole cohort and sex-stratified subgroups. Using the features, we perform an association study and build a metabolomics-based frailty clock. We find that frailty-related metabolites are enriched for amino acid metabolism and metabolism of cofactors and vitamins, include ergothioneine, tryptophan and alpha-ketoglutarate, and present sex dimorphism. We identify B vitamin metabolism related flavin-adenine dinucleotide and pyridoxate as female-specific frailty biomarkers, and lipid metabolism related sphingomyelins, glycerophosphoethanolamine and glycerophosphocholine as male-specific frailty biomarkers. These associations are confirmed in a validation cohort, with ergothioneine and perfluorooctanesulfonate identified as robust frailty biomarkers. Our results identify sex-specific metabolite frailty biomarkers, and shed light on potential mechanisms.

DOI: https://doi.org/10.1038/s41514-025-00237-w
Elife. 2025 May 21. pii: RP100747. [Epub ahead of print]13

Glutamine catabolism supports amino acid biosynthesis and suppresses the integrated stress response to promote photoreceptor survival.

Moloy T Goswami, Eric Weh, Shubha Subramanya, Katherine M Weh, Hima Bindu Durumutla, Heather Hager, Nicholas Miller, Sraboni Chaudhury, Anthony Andren, Peter Sajjakulnukit, Li Zhang, Cagri Besirli, Costas A Lyssiotis, Thomas J Wubben.

  Photoreceptor loss results in vision loss in many blinding diseases, and metabolic dysfunction underlies photoreceptor degeneration. So, exploiting photoreceptor metabolism is an attractive strategy to prevent vision loss. Yet, the metabolic pathways that maintain photoreceptor health remain largely unknown. Here, we investigated the dependence of photoreceptors on glutamine (Gln) catabolism. Gln is converted to glutamate via glutaminase (GLS), so mice lacking GLS in rod photoreceptors were generated to inhibit Gln catabolism. Loss of GLS produced rapid rod photoreceptor degeneration. In vivo metabolomic methodologies and metabolic supplementation identified Gln catabolism as critical for glutamate and aspartate biosynthesis. Concordant with this amino acid deprivation, the integrated stress response (ISR) was activated with protein synthesis attenuation, and inhibiting the ISR delayed photoreceptor loss. Furthermore, supplementing asparagine, which is synthesized from aspartate, delayed photoreceptor degeneration. Hence, Gln catabolism is integral to photoreceptor health, and these data reveal a novel metabolic axis in these metabolically demanding neurons.

Keywords:  cell biology; glutaminase; metabolism; mouse; neurodegeneration; neuroscience; photoreceptor

DOI:  https://doi.org/10.7554/eLife.100747
PLoS Pathog. 2025 May 22. 21(5): e1013207

Cholesterol metabolism and intrabacterial potassium homeostasis are intrinsically related in Mycobacterium tuberculosis.

Yue Chen, Berge Hagopian, Shumin Tan.

Potassium (K+) is the most abundant intracellular cation, but much remains unknown regarding how K+ homeostasis is integrated with other key bacterial biology aspects. Here, we show that K+ homeostasis disruption (CeoBC K+ uptake system deletion) impedes Mycobacterium tuberculosis (Mtb) response to, and growth in, cholesterol, a critical carbon source during infection, with K+ augmenting activity of the Mtb ATPase MceG that is vital for bacterial cholesterol import. Reciprocally, cholesterol directly binds to CeoB, modulating its function, with a residue critical for this interaction identified. Finally, cholesterol binding-deficient CeoB mutant Mtb are attenuated for growth in lipid-rich foamy macrophages and in vivo colonization. Our findings raise the concept of a role for cholesterol as a key co-factor, beyond its role as a carbon source, and illuminate how changes in intrabacterial K+ levels can act as part of the metabolic adaptation critical for bacterial survival and growth in the host.

DOI: https://doi.org/10.1371/journal.ppat.1013207
Sci Adv. 2025 May 23. 11(21): eadv2930

Image-guided targeting of mitochondrial metabolism sensitizes pediatric malignant rhabdoid tumors to low-dose radiotherapy.

