bims-camemi 2025-04-06 papers

bims-camemi

Biomed News

on Mitochondrial metabolism in cancer

Issue of 2025–04–06
thirty-one papers selected by
Christian Frezza, Universität zu Köln

Retromer promotes the lysosomal turnover of mtDNA.
Gang of 3: How the Krebs cycle-linked metabolites itaconate, succinate, and fumarate regulate macrophages and inflammation.
The emerging role of protein L-lactylation in metabolic regulation and cell signalling.
Microenvironmental arginine restriction sensitizes pancreatic cancers to polyunsaturated fatty acids by suppression of lipid synthesis.
Uridine-sensitized screening identifies genes and metabolic regulators of nucleotide synthesis.
Mitochondrial and peroxisomal fission in cortical neurogenesis.
Cancer-cell-derived cGAMP limits the activity of tumor-associated CD8+ T cells.
Shared requirement for MYC upstream super-enhancer region in tissue regeneration and cancer.
Gut Microbiome-Produced Bile Acid Metabolite Lengthens Circadian Period in Host Intestinal Cells.
Detection of liver mitochondrial oxaloacetate by NMR spectroscopy and membrane potential-dependent accumulation.
Neural stimulation suppresses mTORC1-mediated protein synthesis in skeletal muscle.
Invigorating discovery and clinical translation of aging biomarkers.
Connections across the Cancer Continuum.
Essential Biology of Lipid Droplets.
Mitochondrial fission regulates midgut muscle assembly and tick feeding capacity.
Understanding mitochondrial protein import: a revised model of the presequence translocase.
Tumor cell heterogeneity drives spatial organization of the intratumoral immune response.
ABHD11 inhibition drives sterol metabolism to modulate T cell effector function and alleviate autoimmunity.
Diet-induced obesity dampens the temporal oscillation of hepatic mitochondrial lipids.
Integrating Metabolomics and Transcriptomics to Characterize Differential Functional Capabilities of Kidney Proximal Tubule Cell Subtypes.
Gut metagenomes reveal interactions between dietary restriction, ageing and the microbiome in genetically diverse mice.
Mitochondrial heat production: the elephant in the lab….
Resilience and vulnerabilities of tumor cells under purine shortage stress.
Low extracellular pH protects cancer cells from ammonia toxicity.
The best foods for healthy ageing - and the worst.
Protein succinylome analysis identifies citrate synthase as a central regulator of osteoclast metabolic activity.
Translation dysregulation in cancer as a source for targetable antigens.
Quantitative characterization of tissue states using multiomics and ecological spatial analysis.
Energy-ordered resource stratification as an agnostic signature of life.
SIRT5-mediated desuccinylation of PPA2 enhances HIF-1alpha-dependent adaptation to hypoxic stress and colorectal cancer metastasis.
The Hallmarks of Cancer as Eco-Evolutionary Processes.

Sci Adv. 2025 Apr 04. 11(14): eadr6415

Retromer promotes the lysosomal turnover of mtDNA.

Parisa Kakanj, Mari Bonse, Arya Kshirsagar, Aylin Gökmen, Felix Gaedke, Ayesha Sen, Belén Mollá, Elisabeth Vogelsang, Astrid Schauss, Andreas Wodarz, David Pla-Martín.

Mitochondrial DNA (mtDNA) is exposed to multiple insults produced by normal cellular function. Upon mtDNA replication stress, the mitochondrial genome transfers to endosomes for degradation. Using proximity biotinylation, we found that mtDNA stress leads to the rewiring of the mitochondrial proximity proteome, increasing mitochondria's association with lysosomal and vesicle-related proteins. Among these, the retromer complex, particularly VPS35, plays a pivotal role by extracting mitochondrial components. The retromer promotes the formation of mitochondrial-derived vesicles shuttled to lysosomes. The mtDNA, however, directly shuttles to a recycling organelle in a BAX-dependent manner. Moreover, using a Drosophila model carrying a long deletion on the mtDNA (ΔmtDNA), we found that ΔmtDNA activates a specific transcriptome profile to counteract mitochondrial damage. Here, Vps35 expression restores mtDNA homoplasmy and alleviates associated defects. Hence, we demonstrate the existence of a previously unknown quality control mechanism for the mitochondrial matrix and the essential role of lysosomes in mtDNA turnover to relieve mtDNA damage.

DOI: https://doi.org/10.1126/sciadv.adr6415
Cell Metab. 2025 Mar 24. pii: S1550-4131(25)00107-X. [Epub ahead of print]

Gang of 3: How the Krebs cycle-linked metabolites itaconate, succinate, and fumarate regulate macrophages and inflammation.

Eva M Pålsson-McDermott, Luke A J O'Neill.

  The reprogramming of metabolic pathways and processes in immune cells has emerged as an important aspect of the immune response. Metabolic intermediates accumulate as a result of metabolic adaptations and mediate functions outside of metabolism in the regulation of immunity and inflammation. In macrophages, there has been a major focus on 3 metabolites linked to the Krebs cycle, itaconate, succinate, and fumarate, which have been shown to regulate multiple processes. Here, we discuss recent progress on these 3 metabolites with regard to their effect on macrophages in host defense and inflammatory diseases. We also consider the therapeutic opportunities presented from the mimicry of these metabolites or by targeting the enzymes that make or metabolize them in order to leverage the body's own anti-inflammatory response.

Keywords:  ETC; Krebs cycle; immunometabolism; immunometabolites; inflammation; therapeutic targets

DOI:  https://doi.org/10.1016/j.cmet.2025.03.004
Nat Metab. 2025 Apr 02.

The emerging role of protein L-lactylation in metabolic regulation and cell signalling.

Haowen Ren, Yuwei Tang, Di Zhang.

L-Lactate has emerged as a crucial metabolic intermediate, moving beyond its traditional view as a mere waste product. The recent discovery of L-lactate-driven protein lactylation as a post-translational modification has unveiled a pathway that highlights the role of lactate in cellular signalling. In this Perspective, we explore the enzymatic and metabolic mechanisms underlying protein lactylation and its impacts on both histone and non-histone proteins in the contexts of physiology and diseases. We discuss growing evidence suggesting that this modification regulates a wide range of cellular functions and is involved in various physiological and pathological processes, such as cell-fate determination, development, cardiovascular diseases, cancer and autoimmune disorders. We propose that protein lactylation acts as a pivotal mechanism, integrating metabolic and signalling pathways to enable cellular adaptation, and highlight its potential as a therapeutic target in various diseases.

