bims-camemi 2025-04-20 papers

bims-camemi

Biomed News

on Mitochondrial metabolism in cancer

Issue of 2025–04–20
forty-four papers selected by
Christian Frezza, Universität zu Köln

Metabolic rewiring caused by mitochondrial dysfunction promotes mTORC1-dependent skeletal aging.
Integrated analysis of transcriptional and metabolic responses to mitochondrial stress.
The mitochondrial unfolded protein response: acting near and far.
Mitochondria-organelle crosstalk in establishing compartmentalized metabolic homeostasis.
Genetically encoded tool for manipulation of ΔΨm identifies its role as the driver of ISR induced by ATP synthase dysfunction.
The POLγ Y951N patient mutation disrupts the switch between DNA synthesis and proofreading, triggering mitochondrial DNA instability.
UnitedMet harnesses RNA-metabolite covariation to impute metabolite levels in clinical samples.
Cytosolic cytochrome c represses ferroptosis.
In vivo composition of the mitochondrial nucleoid in mice.
Mitochondrial metabolism sustains DNMT3A-R882-mutant clonal haematopoiesis.
ALDH7A1 protects against ferroptosis by generating membrane NADH and regulating FSP1.
Active control of mitochondrial network morphology by metabolism-driven redox state.
Approaches to reduce succinate accumulation by restoration of succinate dehydrogenase activity in cultured adrenal cells.
RRM2B deficiency causes dATP and dGTP depletion through enhanced degradation and slower synthesis.
Spatial analysis of mitochondrial gene expression reveals dynamic translation hubs and remodeling in stress.
Itaconate modulates immune responses via inhibition of peroxiredoxin 5.
Molecular basis of pyruvate transport and inhibition of the human mitochondrial pyruvate carrier.
Environmental and molecular noise buffering by the cyanobacterial clock in individual cells.
Potential bidirectional communication between the liver and the central circadian clock in MASLD.
Coupling of ribosome biogenesis and translation initiation in human mitochondria.
STAR/STARD1: a mitochondrial intermembrane space cholesterol shuttle degraded through mitophagy.
NUDT5 regulates purine metabolism and thiopurine sensitivity by interacting with PPAT.
Metabolic remodelling produces fumarate via the aspartate-argininosuccinate shunt in macrophages as an antiviral defence.
Peritoneal resident macrophages constitute an immunosuppressive environment in peritoneal metastasized colorectal cancer.
The cell origin of reactive oxygen species and its implication for evolutionary trade-offs.
GDF15 links adipose tissue lipolysis with anxiety.
Towards multimodal foundation models in molecular cell biology.
Fumarate integrates metabolism and immunity in diseases.
Lipids: emerging actors in mitochondrial protein import.
Loss of VHL-mediated pRb regulation promotes clear cell renal cell carcinoma.
Metabolic Dialogue Shapes Immune Response in the Tumor Microenvironment.
The unusual metabolism of germinal center B cells.
SLC25A42 promotes gastric cancer growth by conferring ferroptosis resistance through enhancing CPT2-mediated fatty acid oxidation.
A non-canonical cGAS-STING pathway drives cellular and organismal aging.
Epithelial cell competition is promoted by signaling from immune cells.
Mitochondrial complexity is regulated at ER-mitochondria contact sites via PDZD8-FKBP8 tethering.
The proteostasis burden of aneuploidy.
Elevated mitochondrial membrane potential is a therapeutic vulnerability in Dnmt3a-mutant clonal hematopoiesis.
A macrophage-neutrophil program drives mammary carcinogenesis.
MitoSNO inhibits mitochondrial hydrogen peroxide (mtH2O2) generation by α-ketoglutarate dehydrogenase (KGDH).
Simultaneous in vivo multi-organ fluxomics reveals divergent metabolic adaptations in liver, heart, and skeletal muscle during obesity.
Emerging mechanisms of human mitochondrial translation regulation.
Integrator loss leads to dsRNA formation that triggers the integrated stress response.
Emerging roles of transcriptional condensates as temporal signal integrators.

Sci Adv. 2025 Apr 18. 11(16): eads1842

Metabolic rewiring caused by mitochondrial dysfunction promotes mTORC1-dependent skeletal aging.

Kristina Bubb, Julia Etich, Kristina Probst, Tanvi Parashar, Maximilian Schuetter, Frederik Dethloff, Susanna Reincke, Janica L Nolte, Marcus Krüger, Ursula Schlötzer-Schrehard, Julian Nüchel, Constantinos Demetriades, Patrick Giavalisco, Jan Riemer, Bent Brachvogel.

Decline of mitochondrial respiratory chain (mtRC) capacity is a hallmark of mitochondrial diseases. Patients with mtRC dysfunction often present reduced skeletal growth as a sign of premature cartilage degeneration and aging, but how metabolic adaptations contribute to this phenotype is poorly understood. Here we show that, in mice with impaired mtRC in cartilage, reductive/reverse TCA cycle segments are activated to produce metabolite-derived amino acids and stimulate biosynthesis processes by mechanistic target of rapamycin complex 1 (mTORC1) activation during a period of massive skeletal growth and biomass production. However, chronic hyperactivation of mTORC1 suppresses autophagy-mediated organelle recycling and disturbs extracellular matrix secretion to trigger chondrocytes death, which is ameliorated by targeting the reductive metabolism. These findings explain how a primarily beneficial metabolic adaptation response required to counterbalance the loss of mtRC function, eventually translates into profound cell death and cartilage tissue degeneration. The knowledge of these dysregulated key nutrient signaling pathways can be used to target skeletal aging in mitochondrial disease.

DOI: https://doi.org/10.1126/sciadv.ads1842
Cell Rep Methods. 2025 Apr 08. pii: S2667-2375(25)00063-3. [Epub ahead of print] 101027

Integrated analysis of transcriptional and metabolic responses to mitochondrial stress.

Liam P Kelley, Song-Hua Hu, Sarah A Boswell, Peter K Sorger, Alison E Ringel, Marcia C Haigis.

  Mitochondrial stress arises from a variety of sources, including mutations to mitochondrial DNA, the generation of reactive oxygen species, and an insufficient supply of oxygen or fuel. Mitochondrial stress induces a range of dedicated responses that repair damage and restore mitochondrial health. However, a systematic characterization of transcriptional and metabolic signatures induced by distinct types of mitochondrial stress is lacking. Here, we defined how primary human fibroblasts respond to a panel of mitochondrial inhibitors to trigger adaptive stress responses. Using metabolomic and transcriptomic analyses, we established integrated signatures of mitochondrial stress. We developed a tool, stress quantification using integrated datasets (SQUID), to deconvolute mitochondrial stress signatures from existing datasets. Using SQUID, we profiled mitochondrial stress in The Cancer Genome Atlas (TCGA) PanCancer Atlas, identifying a signature of pyruvate import deficiency in IDH1-mutant glioma. Thus, this study defines a tool to identify specific mitochondrial stress signatures, which may be applied to a range of systems.