Wenxi Xia, Esther Need, Carmine Schiavone, Neetu Singh, Jiemin Huang, Matthew Goff, Joseph Cave, David L Gillespie, Randy L Jensen, Mark D Pagel, Prashant Dogra, Sixiang Shi, Shreya Goel.

Tumor hypoxia leads to radioresistance and markedly worse clinical outcomes for pediatric malignant rhabdoid tumors (MRTs). Our transcriptomics and bioenergetic profiling data reveal that mitochondrial oxidative phosphorylation is a metabolic vulnerability of MRT and can be exploited to overcome consumptive hypoxia by repurposing an FDA-approved antimalarial drug, atovaquone (AVO). We then establish the utility of oxygen-enhanced-multispectral optoacoustic tomography, a label-free, ionizing radiation-free imaging modality, to visualize and quantify spatiotemporal changes in tumor hypoxia in response to AVO. We show a potent but transient increase in tumor oxygenation upon AVO treatment that results in complete elimination of tumors in all tested mice when combined with 10-gray radiotherapy, a dose several times lower than the current clinic standard. Last, we use translational mathematical modeling for systematic evaluation of dosing regimens, administration timing, and therapeutic synergy in a virtual patient cohort. Together, our work establishes a framework for safe and pediatric patient-friendly image-guided metabolic radiosensitization of rhabdoid tumors.

DOI: https://doi.org/10.1126/sciadv.adv2930
Nature. 2025 May 21.

PCSK9 drives sterol-dependent metastatic organ choice in pancreatic cancer.

Gilles Rademaker, Grace A Hernandez, Yurim Seo, Sumena Dahal, Lisa Miller-Phillips, Alexander L Li, Xianlu Laura Peng, Changfei Luan, Longhui Qiu, Maude A Liegeois, Bruce Wang, Kwun W Wen, Grace E Kim, Eric A Collisson, Stephan F Kruger, Stefan Boeck, Steffen Ormanns, Michael Guenther, Volker Heinemann, Michael Haas, Mark R Looney, Jen Jen Yeh, Roberto Zoncu, Rushika M Perera.

To grow at distant sites, metastatic cells must overcome major challenges posed by the unique cellular and metabolic composition of secondary organs1. Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease that metastasizes to the liver and lungs. Despite evidence of metabolic reprogramming away from the primary site, the key drivers that dictate the ability of PDAC cells to colonize the liver or lungs and survive there remain undefined. Here we identified PCSK9 as predictive of liver versus lung colonization by integrating metastatic tropism data of human PDAC cell lines2, in vivo metastasis modelling in mice and gene expression correlation analysis. PCSK9 negatively regulates low density lipoprotein (LDL)-cholesterol import and, accordingly, PCSK9-low PDAC cells preferentially colonize LDL-rich liver tissue. LDL-cholesterol taken up by liver-avid PCSK9-low cells supports activation of pro-growth mTORC1 activation at the lysosome, and through conversion into the signalling oxysterol, 24(S)-hydroxycholesterol, reprogrammes the microenvironment to release nutrients from neighbouring hepatocytes. Conversely, PCSK9-high, lung-avid PDAC cells rely on transcriptional upregulation of the distal cholesterol synthesis pathway to generate intermediates-7-dehydrocholesterol and 7-dehydrodesmosterol-with protective action against ferroptosis, a vulnerability in the oxygen-rich microenvironment of the lung. Increasing the amount of PCSK9 redirected liver-avid cells to the lung whereas ablating PCSK9 drove lung-avid cells to the liver, thereby establishing PCSK9 as necessary and sufficient for secondary organ site preference. Our studies reveal PCSK9-driven differential utilization of the distal cholesterol synthesis pathway as a key and potentially actionable driver of metastatic growth in PDAC.

DOI: https://doi.org/10.1038/s41586-025-09017-8
EMBO J. 2025 May 23.

Mechanistic insights into Bcs1-mediated mitochondrial membrane translocation of the folded Rieske protein.

Cristian Rosales-Hernandez, Matthias Thoms, Otto Berninghausen, Thomas Becker, Roland Beckmann.