DOI: https://doi.org/10.1038/s42255-025-01259-0
bioRxiv. 2025 Mar 13. pii: 2025.03.10.642426. [Epub ahead of print]

Microenvironmental arginine restriction sensitizes pancreatic cancers to polyunsaturated fatty acids by suppression of lipid synthesis.

Patrick B Jonker, Mumina Sadullozoda, Guillaume Cognet, Juan J Apiz Saab, Kelly H Sokol, Violet X Wu, Deepa Kumari, Colin Sheehan, Mete E Ozgurses, Darby Agovino, Grace Croley, Smit A Patel, Althea Bock-Hughes, Kay F Macleod, Hardik Shah, Jonathan L Coloff, Evan C Lien, Alexander Muir.

Nutrient limitation is a characteristic feature of poorly perfused tumors. In contrast to well-perfused tissues, nutrient deficits in tumors perturb cellular metabolic activity, which imposes metabolic constraints on cancer cells. The metabolic constraints created by the tumor microenvironment can lead to vulnerabilities in cancers. Identifying the metabolic constraints of the tumor microenvironment and the vulnerabilities that arise in cancers can provide new insight into tumor biology and identify promising antineoplastic targets. To identify how the microenvironment constrains the metabolism of pancreatic tumors, we challenged pancreatic cancer cells with microenvironmental nutrient levels and analyzed changes in cell metabolism. We found that arginine limitation in pancreatic tumors perturbs saturated and monounsaturated fatty acid synthesis by suppressing the lipogenic transcription factor SREBP1. Synthesis of these fatty acids is critical for maintaining a balance of saturated, monounsaturated, and polyunsaturated fatty acids in cellular membranes. As a consequence of microenvironmental constraints on fatty acid synthesis, pancreatic cancer cells and tumors are unable to maintain lipid homeostasis when exposed to polyunsaturated fatty acids, leading to cell death by ferroptosis. In sum, arginine restriction in the tumor microenvironment constrains lipid metabolism in pancreatic cancers, which renders these tumors vulnerable to polyunsaturated-enriched fat sources.

DOI: https://doi.org/10.1101/2025.03.10.642426
bioRxiv. 2025 Mar 13. pii: 2025.03.11.642569. [Epub ahead of print]

Uridine-sensitized screening identifies genes and metabolic regulators of nucleotide synthesis.

Abigail Strefeler, Zakery N Baker, Sylvain Chollet, Rachel M Guerra, Julijana Ivanisevic, Hector Gallart-Ayala, David J Pagliarini, Alexis A Jourdain.

Nucleotides are essential for nucleic acid synthesis, signaling, and metabolism, and can be synthesized de novo or through salvage. Rapidly proliferating cells require large amounts of nucleotides, making nucleotide metabolism a widely exploited target for cancer therapy. However, resistance frequently emerges, highlighting the need for a deeper understanding of nucleotide regulation. Here, we harness uridine salvage and CRISPR-Cas9 screening to reveal regulators of de novo pyrimidine synthesis. We identify several factors and report that pyrimidine synthesis can continue in the absence of coenzyme Q (CoQ), the canonical electron acceptor in de novo synthesis. We further investigate NUDT5 and report its conserved interaction with PPAT, the rate-limiting enzyme in purine synthesis. We show that in the absence of NUDT5, hyperactive purine synthesis siphons the phosphoribosyl pyrophosphate (PRPP) pool at the expense of pyrimidine synthesis, promoting resistance to chemotherapy. Intriguingly, the interaction between NUDT5 and PPAT appears to be disrupted by PRPP, highlighting intricate allosteric regulation. Our findings reveal a fundamental mechanism for maintaining nucleotide balance and position NUDT5 as a potential biomarker for predicting resistance to chemotherapy.

DOI: https://doi.org/10.1101/2025.03.11.642569
Int J Biochem Cell Biol. 2025 Mar 28. pii: S1357-2725(25)00041-X. [Epub ahead of print]182-183 106774

Mitochondrial and peroxisomal fission in cortical neurogenesis.

Gabriella L Robertson, Caroline Bodnya, Vivian Gama.

  The human brain is unique in its cellular diversity, intricate cytoarchitecture, function, and complex metabolic and bioenergetic demands, for which mitochondria and peroxisomes are essential. Mitochondria are multifunctional organelles that coordinate various signaling pathways central to neurogenesis. The dynamic morphological changes of the mitochondrial network have been linked to the regulation of bioenergetic and metabolic states. Specific protein machinery is dedicated to mitochondrial fission and fusion, allowing organelle distribution during cell division, organelle repair, and adaptation to environmental stimuli (excellent reviews have been published on these topics [Kondadi and Reichert, 2024; Giacomello et al., 2020; Tilokani et al., 2018; Kraus et al., 2021; Navaratnarajah et al., 2021]). In parallel, peroxisomes contain over 50 different enzymes which regulate metabolic functions that are critical for neurogenesis (Berger et al., 2016; Hulshagen et al., 2008). Peroxisomes share many of the components of their fission machinery with the mitochondria and undergo fission to help meet metabolic demands in response to environmental stimuli (Schrader et al., 2016). This review focuses primarily on the machinery involved in mitochondrial and peroxisomal fission. Mitochondrial fission has been identified as a critical determinant of cell fate decisions (Iwata et al., 2023, 2020; Khacho et al., 2016; King et al., 2021; Prigione and Adjaye, 2010; Vantaggiato et al., 2019; Kraus et al., 2021). The connection between alterations in peroxisomal fission and metabolic changes associated with cellular differentiation remains less clear. Here, we provide an overview of the functional and regulatory aspects of the mitochondrial and peroxisomal fission machinery and provide insight into the current mechanistic understanding by which mitochondrial and peroxisomal fission influence neurogenesis.