Keywords:  CP: Metabolism; CP: Systems biology; cancer metabolism; integrated multi-omics; integrated stress response; metabolomics; mitochondria; mitochondrial stress response; mitochondrial unfolded protein response; stress signatures

DOI:  https://doi.org/10.1016/j.crmeth.2025.101027
Biol Chem. 2025 Apr 17.

The mitochondrial unfolded protein response: acting near and far.

Nikolaos Charmpilas, Qiaochu Li, Thorsten Hoppe.

  Mitochondria are central hubs of cellular metabolism and their dysfunction has been implicated in a variety of human pathologies and the onset of aging. To ensure proper mitochondrial function under misfolding stress, a retrograde mitochondrial signaling pathway known as UPRmt is activated. The UPRmt ensures that mitochondrial stress is communicated to the nucleus, where gene expression for several mitochondrial proteases and chaperones is induced, forming a protective mechanism to restore mitochondrial proteostasis and function. Importantly, the UPRmt not only acts within cells, but also exhibits a conserved cell-nonautonomous activation across species, where mitochondrial stress in a defined tissue triggers a systemic response that affects distant organs. Here, we summarize the molecular basis of the UPRmt in the invertebrate model organism Caenorhabditis elegans and in mammals. We also describe recent findings on cell-nonautonomous activation of the UPRmt in worms, flies and mice, and how UPRmt activation in specific tissues affects organismal metabolism and longevity.

Keywords:  cell-nonautonomous regulation; integrated stress response; mitochondria; mitochondrial unfolded protein response; stress signaling

DOI:  https://doi.org/10.1515/hsz-2025-0107
Mol Cell. 2025 Apr 17. pii: S1097-2765(25)00196-0. [Epub ahead of print]85(8): 1487-1508

Mitochondria-organelle crosstalk in establishing compartmentalized metabolic homeostasis.

Brandon Chen, Costas A Lyssiotis, Yatrik M Shah.

  Mitochondria serve as central hubs in cellular metabolism by sensing, integrating, and responding to metabolic demands. This integrative function is achieved through inter-organellar communication, involving the exchange of metabolites, lipids, and signaling molecules. The functional diversity of metabolite exchange and pathway interactions is enabled by compartmentalization within organelle membranes. Membrane contact sites (MCSs) are critical for facilitating mitochondria-organelle communication, creating specialized microdomains that enhance the efficiency of metabolite and lipid exchange. MCS dynamics, regulated by tethering proteins, adapt to changing cellular conditions. Dysregulation of mitochondrial-organelle interactions at MCSs is increasingly recognized as a contributing factor in the pathogenesis of multiple diseases. Emerging technologies, such as advanced microscopy, biosensors, chemical-biology tools, and functional genomics, are revolutionizing our understanding of inter-organellar communication. These approaches provide novel insights into the role of these interactions in both normal cellular physiology and disease states. This review will highlight the roles of metabolite transporters, lipid-transfer proteins, and mitochondria-organelle interfaces in the coordination of metabolism and transport.

Keywords:  endoplasmic reticulum; inter-organellar communication; mitochondria; organellar metabolism; organelle membrane contact sites

DOI:  https://doi.org/10.1016/j.molcel.2025.03.003
Cell Chem Biol. 2025 Apr 17. pii: S2451-9456(25)00097-2. [Epub ahead of print]32(4): 620-630.e6

Genetically encoded tool for manipulation of ΔΨm identifies its role as the driver of ISR induced by ATP synthase dysfunction.

Mangyu Choe, Alex E Ekvik, Gretchen Stalnaker, Hijai R Shin, Denis V Titov.

  Mitochondrial membrane potential (ΔΨm) is one of the key parameters controlling cellular bioenergetics. Investigation of the role of ΔΨm in live cells is complicated by a lack of tools for its direct manipulation without off-target effects. Here, we adopted the uncoupling protein UCP1 from brown adipocytes as a genetically encoded tool for direct manipulation of ΔΨm. We validated the ability of exogenously expressed UCP1 to induce uncoupled respiration and lower ΔΨm in mammalian cells. UCP1 expression lowered ΔΨm to the same extent as chemical uncouplers but did not inhibit cell proliferation, suggesting that it manipulates ΔΨm without the off-target effects of chemical uncouplers. Using UCP1, we revealed that elevated ΔΨm is the driver of the integrated stress response induced by ATP synthase inhibition in mammalian cells.

Keywords:  ATP synthase inhibition; GEMMs; ISR; UCP1; genetically encoded tools for manipulation of metabolism; integrated stress response,; mitochondrial membrane potential; ΔΨm

DOI:  https://doi.org/10.1016/j.chembiol.2025.03.007
Proc Natl Acad Sci U S A. 2025 Apr 22. 122(16): e2417477122

The POLγ Y951N patient mutation disrupts the switch between DNA synthesis and proofreading, triggering mitochondrial DNA instability.

Josefin M E Forslund, Tran V H Nguyen, Vimal Parkash, Andreas Berner, Steffi Goffart, Jaakko L O Pohjoismäki, Paulina H Wanrooij, Erik Johansson, Sjoerd Wanrooij.

  Mitochondrial DNA (mtDNA) stability, essential for cellular energy production, relies on DNA polymerase gamma (POLγ). Here, we show that the POLγ Y951N disease-causing mutation induces replication stalling and severe mtDNA depletion. However, unlike other POLγ disease-causing mutations, Y951N does not directly impair exonuclease activity and only mildly affects polymerase activity. Instead, we found that Y951N compromises the enzyme's ability to efficiently toggle between DNA synthesis and degradation, and is thus a patient-derived mutation with impaired polymerase-exonuclease switching. These findings provide insights into the intramolecular switch when POLγ proofreads the newly synthesized DNA strand and reveal a new mechanism for causing mitochondrial DNA instability.

Keywords:  DNA polymerases; mitochondria; mitochondrial disease; mtDNA; mtDNA replication

DOI:  https://doi.org/10.1073/pnas.2417477122
Nat Cancer. 2025 Apr 18.

UnitedMet harnesses RNA-metabolite covariation to impute metabolite levels in clinical samples.

Amy X Xie, Wesley Tansey, Ed Reznik.