  A functional mitochondrial respiratory chain requires coordinated and tightly regulated assembly of mitochondrial- and nuclear-encoded subunits. For bc1 complex (complex III) assembly, the iron-sulfur protein Rip1 must first be imported into the mitochondrial matrix to fold and acquire its 2Fe-2S cluster, then translocated and inserted into the inner mitochondrial membrane (IM). This translocation of folded Rip1 is accomplished by Bcs1, an unusual heptameric AAA ATPase that couples ATP hydrolysis to translocation. However, the molecular and mechanistic details of Bcs1-mediated Rip1 translocation have remained elusive. Here, we provide structural and biochemical evidence on how Bcs1 alternates between conformational states to translocate Rip1 across the IM. Using cryo-electron microscopy (cryo-EM), we identified substrate-bound pre-translocation and pre-release states, revealing how electrostatic interactions promote Rip1 binding to Bcs1. An ATP-induced conformational switch of the Bcs1 heptamer facilitates Rip1 translocation between two distinct aqueous vestibules-one exposed to the matrix, the other to the intermembrane space-in an airlock-like mechanism. This would minimize disruption of the IM permeability barrier, which could otherwise lead to proton leakage and compromised mitochondrial energy conversion.

Keywords:  Bcs1; Cryo-EM; Folded Protein Translocation; Mitochondria; Rieske

DOI:  https://doi.org/10.1038/s44318-025-00459-4
Trends Cancer. 2025 May 19. pii: S2405-8033(25)00125-6. [Epub ahead of print]

Novel metabolic routes to cancer immune evasion.

Ayoub Jaa, Aitziber Buque.

  The tumor microenvironment (TME) comprises heterogeneous cell types that closely interact with each other. Crosstalk among the TME components determines antitumor immune responses and their sensitivity to therapies such as immunotherapy. Recent studies published in Cancer Cell by Tang et al. and Zhu et al. identify two novel metabolic adaptations that tumors use to facilitate immune evasion. These targetable mechanisms suggest new avenues to improve antitumor immune responses.

Keywords:  amino acids; arginine; breast cancer; immunology; metabolism; tryptophan; tumor microenvironment

DOI:  https://doi.org/10.1016/j.trecan.2025.05.002
Res Sq. 2025 May 08. pii: rs.3.rs-6401505. [Epub ahead of print]

Paired mutation calling and spatial transcriptomics identify cellular neighbourhoods dictating the neoplastic outcome of colitis.

Douglas Winton, Elisa Moutin, Linus Chang, Giada Giavara, Shenay Mehmed, Mathilde Colombé, Filipe Lourenco, Maria-Nefeli Skoufou-Papoutsaki, Richard Kemp, Philippe Gascard, Thea Tlsty, David Tourigny.

In the progression from Inflammatory Bowel Disease to associated cancer, the clonal mutational landscape shifts from selection of mutations in inflammatory genes to selection of cancer-driver mutations1-4. How prevalence and expansion of either type of mutated clones could be impacted by the cellular environment in which they arise, and how this affects the neoplastic outcome of colitis is unknown. Here, we combine in vivo lineage tracing, in-silico modelling, mutational profiling and spatial transcriptomics in a mouse model of colitis-associated tumorigenesis to capture clone fates associated with chronic inflammation. We identify epithelial- and immune-enriched neighbourhoods and propose a model in which establishment of a reparative tissue environment facilitates tumours initiation by promoting the selection and expansion of pro-oncogenic clones, reducing the span of inflammation-resistant neighbourhoods containing non-oncogenic clones.

DOI: https://doi.org/10.21203/rs.3.rs-6401505/v1
Nat Immunol. 2025 May 21.

Cholinergic regulation of thymocyte negative selection.

Shaofeng Liu, Chunxing Zheng, Robert Nechanitzky, Ping Luo, Parameswaran Ramachandran, Dat Nguyen, Andrew J Elia, Soode Moghadas Jafari, Rhoda Law, Bryan E Snow, Andrew C Wakeham, Thorsten Berger, Hui Chen, Kyle T Gill, Ryan Mcwilliam, Jerome Fortin, Nastaran Fazel Modares, Mary E Saunders, Kiichi Murakami, Yangmin Qiu, Zhiwei You, Mahmood Mohtashami, Hai Qi, Pamela S Ohashi, Juan Carlos Zúñiga-Pflücker, Tak W Mak.