Keywords:  Brain; DRP1; Metabolism; Mitochondria; Neurons; Peroxisomes

DOI:  https://doi.org/10.1016/j.biocel.2025.106774
Cell Rep. 2025 Apr 02. pii: S2211-1247(25)00281-5. [Epub ahead of print]44(4): 115510

Cancer-cell-derived cGAMP limits the activity of tumor-associated CD8+ T cells.

Michael Herbst, Hakan Köksal, Silvan Brunn, Dominik Zanetti, Ioana Domocos, Viola De Stefani, Marco Gatti, Francesca Vivalda, Paulo Pereira, Marc Nater, Virginia Cecconi, Alessandro A Sartori, Maries van den Broek.

  Using a mouse tumor model with inducible cancer-cell-intrinsic cyclic GMP-AMP (cGAMP) synthase (cGAS) expression, we show that cancer-cell-derived cGAMP is essential and sufficient to trigger a sustained type I interferon response within the tumor microenvironment. This leads to improved CD8+ T cell-dependent tumor restriction. However, cGAMP limits the proliferation, survival, and function of stimulator of IFN genes (STING)-expressing, but not of STING-deficient, CD8+ T cells. In vivo, STING deficiency in CD8+ T cells enhances tumor restriction. Consequently, cancer-cell-derived cGAMP both drives and limits the anti-tumor potential of CD8+ T cells. Mechanistically, T cell-intrinsic STING is associated with pro-apoptotic and antiproliferative gene signatures. Our findings suggest that STING signaling acts as a checkpoint in CD8+ T cells that balances tumor immunity.

Keywords:  CD8(+); CP: Cancer; CP: Immunology; STING; T cells; cGAMP; cGAS; cancer; immunity; tumor microenvironment

DOI:  https://doi.org/10.1016/j.celrep.2025.115510
Life Sci Alliance. 2025 Jun;pii: e202403090. [Epub ahead of print]8(6):

Shared requirement for MYC upstream super-enhancer region in tissue regeneration and cancer.

Inderpreet Sur, Wenshuo Zhao, Jilin Zhang, Margareta Kling Pilström, Anna T Webb, Huaitao Cheng, Ari Ristimäki, Pekka Katajisto, Martin Enge, Helena Rannikmae, Marc de la Roche, Jussi Taipale.

Cancer has been characterized as a wound that does not heal. Malignant cells are morphologically distinct from normal proliferating cells but have extensive similarities to tissues undergoing wound healing and/or regeneration. The mechanistic basis of this similarity has, however, remained enigmatic. Here, we show that the genomic region upstream of Myc, which carries more cancer susceptibility in humans than any other genomic region, is required for intestinal regeneration after radiation damage. Failure to regenerate is associated with inefficient Ly6a/Sca1+ stem/progenitor cell mobilization, and almost complete failure to re-establish Lgr5+ cell compartment in the intestinal crypts. The Myc upstream region is also critical for growth of adult intestinal cells in 3D organoid culture. We show that culture conditions recapitulating most aspects of adult normal tissue architecture still reprogram normal cells to proliferate using a mechanism similar to that employed by cancer cells. Our results establish a function for the Myc 2-540 super-enhancer region as the genetic link between tissue regeneration and tumorigenesis, and demonstrates that normal tissue renewal and regeneration of tissues after severe damage are mechanistically distinct.

DOI: https://doi.org/10.26508/lsa.202403090
bioRxiv. 2025 Mar 13. pii: 2025.03.10.642513. [Epub ahead of print]

Gut Microbiome-Produced Bile Acid Metabolite Lengthens Circadian Period in Host Intestinal Cells.

Chelsea E Powell, Lenka Dohnalová, Robyn J Eisert, Zhen-Yu J Sun, Hyuk-Soo Seo, Sirano Dhe-Paganon, Christoph A Thaiss, A Sloan Devlin.

Host circadian signaling, feeding, and the gut microbiome are tightly interconnected. Changes in the gut microbial community can affect the expression of core clock genes, but the specific metabolites and molecular mechanisms that mediate this relationship remain largely unknown. Here, we sought to identify gut microbial metabolites that impact circadian signaling. Through a phenotypic screen of a focused library of gut microbial metabolites, we identified a bile acid metabolite, lithocholic acid (LCA), as a circadian modulator. LCA lengthened the circadian period of core clock gene hPer2 transcription in a dose-responsive manner in human colonic cells. We found evidence that LCA modulates the casein kinase 1 δ/ε (CK1δ/ε)-protein phosphatase 1 (PP1) feedback loop and stabilizes core clock protein cryptochrome 2 (CRY2). Furthermore, we showed that LCA feeding alters circadian transcription in mouse distal ileum and colon. Taken together, our work identifies LCA as a molecular link between host circadian biology and the microbiome. Because bile acids are secreted in response to feeding, our work provides potential mechanistic insight into the molecular nature of the food-entrainable oscillator by which peripheral clocks adapt to the timing of food intake. Given the association between circadian rhythm, feeding, and metabolic disease, our insights may offer a new avenue for modulating host health.

DOI: https://doi.org/10.1101/2025.03.10.642513
FASEB J. 2025 Apr 15. 39(7): e70490

Detection of liver mitochondrial oxaloacetate by NMR spectroscopy and membrane potential-dependent accumulation.

Liping Yu, Brian D Fink, William I Sivitz.

  Oxaloacetate (OAA) is a central liver metabolite fundamental to critical metabolic pathways. However, understanding OAA metabolism in the liver has been limited because the compound is very difficult to measure by mass spectroscopy and not abundant enough for detection by other methods. Here we describe a novel approach to quantifying OAA in liver mitochondria. Moreover, we provide evidence for membrane potential-dependent OAA accumulation in mitochondria during complex II-energized respiration consistent with OAA inhibition of succinate dehydrogenase.

Keywords:  inner membrane potential; liver; metabolites; mitochondria; oxaloacetate; respiration

DOI:  https://doi.org/10.1096/fj.202500039R
Sci Adv. 2025 Apr 04. 11(14): eadt4955

Neural stimulation suppresses mTORC1-mediated protein synthesis in skeletal muscle.

Ana G Dumitras, Giorgia Piccoli, Frederik Tellkamp, Lena Keufgens, Martina Baraldo, Sabrina Zorzato, Laura Cussonneau, Leonardo Nogara, Marcus Krüger, Bert Blaauw.