Comprehensively studying metabolism requires metabolite measurements. Such measurements, however, are often unavailable in large cohorts of tissue samples. To address this basic barrier, we propose a Bayesian framework ('UnitedMet') that leverages RNA-metabolite covariation to impute otherwise unmeasured metabolite levels from widely available transcriptomic data. UnitedMet is equally capable of imputing whole pool sizes and outcomes of isotope tracing experiments. We apply UnitedMet to investigate the metabolic impact of driver mutations in kidney cancer, identifying an association between BAP1 and a highly oxidative tumor phenotype. We similarly apply UnitedMet to determine that advanced kidney cancers upregulate oxidative phosphorylation relative to early-stage disease, that oxidative metabolism in kidney cancer is associated with inferior outcomes to anti-angiogenic therapy and that kidney cancer metastases demonstrate elevated oxidative phosphorylation. UnitedMet provides a scalable tool for assessing metabolic phenotypes when direct measurements are infeasible, facilitating unexplored avenues for metabolite-focused hypothesis generation.

DOI: https://doi.org/10.1038/s43018-025-00943-0
Cell Metab. 2025 Apr 08. pii: S1550-4131(25)00149-4. [Epub ahead of print]

Cytosolic cytochrome c represses ferroptosis.

Xinxin Song, Zhuan Zhou, Jiao Liu, Jingbo Li, Chunhua Yu, Herbert J Zeh, Daniel J Klionsky, Brent R Stockwell, Jiayi Wang, Rui Kang, Guido Kroemer, Daolin Tang.

  The release of cytochrome c, somatic (CYCS) from mitochondria to the cytosol is an established trigger of caspase-dependent apoptosis. Here, we unveil an unexpected role for cytosolic CYCS in inhibiting ferroptosis-a form of oxidative cell death driven by uncontrolled lipid peroxidation. Mass spectrometry and site-directed mutagenesis revealed the existence of a cytosolic complex composed of inositol polyphosphate-4-phosphatase type I A (INPP4A) and CYCS. This CYCS-INPP4A complex is distinct from the CYCS-apoptotic peptidase activating factor 1 (APAF1)-caspase-9 apoptosome formed during mitochondrial apoptosis. CYCS boosts INPP4A activity, leading to increased formation of phosphatidylinositol-3-phosphate, which prevents phospholipid peroxidation and plasma membrane rupture, thus averting ferroptotic cell death. Unbiased screening led to the identification of the small-molecule compound 10A3, which disrupts the CYCS-INPP4A interaction. 10A3 sensitized cultured cells and tumors implanted in immunocompetent mice to ferroptosis. Collectively, these findings redefine our understanding of cytosolic CYCS complexes that govern diverse cell death pathways.

Keywords:  apoptosis; cytochrome c; ferroptosis; protein complex

DOI:  https://doi.org/10.1016/j.cmet.2025.03.014
Biochim Biophys Acta Mol Cell Res. 2025 Apr 15. pii: S0167-4889(25)00060-6. [Epub ahead of print] 119955

In vivo composition of the mitochondrial nucleoid in mice.

Rodolfo García-Villegas, Franka Odenthal, Yvonne Giannoula, Nina A Bonekamp, Inge Kühl, Chan Bae Park, Henrik Spåhr, Elisa Motori, Fredrik Levander, Nils-Göran Larsson.

  Mitochondrial DNA (mtDNA) is compacted into dynamic structures called mitochondrial nucleoids (mt-nucleoids), with the mitochondrial transcription factor A (TFAM) as the core packaging protein. We generated bacterial artificial chromosome (BAC) transgenic mice expressing FLAG-tagged TFAM protein (Tfam-FLAGBAC mice) to investigate the mt-nucleoid composition in vivo. Importantly, we show that the TFAM-FLAG protein is functional and complements the absence of the wild-type TFAM protein in homozygous Tfam knockout mice. We performed immunoprecipitation experiments from different mouse tissues and identified 12 proteins as core mt-nucleoid components by proteomics analysis. Among these, eight proteins correspond to mtDNA replication and transcription factors, while the other four are involved in the mitoribosome assembly. In addition, we used the Tfam-FLAGBAC mice to identify ten proteins that may stabilize TFAM-FLAG upon depletion of the mitochondrial RNA polymerase despite the absence of mtDNA and induction of the LONP1 protease. Finally, we evaluated the changes in mt-nucleoids caused by very high levels of TFAM unraveling nine interactors that could counteract the high TFAM levels to maintain active mtDNA transcription. Altogether, we demonstrate that the Tfam-FLAGBAC mice are a valuable tool for investigating the mt-nucleoid composition in vivo.

Keywords:  Mitochondrial nucleoid; Mitochondrial translation; TFAM; Transgenic mice; mtDNA expression

DOI:  https://doi.org/10.1016/j.bbamcr.2025.119955
Nature. 2025 Apr 16.

Mitochondrial metabolism sustains DNMT3A-R882-mutant clonal haematopoiesis.

Malgorzata Gozdecka, Monika Dudek, Sean Wen, Muxin Gu, Richard J Stopforth, Justyna Rak, Aristi Damaskou, Guinevere L Grice, Matthew A McLoughlin, Laura Bond, Rachael Wilson, George Giotopoulos, Vijaya Mahalingam Shanmugiah, Rula Bany Bakar, Eliza Yankova, Jonathan L Cooper, Nisha Narayan, Sarah J Horton, Ryan Asby, Dean C Pask, Annalisa Mupo, Graham Duddy, Ludovica Marando, Theodoros Georgomanolis, Paul Carter, Amirtha Priya Ramesh, William G Dunn, Clea Barcena, Paolo Gallipoli, Kosuke Yusa, Slavé Petrovski, Penny Wright, Pedro M Quiros, Christian Frezza, James A Nathan, Arthur Kaser, Siddhartha Kar, Konstantinos Tzelepis, Jonathan Mitchell, Margarete A Fabre, Brian J P Huntly, George S Vassiliou.

Somatic DNMT3A R882 codon mutations drive the most common form of clonal haematopoiesis (CH) and are associated with increased acute myeloid leukaemia (AML) risk1,2. Preventing expansion of DNMT3A-R882-mutant haematopoietic stem/progenitor cells (HSPCs) may therefore avert progression to AML. To identify DNMT3A-R882-mutant-specific vulnerabilities, we conducted a genome-wide CRISPR screen on primary mouse Dnmt3aR882H/+ HSPCs. Amongst the 640 vulnerability genes identified, many were involved in mitochondrial metabolism and metabolic flux analysis confirmed enhanced oxidative phosphorylation usage in Dnmt3aR882H/+ vs Dnmt3a+/+ (WT) HSPCs. We selected citrate/malate transporter Slc25a1 and complex I component Ndufb11, for which pharmacological inhibitors are available, for downstream studies. In vivo administration of SLC25A1 inhibitor CTPI2 and complex I inhibitors IACS-010759 and metformin, suppressed post-transplantation clonal expansion of Dnmt3aR882H/+, but not WT, LT-HSC. The effect of metformin was recapitulated using a primary human DNMT3A-R882 CH sample. Notably, analysis of 412,234 UK Biobank (UKB) participants revealed that individuals taking metformin had markedly lower prevalence of DNMT3A-R882-mutant CH, after controlling for potential confounders including glycated haemoglobin, diabetes and body mass index. Collectively, our data propose modulation of mitochondrial metabolism as a therapeutic strategy for prevention of DNMT3A-R882-mutant AML.