The immune and nervous systems use a common chemical language for communication, namely, the cholinergic signaling involving acetylcholine (ACh) and its receptors (AChRs). Whether and how this language also regulates the development of the immune system is poorly understood. Here, we show that mouse CD4+CD8+ double-positive thymocytes express high levels of α9 nicotinic AChR (nAChR) and that this receptor controls thymic negative selection. α9 nAChR-deficient mice show an altered T cell receptor (TCR) repertoire and reduced CD4+ and CD8+ T cells in a mixed bone marrow chimera setting. α9 nAChR-mediated signaling regulates TCR strength and thymocyte survival. Thymic tuft cells, B cells and some T cells express choline acetyltransferase and are potential ACh sources, with ACh derived from T cells having the most important role. Furthermore, α9 nAChR deficiency during thymocyte development contributes to the altered development of autoimmune diseases in mice. Our results thus reveal a mechanism controlling immune cell development that involves cholinergic signaling.

DOI: https://doi.org/10.1038/s41590-025-02152-4
Nat Chem. 2025 May 22.

Abiotic lipid metabolism enables membrane plasticity in artificial cells.

Alessandro Fracassi, Andrés Seoane, Roberto J Brea, Hong-Guen Lee, Alexander Harjung, Neal K Devaraj.

The plasticity of living cell membranes relies on complex metabolic networks fueled by cellular energy. These metabolic processes exert direct control over membrane properties such as lipid composition and morphological plasticity, which are essential for cellular functions. Despite notable progress in the development of artificial systems mimicking natural membranes, the realization of synthetic membranes capable of sustaining metabolic cycles remains a challenge. Here we present an abiotic phospholipid metabolic network that generates and maintains dynamic artificial cell membranes. Chemical coupling agents drive the in situ synthesis of transiently stable non-canonical phospholipids, leading to the formation and maintenance of phospholipid membranes. We find that phospholipid metabolic cycles can drive lipid self-selection, favouring the enrichment of specific lipid species. Moreover, we demonstrate that controlling lipid metabolism can induce reversible membrane phase transitions, facilitating lipid mixing between distinct populations of artificial membranes. Our work demonstrates that a simple lipid metabolic network can drive dynamic behaviour in artificial membranes, offering insights into mechanisms for engineering functional synthetic compartments.

DOI: https://doi.org/10.1038/s41557-025-01829-5
Cell Rep. 2025 May 21. pii: S2211-1247(25)00518-2. [Epub ahead of print]44(6): 115747

A lncRNA-mediated metabolic rewiring of cell senescence.

Elena Grossi, Francesco P Marchese, Jovanna González, Enrique Goñi, José Miguel Fernández-Justel, Alicia Amadoz, Nicolás Herranz, Leonor Puchades-Carrasco, Marta Montes, Maite Huarte.

  Despite not proliferating, senescent cells remain metabolically active to maintain the senescence program. However, the mechanisms behind this metabolic reprogramming are not well understood. We identify senescence-induced long noncoding RNA (sin-lncRNA), a previously uncharacterized long noncoding RNA (lncRNA), a key player in this response. While strongly activated in senescence by C/EBPβ, sin-lncRNA loss reinforces the senescence program by altering oxidative phosphorylation and rewiring mitochondrial metabolism. By interacting with dihydrolipoamide S-succinyltransferase (DLST), it facilitates its mitochondrial localization. Depletion of sin-lncRNA causes DLST nuclear translocation, leading to transcriptional changes in oxidative phosphorylation (OXPHOS) genes. While not expressed in highly proliferative cancer cells, it is strongly induced upon cisplatin-induced senescence. Depletion of sin-lncRNA in ovarian cancer cells reduces oxygen consumption and increases extracellular acidification, sensitizing cells to cisplatin treatment. Altogether, these results indicate that sin-lncRNA is specifically induced in senescence to maintain metabolic homeostasis, unveiling an RNA-dependent metabolic rewiring specific to senescent cells.