Skeletal muscle fibers are classified as glycolytic or oxidative, with differing susceptibilities to muscle wasting. However, the intracellular signaling pathways regulating fiber-specific muscle trophism remain unclear because of a lack of experimental models measuring protein synthesis. We developed a mouse model overexpressing a mutated transfer RNA synthetase in muscle fibers, enabling specific protein labeling using an artificial methionine substitute, which can be revealed through click chemistry. This model revealed that denervation increases protein labeling in oxidative muscle fibers through mammalian target of rapamycin complex 1 (mTORC1) activation, while deleting the mTORC1 scaffold protein Raptor reduces labeling in glycolytic fibers. On the other hand, increased muscle activity acutely decreases protein synthesis, accompanied by reduced mTORC1 signaling, glycogen depletion, and adenosine 5'-monophosphate kinase activation. Our findings identify nerve activity as an inhibitory signal for mTORC1-dependent protein synthesis in skeletal muscle, enhancing the understanding of fiber-specific responses to exercise and pathological conditions.

DOI: https://doi.org/10.1126/sciadv.adt4955
Nat Aging. 2025 Mar 31.

Invigorating discovery and clinical translation of aging biomarkers.

Erik Jacques, Chiara Herzog, Kejun Ying, Alan Tomusiak, Jessica Kasamoto, Raghav Sehgal, Seth Paulson, Julian Reinhard, Jakob Träuble, Waylon J Hastings, Alexander Tyshkovskiy, Sara Hägg, John C Earls, Christian E Behrens, Jessica Lasky-Su, Gavin Zhou, Eric Morgen, John S Tsang, Riccardo E Marioni, Xiao-Jun Ma, Alexandra Stolzing, Christin Glorioso, Jonathan S Gootenberg, Omar O Abudayyeh, M Austin Argentieri, Raymond H Mak, Lynne S Cox, Andrew S Brack, Gordan Lauc, David Furman, Jason D Buenrostro, Björn Schumacher, Jamie N Justice, Tina Woods, David Gobel, Viviana I Perez, David A Sinclair, Andrea B Maier, Nir Barzilai, Michael P Snyder, Tony Wyss-Coray, Steve Horvath, Luigi Ferrucci, Jesse R Poganik, Mahdi Moqri, Vadim N Gladyshev.

DOI: https://doi.org/10.1038/s43587-025-00838-w
Cancer Discov. 2025 Apr 02. 15(4): 663

Connections across the Cancer Continuum.

Luis A Diaz, Lewis C Cantley.

DOI: https://doi.org/10.1158/2159-8290.CD-25-0210
Annu Rev Biochem. 2025 Apr 01.

Essential Biology of Lipid Droplets.

Robert V Farese, Tobias C Walther.

Lipid droplets (LDs), long overlooked as inert cellular storage organelles, are now recognized for their complex and rich biology as membraneless organelles integral to cell metabolism. Significant advances have revealed that LDs are crucial for cellular processes that include the storage and retrieval of lipids for metabolic energy and membrane synthesis and the detoxification of lipids by sequestering them in the organelle's core. Here, we review current key aspects of LD biology, emphasizing insights into fundamental mechanisms of their formation, the mechanisms of protein targeting, new insights into LD turnover, and how LDs integrate into cellular metabolism. Where possible, we describe how these processes are important in physiology and how alterations in LD biology can lead to metabolic disease. We highlight unresolved questions and key challenges to be addressed for further advancing our understanding of LD biology and its implications for health and disease.

DOI: https://doi.org/10.1146/annurev-biochem-091724-013733
Cell Rep. 2025 Apr 03. pii: S2211-1247(25)00276-1. [Epub ahead of print]44(4): 115505

Mitochondrial fission regulates midgut muscle assembly and tick feeding capacity.

Zhengwei Zhong, Kun Wang, Ting Zhong, Jingwen Wang.

  Ticks ingest over 100 times their body weight in blood. As the primary tissue for blood storage and digestion, the tick midgut's regulation in response to this substantial blood volume remains unclear. Here, we show that blood intake triggers stem cell proliferation and mitochondrial fission in the midgut of Haemaphysalis longicornis. While inhibiting stem cell proliferation does not impact feeding behavior, disruption of mitochondrial fission impairs tick feeding capacity. Mitochondrial fission mediated by dynamin 2 (DNM2) regulates ATP generation, which in turn influences the expression of the tropomyosin-anchoring subunit troponin T (TNT). Knockdown of TNT disrupts muscle fiber assembly, hindering midgut enlargement and contraction, thereby preventing blood ingestion. These findings underscore the indispensable role of musculature in facilitating midgut expansion during feeding in ticks.

Keywords:  CP: Cell biology; Haemaphysalis longicornis; dynamin 2; feeding capacity; mitochondrial fission; muscle assembly

DOI:  https://doi.org/10.1016/j.celrep.2025.115505
Trends Biochem Sci. 2025 Mar 27. pii: S0968-0004(25)00050-7. [Epub ahead of print]

Understanding mitochondrial protein import: a revised model of the presequence translocase.

Naintara Jain, Agnieszka Chacinska, Peter Rehling.

  Mitochondrial function relies on the precise targeting and import of cytosolic proteins into mitochondrial subcompartments. Most matrix-targeted proteins follow the presequence pathway, which directs precursor proteins across the outer mitochondrial membrane (OMM) via the Translocase of the Outer Membrane (TOM) complex and into the matrix or inner mitochondrial membrane (IMM) via the Translocase of the Inner Membrane 23 (TIM23) complex. While classical biochemical studies provided detailed mechanistic insights into the composition and mechanism of the TIM23 complex, recent cryogenic-electron microscopy (cryo-EM) data challenge these established models and propose a revised model of translocation in which the TIM17 subunit acts as a 'slide' for precursor proteins, with Tim23 acting as a structural element. In this review, we summarize existing models, highlighting the questions and data needed to reconcile these perspectives, and enhance our understanding of TIM23 complex function.