DOI: https://doi.org/10.1038/s41586-025-08980-6
Cell. 2025 Apr 08. pii: S0092-8674(25)00292-2. [Epub ahead of print]

ALDH7A1 protects against ferroptosis by generating membrane NADH and regulating FSP1.

Jia-Shu Yang, Andrew J Morris, Koki Kamizaki, Jianzhong Chen, Jillian Stark, William M Oldham, Toshitaka Nakamura, Eikan Mishima, Joseph Loscalzo, Yasuhiro Minami, Marcus Conrad, Whitney S Henry, Victor W Hsu.

  Ferroptosis is a form of cell death due to iron-induced lipid peroxidation. Ferroptosis suppressor protein 1 (FSP1) protects against this death by generating antioxidants, which requires nicotinamide adenine dinucleotide, reduced form (NADH) as a cofactor. We initially uncover that NADH exists at significant levels on cellular membranes and then find that this form of NADH is generated by aldehyde dehydrogenase 7A1 (ALDH7A1) to support FSP1 activity. ALDH7A1 activity also acts directly to decrease lipid peroxidation by consuming reactive aldehydes. Furthermore, ALDH7A1 promotes the membrane recruitment of FSP1, which is instigated by ferroptotic stress activating AMP-activated protein kinase (AMPK) to promote the membrane localization of ALDH7A1 that stabilizes FSP1 on membranes. These findings advance a fundamental understanding of NADH by revealing a previously unappreciated pool on cellular membranes, with the elucidation of its function providing a major understanding of how FSP1 acts and how an aldehyde dehydrogenase protects against ferroptosis.

Keywords:  aldehyde dehydrogenase 7A1; ferroptosis; ferroptosis suppressor protein 1; nicotinamide adenine dinucleotide reduced form

DOI:  https://doi.org/10.1016/j.cell.2025.03.019
Proc Natl Acad Sci U S A. 2025 Apr 22. 122(16): e2421953122

Active control of mitochondrial network morphology by metabolism-driven redox state.

Gaurav Singh, Vineeth Vengayil, Aayushee Khanna, Swagata Adhikary, Sunil Laxman.

  Mitochondria are dynamic organelles that constantly change morphology. What controls mitochondrial morphology however remains unresolved. Using actively respiring yeast cells growing in distinct carbon sources, we find that mitochondrial morphology and activity are unrelated. Cells can exhibit fragmented or networked mitochondrial morphology in different nutrient environments independent of mitochondrial activity. Instead, mitochondrial morphology is controlled by the intracellular redox state, which itself depends on the nature of electron entry into the electron transport chain (ETC)-through complex I/II or directly to coenzyme Q/cytochrome c. In metabolic conditions where direct electron entry is high, reactive oxygen species (ROS) increase, resulting in an oxidized cytosolic environment and rapid mitochondrial fragmentation. Decreasing direct electron entry into the ETC by genetic or chemical means, or reducing the cytosolic environment rapidly restores networked morphologies. Using controlled disruptions of electron flow to alter ROS and redox state, we demonstrate minute-scale, reversible control between networked and fragmented forms in an activity-independent manner. Mechanistically, the fission machinery through Dnm1 responds in minute-scale to redox state changes, preceding the change in mitochondrial form. Thus, the metabolic state of the cell and its consequent cellular redox state actively control mitochondrial form.

Keywords:  electron transport chain; mitochondrial network; reactive oxygen species; redox state

DOI:  https://doi.org/10.1073/pnas.2421953122
J Cell Sci. 2025 Apr 16. pii: jcs.263925. [Epub ahead of print]

Approaches to reduce succinate accumulation by restoration of succinate dehydrogenase activity in cultured adrenal cells.

Fatimah Al Khazal, Leili Rahimi, Fan Feng, Nicole A Becker, Clifford D Folmes, Judith Favier, L James Maher.

  The rare human neuroendocrine tumors pheochromocytoma and paraganglioma (PPGL) can result from loss of mitochondrial succinate dehydrogenase. The resulting succinate accumulation is tumorigenic in certain neuroendocrine cells. Here we explore two theoretical approaches to mitigate tumorigenic succinate accumulation in a cell culture model of PPGL. We first study a gene replacement strategy using transposition technology and conclude that many aspects of mitochondrial morphology, oxidative cell metabolism and succinate accumulation are reversible by this process. We then investigate if riboflavin supplementation has the potential to rescue succinate dehydrogenase activity in the intact SDHA catalytic subunit to suppress succinate accumulation even in the absence of SDHB. We show that this latter strategy is not successful.

Keywords:  Paraganglioma; Pheochromocytoma; Riboflavin; Succinate dehydrogenase

DOI:  https://doi.org/10.1242/jcs.263925
Proc Natl Acad Sci U S A. 2025 Apr 22. 122(16): e2503531122

RRM2B deficiency causes dATP and dGTP depletion through enhanced degradation and slower synthesis.

Ololade Folajimi Awoyomi, Choco Michael Gorospe, Biswajit Das, Pradeep Mishra, Sushma Sharma, Olena Diachenko, Anna Karin Nilsson, Phong Tran, Paulina H Wanrooij, Andrei Chabes.

  Mitochondrial DNA (mtDNA) replication requires a steady supply of deoxyribonucleotides (dNTPs), synthesized de novo by ribonucleotide reductase (RNR). In nondividing cells, RNR consists of RRM1 and RRM2B subunits. Mutations in RRM2B cause mtDNA depletion syndrome, linked to muscle weakness, neurological decline, and early mortality. The impact of RRM2B deficiency on dNTP pools in nondividing tissues remains unclear. Using a mouse knockout model, we demonstrate that RRM2B deficiency selectively depletes dATP and dGTP, while dCTP and dTTP levels remain stable or increase. This depletion pattern resembles the effects of hydroxyurea, an inhibitor that reduces overall RNR activity. Mechanistically, we propose that the depletion of dATP and dGTP arises from their preferred degradation by the dNTPase SAMHD1 and the lower production rate of dATP by RNR. Identifying dATP and dGTP depletion as a hallmark of RRM2B deficiency provides insights for developing nucleoside bypass therapies to alleviate the effects of RRM2B mutations.

Keywords:  dNTP metabolism; genome stability; mtDNA stability; ribonucleotide reductase

DOI:  https://doi.org/10.1073/pnas.2503531122
Sci Adv. 2025 Apr 18. 11(16): eads6830

Spatial analysis of mitochondrial gene expression reveals dynamic translation hubs and remodeling in stress.