Keywords:  CP: Metabolism; CP: Molecular biology; RNA-binding proteins; lncRNA; metabolism; senescence; therapy resistance

DOI:  https://doi.org/10.1016/j.celrep.2025.115747
J Cell Biol. 2025 Jul 07. pii: e202409039. [Epub ahead of print]224(7):

Pex30-dependent membrane contact sites maintain ER lipid homeostasis.

Joana Veríssimo Ferreira, Yara Ahmed, Tiaan Heunis, Aamna Jain, Errin Johnson, Markus Räschle, Robert Ernst, Stefano Vanni, Pedro Carvalho.

In eukaryotic cells, communication between organelles and the coordination of their activities depend on membrane contact sites (MCS). How MCS are regulated under the dynamic cellular environment remains poorly understood. Here, we investigate how Pex30, a membrane protein localized to the endoplasmic reticulum (ER), regulates multiple MCS in budding yeast. We show that Pex30 is critical for the integrity of ER MCS with peroxisomes and vacuoles. This requires the dysferlin (DysF) domain on the Pex30 cytosolic tail. This domain binds to phosphatidic acid (PA) both in vitro and in silico, and it is important for normal PA metabolism in vivo. The DysF domain is evolutionarily conserved and may play a general role in PA homeostasis across eukaryotes. We further show that the ER-vacuole MCS requires a Pex30 C-terminal domain of unknown function and that its activity is controlled by phosphorylation in response to metabolic cues. These findings provide new insights into the dynamic nature of MCS and their coordination with cellular metabolism.

DOI: https://doi.org/10.1083/jcb.202409039
Cell Stem Cell. 2025 May 21. pii: S1934-5909(25)00179-1. [Epub ahead of print]

Deconvoluting clonal and cellular architecture in IDH-mutant acute myeloid leukemia.

Maria Sirenko, Soobeom Lee, Zhengxi Sun, Ronan Chaligne, Sanam Loghavi, Georgios Asimomitis, Charlotte K Brierley, Elsa Bernard, Sheng F Cai, Robert M Myers, Bettina Nadorp, Junya Sango, Morgan Lallo, Max F Levine, Dylan Domenico, Juan E Arango Ossa, Juan S Medina-Martinez, Kamal Menghrajani, Audrey Lasry, Alice S Mims, Helee Desai, Andrea Laganson, Chris Famulare, Minal Patel, Gerard Lozanski, Kelly L Bolton, Aaron D Viny, Mikhail Roshal, Ross L Levine, Eirini P Papapetrou, Eytan M Stein, Dan A Landau, Ann-Kathrin Eisfeld, Iannis Aifantis, Elli Papaemmanuil.

  Isocitrate dehydrogenase 1/2 (IDH) mutations are early initiating events in acute myeloid leukemia (AML). The complex clonal architecture and cellular heterogeneity in IDH-mutant AML underlies the heterogeneous clinical presentation and outcomes. Integrating single-cell genotyping and transcriptomics, we demonstrate a stem-like and inflammatory phenotype of IDH-mutant AML and identify clone-specific programs associated with NPM1, NRAS, and SRSF2 co-mutations. Furthermore, these clones had distinct responses to treatment with combination IDH inhibitors and chemotherapy, including elimination, reconstitution of myeloid differentiation, or retention within progenitor populations. At relapse after IDH inhibitor monotherapy, we identify upregulated stemness, inflammation, mitochondrial metabolism, and anti-apoptotic factors, as well as downregulated major histocompatibility complex (MHC) class II antigen presentation. At the pre-leukemic stage, we observe upregulation of IDH2-associated pathways, including inflammation. We deliver a detailed phenotyping of IDH-mutant AML and a framework for dissecting contributions of recurrently mutated genes in AML at diagnosis and following therapy, with implications for precision medicine.

Keywords:  IDH inhibitors; IDH1/2 mutations; acute myeloid leukemia; cellular hierarchy; clonal architecture; clonal evolution; relapse; single-cell transcriptomics; targeted therapy; treatment resistance

DOI:  https://doi.org/10.1016/j.stem.2025.04.012
Nat Commun. 2025 May 16. 16(1): 4570

Dietary lipids are largely deposited in skin and rapidly affect insulating properties.