Keywords:  inner mitochondrial membrane (IMM); mitochondria; presequence pathway; protein sorting; protein translocation; translocase of the inner membrane 23 (TIM23)

DOI:  https://doi.org/10.1016/j.tibs.2025.03.001
J Exp Med. 2025 Jun 02. pii: e20242282. [Epub ahead of print]222(6):

Tumor cell heterogeneity drives spatial organization of the intratumoral immune response.

Miho Tanaka, Lotus Lum, Kenneth H Hu, Piyush Chaudhary, Savannah Hughes, Cecilia Ledezma-Soto, Bushra Samad, Daphne Superville, Kenneth Ng, Arun Chumber, Ciara Benson, Zoe N Adams, Kelly Kersten, Oscar A Aguilar, Lawrence Fong, Alexis J Combes, Matthew F Krummel, Melissa Q Reeves.

Intratumoral heterogeneity (ITH)-defined as genetic and cellular diversity within a tumor-is linked to failure of immunotherapy and an inferior anti-tumor immune response. We modeled heterogeneous tumors comprised of "hot" and "cold" tumor populations (giving rise to T cell-rich and T cell-poor tumors, respectively) and introduced fluorescent labels to enable precise spatial tracking. We found the cold tumor cell population exerted a "dominant cold" effect in mixed tumors. Strikingly, spatial analysis revealed that the tumor cells themselves created distinct local microenvironments within heterogeneous tumors: regions occupied by cold tumor cells showed pronounced immunosuppression, harboring increased CD206Hi macrophages and diminished local T cell function. This inferior T cell activity in cold regions persisted even after immunotherapy and mechanistically was mediated by CX3CL1 produced by the cold tumor cells. An immune cold tumor population within a heterogeneous tumor thus impairs tumor immunity on both a tumor-wide and a highly localized spatial scale.

DOI: https://doi.org/10.1084/jem.20242282
bioRxiv. 2025 Mar 19. pii: 2025.03.19.643996. [Epub ahead of print]

ABHD11 inhibition drives sterol metabolism to modulate T cell effector function and alleviate autoimmunity.

Benjamin J Jenkins, Yasmin R Jenkins, Fernando M Ponce-Garcia, Chloe Moscrop, Iain A Perry, Matthew D Hitchings, Alejandro H Uribe, Federico Bernuzzi, Simon Eastham, James G Cronin, Ardena Berisha, Alexandra Howell, Joanne Davies, Julianna Blagih, Douglas J Veale, Luke C Davies, Micah Niphakis, David K Finlay, Linda V Sinclair, Benjamin F Cravatt, Andrew E Hogan, James A Nathan, Ursula Fearon, David Sumpton, Johan Vande Voorde, Goncalo Dias do Vale, Jeffrey G McDonald, Gareth W Jones, James A Pearson, Emma E Vincent, Nicholas Jones.

Chronic inflammation in autoimmunity is driven by T cell hyperactivation. This unregulated response to self is fuelled by heightened metabolic programmes, which offers a promising new direction to uncover novel treatment strategies. α/β-hydrolase domain-containing protein 11 (ABHD11) is a mitochondrial hydrolase that maintains the catalytic function of α-ketoglutarate dehydrogenase (α-KGDH), and its expression in CD4+ T cells has been linked to remission status in rheumatoid arthritis (RA). However, the importance of ABHD11 in regulating T cell metabolism and function - and thus, the downstream implication for autoimmunity - is yet to be explored. Here, we show that pharmacological inhibition of ABHD11 dampens cytokine production by human and mouse T cells. Mechanistically, the anti-inflammatory effects of ABHD11 inhibition are attributed to increased 24,25-epoxycholesterol (24,25-EC) biosynthesis and subsequent liver X receptor (LXR) activation, which arise from a compromised TCA cycle. The impaired cytokine profile established by ABHD11 inhibition is extended to two patient cohorts of autoimmunity. Importantly, using a murine model of accelerated type 1 diabetes (T1D), we show that targeting ABHD11 suppresses cytokine production in antigen-specific T cells and delays the onset of diabetes in vivo . Collectively, our work provides pre-clinical evidence that ABHD11 is an encouraging drug target in T cell-mediated autoimmunity.

DOI: https://doi.org/10.1101/2025.03.19.643996
J Lipid Res. 2025 Apr 01. pii: S0022-2275(25)00050-1. [Epub ahead of print] 100790

Diet-induced obesity dampens the temporal oscillation of hepatic mitochondrial lipids.

Rashi Jain, Rajprabu Rajendran, Sona Rajakumari.

  Mitochondria play a pivotal role in energy homeostasis and regulate several metabolic pathways. The inner and outer membrane of mitochondria comprises unique lipid composition and proteins that are essential to form electron transport chain complexes, orchestrate oxidative phosphorylation, β-oxidation, ATP synthesis, etc. As known diet-induced obesity affects mitochondrial function, dynamics, and mitophagy, which are governed by circadian clock machinery. Though DIO impairs the interplay between circadian oscillation and lipid metabolism, the impact of DIO on mitochondrial membrane lipid composition and their temporal oscillation is unknown. Thus, we investigated the diurnal oscillation of liver mitochondrial lipidome at various Zeitgeber times using quantitative lipidomics. Our data suggested that obesity disrupted lipid accumulation profiles and diminished the oscillating lipid species in the hepatic mitochondria. Strikingly, HFD manifested a more homogenous temporal oscillation pattern in phospholipids regardless of possessing different fatty acyl-chain lengths and degrees of unsaturation. In particular, DIO impaired the circadian rhythmicity of phosphatidyl ethanolamine, phosphatidyl choline, phosphatidyl serine and ether-linked phosphatidyl ethanolamine. Also, DIO altered the rhythmic profile of PE/PC, ePE/PC, PS/PC ratio and key proteins related to mitochondrial function, dynamics, and quality control. Since HFD dampened lipid oscillation, we examined whether the diurnal oscillation of mitochondrial lipids synchronized with mitochondrial function. Also, our data emphasized that acrophase of mitochondrial lipids synchronized with increased oxygen consumption rate and Parkin levels at ZT16 in chow-fed mice. Our study revealed that obesity altered the mitochondrial lipid composition and hampered the rhythmicity of mitochondrial lipids, oxygen consumption rate and Parkin levels in the liver.