Adam Begeman, John A Smolka, Ahmad Shami, Tejashree Pradip Waingankar, Samantha C Lewis.

Protein- and RNA-rich bodies contribute to the spatial organization of gene expression in the cell and are also sites of quality control critical to cell fitness. In most eukaryotes, mitochondria harbor their own genome, and all steps of mitochondrial gene expression co-occur within a single compartment-the matrix. Here, we report that processed mitochondrial RNAs are consolidated into micrometer-scale translation hubs distal to mitochondrial DNA transcription and RNA processing sites in human cells. We find that, during stress, mitochondrial messenger and ribosomal RNA are sequestered in mesoscale bodies containing mitoribosome components, concurrent with suppression of active translation. Stress bodies are triggered by proteotoxic stress downstream of double-stranded RNA accumulation in cells lacking unwinding activity of the highly conserved helicase SUPV3L1/SUV3. We propose that the spatial organization of nascent polypeptide synthesis into discrete domains serves to throttle the flow of genetic information to support recovery of mitochondrial quality control.

DOI: https://doi.org/10.1126/sciadv.ads6830
Nat Metab. 2025 Apr 18.

Itaconate modulates immune responses via inhibition of peroxiredoxin 5.

Tomas Paulenda, Barbora Echalar, Lucie Potuckova, Veronika Vachova, Denis A Kleverov, Johannes Mehringer, Ekaterina Potekhina, Alex Jacoby, Devashish Sen, Chris Nelson, Rick Stegeman, Vladimir Sukhov, Danielle Kemper, Cheryl F Lichti, Nicholas J Day, Tong Zhang, Kamila Husarcikova, Monika Bambouskova, Daved H Fremont, Wei-Jun Qian, Sergej Djuranovic, Slavica Pavlovic-Djuranovic, Vsevolod V Belousov, Andrzej M Krezel, Maxim N Artyomov.

The immunoregulatory metabolite itaconate accumulates in innate immune cells upon Toll-like receptor stimulation. In response to macrophage activation by lipopolysaccharide, itaconate inhibits inflammasome activation and boosts type I interferon signalling; however, the molecular mechanism of this immunoregulation remains unclear. Here, we show that the enhancement of type I interferon secretion by itaconate depends on the inhibition of peroxiredoxin 5 and on mitochondrial reactive oxygen species. We find that itaconate non-covalently inhibits peroxiredoxin 5, leading to the modulation of mitochondrial peroxide in activating macrophages. Through genetic manipulation, we confirm that peroxiredoxin 5 modulates type I interferon secretion in macrophages. The non-electrophilic itaconate mimetic 2-methylsuccinate inhibits peroxiredoxin 5 and phenocopies immunoregulatory action of itaconate on type I interferon and inflammasome activation, providing further support for a non-covalent inhibition of peroxiredoxin 5 by itaconate. Our work provides insight into the molecular mechanism of actions and biological rationale for the predominantly immune specification of itaconate.

DOI: https://doi.org/10.1038/s42255-025-01275-0
Sci Adv. 2025 Apr 18. 11(16): eadw1489

Molecular basis of pyruvate transport and inhibition of the human mitochondrial pyruvate carrier.

Maximilian Sichrovsky, Denis Lacabanne, Jonathan J Ruprecht, Jessica J Rana, Klaudia Stanik, Mariangela Dionysopoulou, Alice P Sowton, Martin S King, Scott A Jones, Lee Cooper, Steven W Hardwick, Giulia Paris, Dimitri Y Chirgadze, Shujing Ding, Ian M Fearnley, Shane M Palmer, Els Pardon, Jan Steyaert, Vanessa Leone, Lucy R Forrest, Sotiria Tavoulari, Edmund R S Kunji.

The mitochondrial pyruvate carrier transports pyruvate, produced by glycolysis from sugar molecules, into the mitochondrial matrix, as a crucial transport step in eukaryotic energy metabolism. The carrier is a drug target for the treatment of cancers, diabetes mellitus, neurodegeneration, and metabolic dysfunction-associated steatotic liver disease. We have solved the structure of the human MPC1L/MPC2 heterodimer in the inward- and outward-open states by cryo-electron microscopy, revealing its alternating access rocker-switch mechanism. The carrier has a central binding site for pyruvate, which contains an essential lysine and histidine residue, important for its ΔpH-dependent transport mechanism. We have also determined the binding poses of three chemically distinct inhibitor classes, which exploit the same binding site in the outward-open state by mimicking pyruvate interactions and by using aromatic stacking interactions.

DOI: https://doi.org/10.1126/sciadv.adw1489
Nat Commun. 2025 Apr 15. 16(1): 3566

Environmental and molecular noise buffering by the cyanobacterial clock in individual cells.

Aleksandra Eremina, Christian Schwall, Teresa Saez, Lennart Witting, Dietrich Kohlheyer, Bruno M C Martins, Philipp Thomas, James C W Locke.

Circadian clocks enable organisms to anticipate daily cycles, while being robust to molecular and environmental noise. Here, we show how the clock of the cyanobacterium Synechococcus elongatus PCC 7942 buffers genetic and environmental perturbations through its core KaiABC phosphorylation loop. We first characterise single-cell clock dynamics in clock mutants using a microfluidics device that allows precise control of the microenvironment. We find that known clock regulators are dispensable for clock robustness, whilst perturbations of the core clock reveal that the wild type operates at a noise optimum that we can reproduce in a stochastic model of just the core phosphorylation loop. We then examine how the clock responds to noisy environments, including natural light conditions. The model accurately predicts how the clock filters out environmental noise, including fast light fluctuations, to keep time while remaining responsive to environmental shifts. Our findings illustrate how a simple clock network can exhibit complex noise filtering properties, advancing our understanding of how biological circuits can perform accurately in natural environments.

DOI: https://doi.org/10.1038/s41467-025-58169-8
NPJ Metab Health Dis. 2025 ;3(1): 15

Potential bidirectional communication between the liver and the central circadian clock in MASLD.

Frédéric Gachon, Elisabetta Bugianesi, Gabriele Castelnuovo, Henrik Oster, Julie S Pendergast, Sara Montagnese.

  Most aspects of physiology and behaviour fluctuate every 24 h in mammals. These circadian rhythms are orchestrated by an autonomous central clock located in the suprachiasmatic nuclei that coordinates the timing of cellular clocks in tissues throughout the body. The critical role of this circadian system is emphasized by increasing evidence associating disruption of circadian rhythms with diverse pathologies. Accordingly, mounting evidence suggests a bidirectional relationship where disruption of rhythms by circadian misalignment may contribute to liver diseases while liver diseases alter the central clock and circadian rhythms in other tissues. Therefore, liver pathophysiology may broadly impact the circadian system and may provide a mechanistic framework for understanding and targeting metabolic diseases and adjust metabolic setpoints.