Nick Riley, Ildiko Kasza, Isabel D K Hermsmeyer, Michaela E Trautman, Greg Barrett-Wilt, Raghav Jain, Judith A Simcox, Chi-Liang E Yen, Ormond A MacDougald, Dudley W Lamming, Caroline M Alexander.

Skin is a regulatory hub for energy expenditure and metabolism, and alteration of lipid metabolism enzymes in skin impacts thermogenesis and obesogenesis in mice. Here we show that thermal properties of skin are highly reactive to diet: within three days, a high fat diet reduces heat transfer through skin. In contrast, a dietary manipulation that prevents obesity accelerates energy loss through skins. We find that skin is the largest target for dietary fat delivery, and that dietary triglyceride is assimilated by epidermis and dermal white adipose tissue, persisting for weeks after feeding. With caloric-restriction, mouse skins thin and assimilation of circulating lipids decreases. Using multi-modal lipid profiling, keratinocytes and sebocytes are implicated in lipid changes, which correlate with thermal function. We propose that skin should be routinely included in physiological studies of lipid metabolism, given the size of the skin lipid reservoir and its adaptable functionality.

DOI: https://doi.org/10.1038/s41467-025-59869-x
Trends Cell Biol. 2025 May 22. pii: S0962-8924(25)00108-4. [Epub ahead of print]

Translational control of leukemic metabolism and disease progression.

François E Mercier, Victor Gife, Raquel Aloyz, Laura Hulea.

  Acute myeloid leukemia (AML) is an aggressive hematological cancer with a 70% five-year mortality rate. Relapse occurs in approximately half of adults treated with intensive chemotherapy, while responses to targeted therapies are short-lasting. Frequent mutations in signaling pathways, such as FLT3 tyrosine kinase and RAS, lead to dysregulated mammalian target of rapamycin complex 1 (mTORC1)and mitogen-activated protein kinase (MAPK) signaling, increased protein synthesis, enhanced mitochondrial fitness, and metabolic adaptations that drive leukemic cell proliferation and survival. Here, emerging evidence supporting the unique role of eukaryotic initiation factor 4F as a key driver of the expression of proteins regulating leukemic cell metabolism and survival and the potential therapeutic benefit of targeting this pathway pharmacologically in AML are discussed.

Keywords:  BCL2; FLT3; eIF4F; leukemic stem cells; mTORC1; metabolism

DOI:  https://doi.org/10.1016/j.tcb.2025.04.006
Nat Genet. 2025 May 21.

Genomic landscape of multiple myeloma and its precursor conditions.

Jean-Baptiste Alberge, Ankit K Dutta, Andrea Poletti, Tim H H Coorens, Elizabeth D Lightbody, Rosa Toenges, Xavi Loinaz, Sofia Wallin, Andrew Dunford, Oliver Priebe, Johnathan Dagan, Cody J Boehner, Erica Horowitz, Nang K Su, Hadley Barr, Laura Hevenor, Katherine Towle, Rashmika Beesam, Jenna B Beckwith, Jacqueline Perry, David M Cordas Dos Santos, Luca Bertamini, Patricia T Greipp, Kirsten Kübler, Peter F Arndt, Carolina Terragna, Elena Zamagni, Eileen M Boyle, Kwee Yong, Gareth Morgan, Brian A Walker, Meletios Athanasios Dimopoulos, Efstathios Kastritis, Julian Hess, Romanos Sklavenitis-Pistofidis, Chip Stewart, Gad Getz, Irene M Ghobrial.

Reliable strategies to capture patients at risk of progression from precursor stages of multiple myeloma (MM) to overt disease are still missing. We assembled a comprehensive collection of MM genomic data comprising 1,030 patients (218 with precursor conditions) that we used to identify recurrent coding and non-coding candidate drivers as well as significant hotspots of structural variation. We used those drivers to define and validate a simple 'MM-like' score, which we could use to place patients' tumors on a gradual axis of progression toward active disease. Our MM precursor genomic map provides insights into the time of initiation and cell-of-origin of the disease, order of acquisition of genomic alterations and mutational processes found across the stages of transformation. Taken together, we highlight here the potential of genome sequencing to better inform risk assessment and monitoring of MM precursor conditions.