Keywords:  Circadian rhythm; Diet-induced obesity; High-fat diet; MASLD; Membrane lipids; Mitochondrial lipidome; OXPHOS; Temporal oscillation

DOI:  https://doi.org/10.1016/j.jlr.2025.100790
Semin Nephrol. 2025 Apr 02. pii: S0270-9295(25)00014-2. [Epub ahead of print] 151577

Integrating Metabolomics and Transcriptomics to Characterize Differential Functional Capabilities of Kidney Proximal Tubule Cell Subtypes.

Jens Hansen, Mustafa M Siddiq, John Cijiang He, Ravi Iyengar.

  The coupling between energy metabolism and transport processes is a key feature that defines the functional capability of proximal tubule cells. Recent studies using metabolomics and transcriptomics provide insights into the relationships between changes in single-cell transcriptomic profiles and energy metabolism during kidney development and in disease states. In this review, we describe insights from these studies and how mapping of metabolites to functional pathways within cells enables these insights. We also describe our analyses of fatty acid metabolism pathways from single-cell transcriptomic data obtained by the Kidney Precision Medicine Project, which indicate that proximal tubule cell subtypes can be divided into two major groups with high and low levels of mRNAs for fatty acid (beta) oxidation enzymes. On average, patients with CKD have higher levels of cells with low fatty acid oxidation capability. These cells also have lower levels of sodium transporters. Within each group of proximal tubule cell subtypes there is considerable variability between individual patients. Integrating these data with metabolomics analyses can provide insights into how the differential metabolic capabilities of proximal tubule cells are related to disease features in individual patients. Identifying such relationships can lead to development of precision medicine approaches in nephrology.

Keywords:  Heterogeneity of metabolic functions; integrating transcriptomics and metabolomics; proximal tubule cell subtypes; spatial metabolomics

DOI:  https://doi.org/10.1016/j.semnephrol.2025.151577
Nat Microbiol. 2025 Mar 31.

Gut metagenomes reveal interactions between dietary restriction, ageing and the microbiome in genetically diverse mice.

Lev Litichevskiy, Maya Considine, Jasleen Gill, Vasuprada Shandar, Timothy O Cox, Hélène C Descamps, Kevin M Wright, Kevin R Amses, Lenka Dohnalová, Megan J Liou, Monika Tetlak, Mario R Galindo-Fiallos, Andrea C Wong, Patrick Lundgren, Junwon Kim, Giulia T Uhr, Ryan J Rahman, Sydney Mason, Carter Merenstein, Frederic D Bushman, Anil Raj, Fiona Harding, Zhenghao Chen, G V Prateek, Martin Mullis, Andrew G Deighan, Laura Robinson, Ceylan Tanes, Kyle Bittinger, Meenakshi Chakraborty, Ami S Bhatt, Hongzhe Li, Ian Barnett, Emily R Davenport, Karl W Broman, Maayan Levy, Robert L Cohen, David Botstein, Adam Freund, Andrea Di Francesco, Gary A Churchill, Mingyao Li, Christoph A Thaiss.

The gut microbiome changes with age and has been proposed to mediate the benefit of lifespan-extending interventions such as dietary restriction. However, the causes and consequences of microbiome ageing and the potential of such interventions remain unclear. Here we analysed 2,997 metagenomes collected longitudinally from 913 deeply phenotyped, genetically diverse mice to investigate interactions between the microbiome, ageing, dietary restriction (caloric restriction and fasting), host genetics and a range of health parameters. Among the numerous age-associated microbiome changes that we find in this cohort, increased microbiome uniqueness is the most consistent parameter across a second longitudinal mouse experiment that we performed on inbred mice and a compendium of 4,101 human metagenomes. Furthermore, cohousing experiments show that age-associated microbiome changes may be caused by an accumulation of stochastic environmental exposures (neutral theory) rather than by the influence of an ageing host (selection theory). Unexpectedly, the majority of taxonomic and functional microbiome features show small but significant heritability, and the amount of variation explained by host genetics is similar to ageing and dietary restriction. We also find that more intense dietary interventions lead to larger microbiome changes and that dietary restriction does not rejuvenate the microbiome. Lastly, we find that the microbiome is associated with multiple health parameters, including body composition, immune components and frailty, but not lifespan. Overall, this study sheds light on the factors influencing microbiome ageing and aspects of host physiology modulated by the microbiome.

DOI: https://doi.org/10.1038/s41564-025-01963-3
Trends Biochem Sci. 2025 Mar 31. pii: S0968-0004(25)00051-9. [Epub ahead of print]

Mitochondrial heat production: the elephant in the lab….

Pierre Rustin, Howard T Jacobs, Mügen Terzioglu, Paule Bénit.

  It has long been established that heat represents a major part of the energy released during the oxidation of mitochondrial substrates. However, with a few exceptions, the release of heat is rarely mentioned other than as being produced at the expense of ATP, without having any specific function. Here, after briefly surveying the literature on mitochondrial heat production, we argue for its cellular and organismal importance, sharing our opinions as to what could account for this unbalanced portrayal of mitochondrial energy transactions.

Keywords:  ATP; H(+)-ATPase; heat diffusion; mitochondria; nanoscale; respiratory chain

DOI:  https://doi.org/10.1016/j.tibs.2025.03.002
bioRxiv. 2025 Mar 20. pii: 2025.03.19.644180. [Epub ahead of print]

Resilience and vulnerabilities of tumor cells under purine shortage stress.

Jianpeng Yu, Chen Jin, Cheng Su, David Moon, Michael Sun, Hong Zhang, Xue Jiang, Fan Zhang, Nomi Tserentsoodol, Michelle L Bowie, Christopher J Pirozzi, Daniel J George, Robert Wild, Xia Gao, David M Ashley, Yiping He, Jiaoti Huang.