Keywords:  Endocrine system and metabolic diseases; Hepatology; Metabolic syndrome; Metabolism; Obesity; Physiology

DOI:  https://doi.org/10.1038/s44324-025-00058-1
Nat Commun. 2025 Apr 17. 16(1): 3641

Coupling of ribosome biogenesis and translation initiation in human mitochondria.

Marleen Heinrichs, Anna Franziska Finke, Shintaro Aibara, Angelique Krempler, Angela Boshnakovska, Peter Rehling, Hauke S Hillen, Ricarda Richter-Dennerlein.

Biogenesis of mitoribosomes requires dedicated chaperones, RNA-modifying enzymes, and GTPases, and defects in mitoribosome assembly lead to severe mitochondriopathies in humans. Here, we characterize late-step assembly states of the small mitoribosomal subunit (mtSSU) by combining genetic perturbation and mutagenesis analysis with biochemical and structural approaches. Isolation of native mtSSU biogenesis intermediates via a FLAG-tagged variant of the GTPase MTG3 reveals three distinct assembly states, which show how factors cooperate to mature the 12S rRNA. In addition, we observe four distinct primed initiation mtSSU states with an incompletely matured rRNA, suggesting that biogenesis and translation initiation are not mutually exclusive processes but can occur simultaneously. Together, these results provide insights into mtSSU biogenesis and suggest a functional coupling between ribosome biogenesis and translation initiation in human mitochondria.

DOI: https://doi.org/10.1038/s41467-025-58827-x
bioRxiv. 2025 Apr 10. pii: 2025.04.03.647084. [Epub ahead of print]

STAR/STARD1: a mitochondrial intermembrane space cholesterol shuttle degraded through mitophagy.

Prasanthi P Koganti, Amy H Zhao, Michael C Kern, Auriole C R Fassinou, Vimal Selvaraj.

The import of cholesterol to the inner mitochondrial membrane by the steroidogenic acute regulatory protein (STAR/STARD1) is essential for de novo steroid hormone biosynthesis and the acidic pathway of bile acid synthesis. This robust system, evolved to start and stop colossal cholesterol movement, ensures pulsatile yet swift mitochondrial steroid metabolism in cells. Nonetheless, the proposed mechanism and components involved in this process has remained a topic of ongoing debate. In this study, we elucidate the mitochondrial import machinery and structural aspects of STAR, revealing its role as an intermembrane space cholesterol shuttle that subsequently undergoes rapid degradation by mitophagy. This newfound mechanism illuminates a fundamental process in cell biology and provides precise interpretations for the full range of human STAR mutation-driven lipoid congenital adrenal hyperplasia in patients.

DOI: https://doi.org/10.1101/2025.04.03.647084
bioRxiv. 2025 Apr 01. pii: 2025.03.29.646096. [Epub ahead of print]

NUDT5 regulates purine metabolism and thiopurine sensitivity by interacting with PPAT.

Zheng Wu, Phong T Nguyen, Varun Sondhi, Run-Wen Yao, Tao Dai, Jui-Chung Chiang, Zengfu Shang, Feng Cai, Ling Cai, Jing Zhang, Mya D Moore, Islam Alshamleh, Xiangyi Li, Tamaratare Ogu, Lauren G Zacharias, Rainah Winston, Joao S Patricio, Xandria Johnson, Wei-Min Chen, Qian Cong, Thomas P Mathews, Yuanyuan Zhang, Ralph J DeBerardinis.

Cells generate purine nucleotides through both de novo purine biosynthesis (DNPB) and purine salvage. Purine accumulation represses energetically costly DNPB through feedback inhibition of the enzymatic steps that produce the precursor phosphoribosylamine. Excessive DNPB is associated with human diseases including neurological dysfunction and hyperuricemia. However, the mechanisms explaining how cells balance DNPB and purine salvage are incompletely understood. Data from a genome-wide CRISPR loss-of-function screen and extensive stable isotope tracing identified Nudix hydrolase 5 (NUDT5) as a suppressor of DNPB during purine salvage. NUDT5 ablation allows DNPB to persist in the presence of either native purines or thiopurine drugs; this renders NUDT5-deficient cells insensitive to thiopurine treatment. Surprisingly, this regulation occurs independently of NUDT5's known function in hydrolyzing ADP-ribose to AMP and ribose-5-phosphate. Rather, NUDT5 interacts with phosphoribosyl pyrophosphate amidotransferase (PPAT), the rate-limiting enzyme in DNPB that generates phosphoribosylamine. Upon induction of purine salvage, the PPAT-NUDT5 interaction is required to trigger disassembly of the purinosome, a cytosolic metabolon involved in efficient DNPB. Mutations that disrupt NUDT5's interaction with PPAT but leave its catalytic activity intact permit excessive DNPB during purine salvage, inducing thiopurine resistance. Collectively, our findings identify NUDT5 as a regulator governing the balance between DNPB and purine salvage, underscoring its impact on nucleotide metabolism and efficacy of thiopurine treatment.

DOI: https://doi.org/10.1101/2025.03.29.646096
Nat Microbiol. 2025 Apr 18.

Metabolic remodelling produces fumarate via the aspartate-argininosuccinate shunt in macrophages as an antiviral defence.

Wenjun Xia, Youxiang Mao, Ziyan Xia, Jie Cheng, Peng Jiang.

Metabolic remodelling underpins macrophage effector functions in response to various stimuli, but the mechanisms involved are unclear. Here we report that viral-infection-induced inflammatory stimulation causes a rewiring of the urea cycle and the tricarboxylic acid cycle metabolism in macrophages to form a cyclic pathway called the aspartate-argininosuccinate (AAS) shunt. Using RNA sequencing, unbiased metabolomics and stable isotope tracing, we found that fumarate generated from the AAS shunt is driven by argininosuccinate synthase (ASS1) in the cytosol and potentiates inflammatory effects. Genetic ablation of ASS1 reduces intracellular fumarate levels and interferon-β production, and mitochondrial respiration is also suppressed. Notably, viral challenge or fumarate esters enhance interferon-β production via direct succination of the mitochondrial antiviral signalling protein and activation of the retinoic acid-inducible gene-I-like receptor signalling. In addition to the vesicular stomatitis virus, the Sendai virus and influenza A virus can also exert these effects. In addition, patients with Ebola virus disease have increased ASS1 expression and ASS1-deficient mice show suppressed macrophage interferon responses to vesicular stomatitis virus infection. These findings reveal that fumarate can be produced from the viral inflammation-induced AAS shunt and is essential for antiviral innate immunity.