DOI: https://doi.org/10.1038/s41588-025-02196-0
Nat Commun. 2025 May 24. 16(1): 4823

Interplay of kinetochores and catalysts drives rapid assembly of the mitotic checkpoint complex.

Suruchi Sethi, Sabrina Ghetti, Verena Cmentowski, Teresa Benedetta Guerriere, Patricia Stege, Valentina Piano, Andrea Musacchio.

The spindle assembly checkpoint (SAC) ensures mitotic exit occurs only after sister chromatid biorientation, but how this coordination is mechanistically achieved remains unclear. Kinetochores, the megadalton complexes linking chromosomes to spindle microtubules, contribute to SAC signaling. However, whether they act solely as docking platforms or actively promote the co-orientation of SAC catalysts such as MAD1:MAD2 and BUB1:BUB3 remains unresolved. Here, we reconstitute kinetochores and SAC signaling in vitro to address this question. We engineer recombinant kinetochore particles that recruit core SAC components and trigger checkpoint signaling upon Rapamycin induction, and test their function using a panel of targeted mutants. At approximately physiological concentrations of SAC proteins, kinetochores are essential for efficient mitotic checkpoint complex (MCC) assembly, the key effector of SAC signaling. Our results suggest that kinetochores serve not only as structural hubs but also as catalytic platforms that concentrate and spatially organize SAC components to accelerate MCC formation and ensure timely checkpoint activation.

DOI: https://doi.org/10.1038/s41467-025-59970-1
Nature. 2025 May 21.

Glioblastoma-instructed astrocytes suppress tumour-specific T cell immunity.

Camilo Faust Akl, Brian M Andersen, Zhaorong Li, Federico Giovannoni, Martin Diebold, Liliana M Sanmarco, Michael Kilian, Luca Fehrenbacher, Florian Pernin, Joseph M Rone, Hong-Gyun Lee, Gavin Piester, Jessica E Kenison, Joon-Hyuk Lee, Tomer Illouz, Carolina M Polonio, Léna Srun, Jazmin Martinez, Elizabeth N Chung, Anton Schüle, Agustin Plasencia, Lucinda Li, Kylynne Ferrara, Mercedes Lewandrowski, Craig A Strathdee, Lorena Lerner, Christophe Quéva, Iain C Clark, Benjamin Deneen, Judy Lieberman, David H Sherr, Jack P Antel, Michael A Wheeler, Keith L Ligon, E Antonio Chiocca, Marco Prinz, David A Reardon, Francisco J Quintana.

Glioblastoma is the most common and aggressive primary brain cancer and shows minimal response to therapies. The immunosuppressive tumour microenvironment in glioblastoma contributes to the limited therapeutic response. Astrocytes are abundant in the central nervous system and have important immunoregulatory roles. However, little is known about their role in the immune response to glioblastoma1. Here we used single-cell and bulk RNA sequencing of clinical glioblastoma samples and samples from preclinical models, multiplexed immunofluorescence, in vivo CRISPR-based cell-specific genetic perturbations and in vitro mouse and human experimental systems to address this gap in knowledge. We identified an astrocyte subset that limits tumour immunity by inducing T cell apoptosis through the death receptor ligand TRAIL. Moreover, we identified that IL-11 produced by tumour cells is a driver of STAT3-dependent TRAIL expression in astrocytes. Astrocyte signalling through STAT3 and TRAIL expression were associated with a shorter time to recurrence and overall decreased survival in patients with glioblastoma. Genetic inactivation of the IL-11 receptor or TRAIL in astrocytes extended survival in mouse models of glioblastoma and enhanced T cell and macrophage responses. Finally, treatment with an oncolytic HSV-1 virus engineered to express a TRAIL-blocking single-chain antibody in the tumour microenvironment extended survival and enhanced tumour-specific immunity in preclinical models of glioblastoma. In summary, we establish that IL-11-STAT3-driven astrocytes suppress glioblastoma-specific protective immunity by inducing TRAIL-dependent T cell apoptosis, and engineered therapeutic viruses can be used to target this mechanism of astrocyte-driven tumour immunoevasion.

DOI: https://doi.org/10.1038/s41586-025-08997-x