Purine metabolism is a promising therapeutic target in cancer; however how cancer cells respond to purine shortage,particularly their adaptation and vulnerabilities, remains unclear. Using the recently developed purine shortage-inducing prodrug DRP-104 and genetic approaches, we investigated these responses in prostate, lung and glioma cancer models. We demonstrate that when de novo purine biosynthesis is compromised, cancer cells employ microtubules to assemble purinosomes, multi-protein complexes of de novo purine biosynthesis enzymes that enhance purine biosynthesis efficiency. While this process enables tumor cells to adapt to purine shortage stress, it also renders them more susceptible to the microtubule-stabilizing chemotherapeutic drug Docetaxel. Furthermore, we show that although cancer cells primarily rely on de novo purine biosynthesis, they also exploit Methylthioadenosine Phosphorylase (MTAP)-mediated purine salvage as a crucial alternative source of purine supply, especially under purine shortage stress. In support of this finding, combining DRP-104 with an MTAP inhibitor significantly enhances tumor suppression in prostate cancer (PCa) models in vivo. Finally, despite the resilience of the purine supply machinery, purine shortage-stressed tumor cells exhibit increased DNA damage and activation of the cGAS-STING pathway, which may contribute to impaired immunoevasion and provide a molecular basis of the previously observed DRP-104-induced anti-tumor immunity. Together, these findings reveal purinosome assembly and purine salvage as key mechanisms of cancer cell adaptation and resilience to purine shortage while identifying microtubules, MTAP, and immunoevasion deficits as therapeutic vulnerabilities.

DOI: https://doi.org/10.1101/2025.03.19.644180
Cell Death Discov. 2025 Apr 03. 11(1): 137

Low extracellular pH protects cancer cells from ammonia toxicity.

Maria Dravecka, Ingvild Mikkola, Terje Johansen, Ole Morten Seternes, Jakob Mejlvang.

Ammonia is a natural waste product of cellular metabolism which, through its lysosomotropic ability, can have detrimental effects on various cellular functions. Increased levels of ammonia were recently detected in the interstitial fluid of various tumours, substantiating that high ammonia concentrations are a pathophysiological condition in the tumour microenvironment, alongside hypoxia and acidosis. Since little is known about how cancer cells respond to elevated levels of ammonia in the tumour microenvironment, we investigated how a panel of cancer cell lines derived from solid tumours behaved when exposed to increasing concentrations of ammonia. We found that ammonia represses cell growth, induces genome instability, and inhibits lysosome-mediated proteolysis in a dose-dependent manner. Unexpectedly, we also found that small fluctuations in the pH of the extracellular environment, had a significant impact on the cytotoxic effects of ammonia. In summary, our data show that the balance of pH and ammonia within the interstitial fluids of cancerous tumours significantly impacts the behaviour and fate of cells residing in the tumour microenvironment.

DOI: https://doi.org/10.1038/s41420-025-02440-w
Nature. 2025 Apr;640(8057): 11

The best foods for healthy ageing - and the worst.



Keywords:  Ageing

DOI:  https://doi.org/10.1038/d41586-025-00879-6
FEBS J. 2025 Apr 02.

Protein succinylome analysis identifies citrate synthase as a central regulator of osteoclast metabolic activity.

Dayoung Yu, Yue Gao, Marcin Luzarowski, Elisabeth Seebach, Thomas Heitkamp, Michael Börsch, Thomas Ruppert, Katharina F Kubatzky.

  Tumour necrosis factor ligand superfamily member 11 (TNFSF11; RANKL) and macrophage colony-stimulating factor 1 receptor (M-CSF) differentiate macrophages into osteoclasts. This process is characterised by changes in metabolic activity that support energy-consuming processes. Treatment with RANKL triggers a phenotype of accelerated metabolism with enhanced glycolysis and an initial disruption of the tricarboxylic acid cycle (TCA) through increased expression of the enzyme aconitate decarboxylase (ACOD1), which results in an upregulation of intracellular succinate levels. Succinate then causes post-translational succinylation of lysine residues. ACOD1 as an inducer of protein succinylation and the desuccinylase NAD-dependent protein deacylase sirtuin-5, mitochondrial (SIRT5) are regulated differentially, and the initially high expression of ACOD1 decreases towards the end of differentiation, whereas SIRT5 levels increase. To mimic the effect of protein succinylation, diethyl succinate or a SIRT5 inhibitor was added during differentiation, which reduced the formation of large osteoclasts, showing its relevance for osteoclastogenesis. To identify succinylated proteins, we used an immunoaffinity-based liquid chromatography-tandem mass spectrometry (LC-MS/MS) approach. Most lysine succinylated proteins were mitochondrial metabolic enzymes. Citrate synthase (CS), the enzyme catalysing the first reaction of the TCA cycle, showed a notable difference in succinylation levels before and after RANKL stimulation, with succinylation detected exclusively in stimulated cells. Immunoprecipitation assays confirmed CS succinylation. Using whole cell extracts, we observed that RANKL treatment decreased CS activity in a concentration-dependent manner. This suggests that CS could be critical in the context of energy production during osteoclastogenesis and that protein succinylation modulates the differentiation program of osteoclasts.

Keywords:  PTM scan; RANKL; citrate synthase; metabolism; mitochondria; osteoclast; post‐translational modification; succinylation

DOI:  https://doi.org/10.1111/febs.70090
Cancer Cell. 2025 Mar 21. pii: S1535-6108(25)00082-0. [Epub ahead of print]

Translation dysregulation in cancer as a source for targetable antigens.

Chen Weller, Osnat Bartok, Christopher S McGinnis, Heyilimu Palashati, Tian-Gen Chang, Dmitry Malko, Merav D Shmueli, Asuteka Nagao, Deborah Hayoun, Ayaka Murayama, Yuriko Sakaguchi, Panagiotis Poulis, Aseel Khatib, Bracha Erlanger Avigdor, Sagi Gordon, Sapir Cohen Shvefel, Marie J Zemanek, Morten M Nielsen, Sigalit Boura-Halfon, Shira Sagie, Nofar Gumpert, Weiwen Yang, Dmitry Alexeev, Pelgia Kyriakidou, Winnie Yao, Mirie Zerbib, Polina Greenberg, Gil Benedek, Kevin Litchfield, Ekaterina Petrovich-Kopitman, Adi Nagler, Roni Oren, Shifra Ben-Dor, Yishai Levin, Yitzhak Pilpel, Marina Rodnina, Jürgen Cox, Yifat Merbl, Ansuman T Satpathy, Yaron Carmi, Florian Erhard, Tsutomu Suzuki, Allen R Buskirk, Johanna Olweus, Eytan Ruppin, Andreas Schlosser, Yardena Samuels.