DOI: https://doi.org/10.1038/s41564-025-01985-x
Nat Commun. 2025 Apr 17. 16(1): 3669

Peritoneal resident macrophages constitute an immunosuppressive environment in peritoneal metastasized colorectal cancer.

J Saris, A Y F Li Yim, S Bootsma, K J Lenos, R Franco Fernandez, H N Khan, J Verhoeff, D Poel, N M Mrzlikar, L Xiong, M P Schijven, N C T van Grieken, O Kranenburg, M E Wildenberg, A Logiantara, C Jongerius, J J Garcia Vallejo, S S Gisbertz, S Derks, J B Tuynman, G R A M D'Haens, L Vermeulen, J Grootjans.

Patients with peritoneal metastasized colorectal cancer (PM-CRC) have a dismal prognosis. We hypothesized that an immunosuppressive environment in the peritoneal cavity underlies poor prognosis. We define the composition of the human peritoneal immune system (PerIS) using single-cell technologies in 18 patients with- and without PM-CRC, as well as in matched peritoneal metastases (n = 8). Here we show that the PerIS contains abundant immunosuppressive C1Q+VSIG4+ and SPP1+VSIG4+ peritoneal-resident macrophages (PRMs), as well as monocyte-like cavity macrophages (mono-CMs), which share features with tumor-associated macrophages, even in homeostasis. In PM-CRC, expression of immunosuppressive cytokines IL10 and VEGF increases, while simultaneously expression of antigen-presenting molecules decreases in PRMs. These intratumoral suppressive PRMs originate from the PerIS, and intraperitoneal depletion of PRMs in vivo using anti-CSF1R combined with anti-PD1 significantly reduces tumor burden and improves survival. Thus, PRMs define a metastatic site-specific immunosuppressive niche, and targeting PRMs is a promising treatment strategy for PM-CRC.

DOI: https://doi.org/10.1038/s41467-025-58999-6
Open Biol. 2025 Apr;15(4): 240312

The cell origin of reactive oxygen species and its implication for evolutionary trade-offs.

Maïly Kervella, Fabrice Bertile, Frédéric Bouillaud, François Criscuolo.

  The allocation of resources in animals is shaped by adaptive trade-offs aimed at maximizing fitness. At the heart of these trade-offs, lies metabolism and the conversion of food resources into energy, a process mostly occurring in mitochondria. Yet, the conversion of nutrients to utilizable energy molecules (adenosine triphosphate) inevitably leads to the by-production of reactive oxygen species (ROS) that may cause damage to important biomolecules such as proteins or lipids. The 'ROS theory of ageing' has thus proposed that the relationship between lifespan and metabolic rate may be mediated by ROS production. However, the relationship is not as straightforward as it may seem: not only are mitochondrial ROS crucial for various cellular functions, but mitochondria are also actually equipped with antioxidant systems, and many extra-mitochondrial sources also produce ROS. In this review, we discuss how viewing the mitochondrion as a regulator of cellular oxidative homeostasis, not merely a ROS producer, may provide new insights into the role of oxidative stress in the reproduction-survival trade-off. We suggest several avenues to test how mitochondrial oxidative buffering capacity might complement current bioenergetic and evolutionary studies.

Keywords:  ageing theory; bioenergetics; longevity; oxidative metabolism; oxidative stress

DOI:  https://doi.org/10.1098/rsob.240312
Nat Metab. 2025 Apr 15.

GDF15 links adipose tissue lipolysis with anxiety.

Logan K Townsend, Dongdong Wang, Carly M Knuth, Russta Fayyazi, Ahmad Mohammad, Léa J Becker, Evangelia E Tsakiridis, Eric M Desjardins, Zeel Patel, Celina M Valvano, Junfeng Lu, Alice E Payne, Ofure Itua, Kyle D Medak, Daniel M Marko, Jonathan D Schertzer, David C Wright, Shawn M Beaudette, Katherine M Morrison, André C Carpentier, Denis P Blondin, Rebecca E K MacPherson, Jordan G McCall, Marc G Jeschke, Gregory R Steinberg.

Psychological stress changes both behaviour and metabolism to protect organisms. Adrenaline is an important driver of this response. Anxiety correlates with circulating free fatty acid levels and can be alleviated by a peripherally restricted β-blocker, suggesting a peripheral signal linking metabolism with behaviour. Here we show that adrenaline, the β3 agonist CL316,243 and acute restraint stress induce growth differentiation factor 15 (GDF15) secretion in white adipose tissue of mice. Genetic inhibition of adipose triglyceride lipase or genetic deletion of β-adrenergic receptors blocks β-adrenergic-induced increases in GDF15. Increases in circulating GDF15 require lipolysis-induced free fatty acid stimulation of M2-like macrophages within white adipose tissue. Anxiety-like behaviour elicited by adrenaline or restraint stress is eliminated in mice lacking the GDF15 receptor GFRAL. These data provide molecular insights into the mechanisms linking metabolism and behaviour and suggest that inhibition of GDF15-GFRAL signalling might reduce acute anxiety.

DOI: https://doi.org/10.1038/s42255-025-01264-3
Nature. 2025 Apr;640(8059): 623-633

Towards multimodal foundation models in molecular cell biology.

Haotian Cui, Alejandro Tejada-Lapuerta, Maria Brbić, Julio Saez-Rodriguez, Simona Cristea, Hani Goodarzi, Mohammad Lotfollahi, Fabian J Theis, Bo Wang.

The rapid advent of high-throughput omics technologies has created an exponential growth in biological data, often outpacing our ability to derive molecular insights. Large-language models have shown a way out of this data deluge in natural language processing by integrating massive datasets into a joint model with manifold downstream use cases. Here we envision developing multimodal foundation models, pretrained on diverse omics datasets, including genomics, transcriptomics, epigenomics, proteomics, metabolomics and spatial profiling. These models are expected to exhibit unprecedented potential for characterizing the molecular states of cells across a broad continuum, thereby facilitating the creation of holistic maps of cells, genes and tissues. Context-specific transfer learning of the foundation models can empower diverse applications from novel cell-type recognition, biomarker discovery and gene regulation inference, to in silico perturbations. This new paradigm could launch an era of artificial intelligence-empowered analyses, one that promises to unravel the intricate complexities of molecular cell biology, to support experimental design and, more broadly, to profoundly extend our understanding of life sciences.

DOI: https://doi.org/10.1038/s41586-025-08710-y
Trends Endocrinol Metab. 2025 Apr 16. pii: S1043-2760(25)00051-7. [Epub ahead of print]

Fumarate integrates metabolism and immunity in diseases.

Jie Cheng, Yifeng Xiao, Peng Jiang.