  Aberrant peptides presented by major histocompatibility complex (MHC) molecules are targets for tumor eradication, as these peptides can be recognized as foreign by T cells. Protein synthesis in malignant cells is dysregulated, which may result in the generation and presentation of aberrant peptides that can be exploited for T cell-based therapies. To investigate the role of translational dysregulation in immunological tumor control, we disrupt translation fidelity by deleting tRNA wybutosine (yW)-synthesizing protein 2 (TYW2) in tumor cells and characterize the downstream impact on translation fidelity and immunogenicity using immunopeptidomics, genomics, and functional assays. These analyses reveal that TYW2 knockout (KO) cells generate immunogenic out-of-frame peptides. Furthermore, Tyw2 loss increases tumor immunogenicity and leads to anti-programmed cell death 1 (PD-1) checkpoint blockade sensitivity in vivo. Importantly, reduced TYW2 expression is associated with increased response to checkpoint blockade in patients. Together, we demonstrate that defects in translation fidelity drive tumor immunogenicity and may be leveraged for cancer immunotherapy.

Keywords:  cancer immunopeptidome; immune checkpoint blockade; neoantigens; non-canonical peptides; translation fidelity

DOI:  https://doi.org/10.1016/j.ccell.2025.03.003
Nat Genet. 2025 Apr 01.

Quantitative characterization of tissue states using multiomics and ecological spatial analysis.

Daisy Yi Ding, Zeyu Tang, Bokai Zhu, Hongyu Ren, Alex K Shalek, Robert Tibshirani, Garry P Nolan.

The spatial organization of cells in tissues underlies biological function, and recent advances in spatial profiling technologies have enhanced our ability to analyze such arrangements to study biological processes and disease progression. We propose MESA (multiomics and ecological spatial analysis), a framework drawing inspiration from ecological concepts to delineate functional and spatial shifts across tissue states. MESA introduces metrics to systematically quantify spatial diversity and identify hot spots, linking spatial patterns to phenotypic outcomes, including disease progression. Furthermore, MESA integrates spatial and single-cell multiomics data to facilitate an in-depth, molecular understanding of cellular neighborhoods and their spatial interactions within tissue microenvironments. Applying MESA to diverse datasets demonstrates additional insights it brings over prior methods, including newly identified spatial structures and key cell populations linked to disease states. Available as a Python package, MESA offers a versatile framework for quantitative decoding of tissue architectures in spatial omics across health and disease.

DOI: https://doi.org/10.1038/s41588-025-02119-z
Nat Commun. 2025 Mar 28. 16(1): 2867

Energy-ordered resource stratification as an agnostic signature of life.

Akshit Goyal, Mikhail Tikhonov.

The search for extraterrestrial life hinges on identifying biosignatures, often focusing on gaseous metabolic byproducts as indicators. However, most such biosignatures require assuming specific metabolic processes. It is widely recognized that life on other planets may not resemble that of Earth, but identifying biosignatures "agnostic" to such assumptions has remained a challenge. Here, we propose a novel approach by considering the generic outcome of life: the formation of competing ecosystems. We use a minimal model to argue that the presence of ecosystem-level dynamics, characterized by ecological interactions and resource competition, may yield biosignatures independent of specific metabolic activities. Specifically, we propose the emergent stratification of chemical resources in order of decreasing energy content as a candidate new biosignature. While likely inaccessible to remote sensing, this signature could be relevant for sample return missions, or for detection of ancient signatures of life on Earth itself.

DOI: https://doi.org/10.1038/s41467-025-58206-6
EMBO J. 2025 Mar 31.

SIRT5-mediated desuccinylation of PPA2 enhances HIF-1alpha-dependent adaptation to hypoxic stress and colorectal cancer metastasis.

Xiang Zhang, Yuqin Di, Youpeng Wang, Jiale Qin, Lvlan Ye, Xiangqiong Wen, Zunfu Ke, Ziyang Wang, Weiling He.

  Metastasis is the primary cause of death in patients with colorectal cancer (CRC). Hypoxia is a hallmark of solid tumors that promotes cellular metabolic adaptation and dissemination. However, the mechanisms linking hypoxia-regulated metabolic adaptation to CRC metastasis remain unclear. Here, we found that inorganic pyrophosphatase 2 (PPA2) suppresses metastatic progression of CRC via its phosphatase function. PPA2 expression levels are reduced in CRC specimen and correlate with enhanced response to hypoxia by promoting hypoxia-inducible factor-1 (HIF-1) signaling to promote CRC cell glycolysis and dissemination. Mechanistically, PPA2 decreases HIF-1alpha stability through non-canonical ubiquitin-mediated proteasomal degradation via recruitment of E3 ligase NEDD4. Furthermore, PPA2 directly dephosphorylates NEDD4 at threonine 758 residue, resulting in its activation. Under hypoxic stress, NAD-dependent protein deacetylase sirtuin-5 promotes the dissociation of PPA2 and NEDD4 by inducing PPA2 desuccinylation at lysine 176, contributing to the improved stability of HIF-1alpha under hypoxic conditions. Our findings reveal a tumor-suppressive role of PPA2 in HIF-1alpha-dependent colorectal cancer, providing a potential therapeutic target and prognostic strategy.

Keywords:  HIF-1α; Hypoxia; Metastatic Colorectal Cancer; NEDD4; PPA2 Succinylation

DOI:  https://doi.org/10.1038/s44318-025-00416-1
Cancer Discov. 2025 Apr 02. 15(4): 685-701

The Hallmarks of Cancer as Eco-Evolutionary Processes.

Ranjini Bhattacharya, Stanislav S Avdieiev, Anuraag Bukkuri, Christopher J Whelan, Robert A Gatenby, Kenneth Y Tsai, Joel S Brown.

SIGNIFICANCE: Viewing the hallmarks as a sequence of adaptations captures the "why" behind the "how" of the molecular changes driving cancer. This eco-evolutionary view distils the complexity of cancer progression into logical steps, providing a framework for understanding all existing and emerging hallmarks of cancer and developing therapeutic interventions.

DOI: https://doi.org/10.1158/2159-8290.CD-24-0861