  Fumarate is a key metabolite produced primarily by the tricarboxylic acid (TCA) and urea cycles. In addition to having a metabolic role, its electrophilicity enables it to covalently modify cysteines; moreover, because of its α-ketoglutarate (α-KG)-like structure, it can also act as a competitive inhibitor of α-KG-dependent dioxygenases for epigenetic remodeling. Recent advances have broadened the role of fumarate as a bridge between metabolism and both innate and adaptive immunity, suggesting potentially important functions in anticancer immunity and autoimmune diseases. Here we review the connections between fumarate metabolism and immunity; we describe the mechanisms of fumarate regulation in cancer, autoimmunity, and other diseases; and we explore the clinical implications of fumarate and its esters for immunotherapy.

Keywords:  diseases; fumarate metabolism; immunity; succination

DOI:  https://doi.org/10.1016/j.tem.2025.03.008
Trends Biochem Sci. 2025 Apr 15. pii: S0968-0004(25)00060-X. [Epub ahead of print]

Lipids: emerging actors in mitochondrial protein import.

Mayra A Borrero-Landazabal, Vanessa Linke, Agnieszka Chacinska.

  Lipids are emerging as functional players in mitochondrial protein import beyond constituting membranes. Cryo-electron microscopy structures of protein translocases such as translocase of the outer membrane (TOM) and insertases such as translocase of the inner membrane (TIM22) link lipids to protein import by suggesting structural and functional roles for lipids in protein translocation and insertion, and for protein insertases in lipid scrambling.

Keywords:  membrane complexes; mitochondrial biology; mitochondrial protein import; protein–lipid interactions

DOI:  https://doi.org/10.1016/j.tibs.2025.03.011
Cell Death Dis. 2025 Apr 16. 16(1): 307

Loss of VHL-mediated pRb regulation promotes clear cell renal cell carcinoma.

Mercy Akuma, Minjun Kim, Chenxuan Zhu, Ellis Wiljer, Antoine Gaudreau-Lapierre, Leshan D Patterson, Lars Egevad, Simon Tanguay, Laura Trinkle-Mulcahy, William L Stanford, Yasser Riazalhosseini, Ryan C Russell.

The von Hippel-Lindau (VHL) tumor suppressor is a substrate-defining component of E3 ubiquitin ligase complexes that target cellular substrates for proteasome-mediated degradation. VHL inactivation by mutation or transcriptional silencing is observed in most sporadic cases of clear cell renal cell carcinoma (ccRCC). VHL loss in ccRCC leads to constitutive stabilization of E3 ligase substrates, including hypoxia inducible factor α (HIFα). HIFα stabilization upon VHL loss is known to contribute to ccRCC development through transactivation of hypoxia-responsive genes. HIF-independent VHL targets have been implicated in oncogenesis, although those mechanisms are less well-defined than for HIFα. Using proximity labeling to identify proteasomal-sensitive VHL interactors, we identified retinoblastoma protein (pRb) as a novel substrate of VHL. Mechanistically, VHL interacts with pRb in a proteasomal-sensitive manner, promoting its ubiquitin-mediated degradation. Concordantly, VHL-inactivation results in pRb hyperstabilization. Functionally, loss of pRb in ccRCC led to increased cell death, transcriptional changes, and loss of oncogenic properties in vitro and in vivo. We also show that downstream transcriptional changes induced by pRb hyperstabilization may contribute to ccRCC tumor development. Together, our findings reveal a novel VHL-related pathway which can be therapeutically targeted to inhibit ccRCC tumor development.

DOI: https://doi.org/10.1038/s41419-025-07623-y
Eur J Immunol. 2025 Apr;55(4): e202451102

Metabolic Dialogue Shapes Immune Response in the Tumor Microenvironment.

Fengxia Gao, Rushil Shah, Gang Xin, Ruoning Wang.

The fate of immune cells is fundamentally linked to their metabolic program, which is also influenced by the metabolic landscape of their environment. The tumor microenvironment represents a unique system for intercellular metabolic interactions, where tumor-derived metabolites suppress effector CD8+ T cells and promote tumor-promoting macrophages, reinforcing an immune-suppressive niche. This review will discuss recent advancements in metabolism research, exploring the interplay between various metabolites and their effects on immune cells within the tumor microenvironment.

DOI: https://doi.org/10.1002/eji.202451102
Trends Immunol. 2025 Apr 11. pii: S1471-4906(25)00058-4. [Epub ahead of print]

The unusual metabolism of germinal center B cells.

Caitlin J Gracie, Robert Mitchell, Julia C Johnstone, Alexander J Clarke.

  In the germinal center (GC), B cells undergo rounds of somatic hypermutation (SHM), proliferation, and positive selection to develop into high-affinity, long-lived plasma cells and memory B cells. It is well established that, upon activation, B cells significantly alter their metabolism, but until recently little was understood about their metabolism within the GC. In this review we discuss novel in vivo models in which GC B cell (GCBC) metabolism is disrupted; these have greatly increased our understanding of B cell metabolic phenotype. GCBCs are unusual in that, unlike almost all other rapidly proliferating immune cells, they use little glycolysis but prefer fatty acid oxidation (FAO) to fuel ATP synthesis, whilst preferentially utilizing glucose and amino acids as carbon and nitrogen sources for biosynthetic pathways.

Keywords:  B cell; germinal center; metabolism

DOI:  https://doi.org/10.1016/j.it.2025.02.015
Cell Death Dis. 2025 Apr 17. 16(1): 309

SLC25A42 promotes gastric cancer growth by conferring ferroptosis resistance through enhancing CPT2-mediated fatty acid oxidation.

Haoying Wang, Weijia Dou, Mengxiao Liu, Weifang Wang, Ying Yang, Jibin Li, Zhenxiong Liu, Nan Wang.

Accumulating evidence has shown that the dysfunction of mitochondria, the multifunctional organelles in various cellular processes, is a pivotal event in the development of various diseases, including human cancers. Solute Carrier Family 25 Member 42 (SLC25A42) is a mitochondrial protein governing the transport of coenzyme A (CoA). However, the biological roles of SLC25A42 in human cancers are still unexplored. Here we uncovered that SLC25A42 is upregulated and correlated with a worse prognosis in GC patients. SLC25A42 promotes the proliferation of gastric cancer (GC) cells while suppresses apoptosis in vitro and in vivo. Mechanistically, SLC25A42 promotes the growth and inhibits apoptosis of GC cells by reprograming lipid metabolism. On the one hand, SLC25A42 enhances fatty acid oxidation-mediated mitochondrial respiration to provide energy for cell survival. On the other hand, SLC25A42 decreases the levels of free fatty acids and ROS to inhibit ferroptosis. Moreover, we found that SLC25A42 reprograms lipid metabolism in GC cells by upregulating the acetylation and thus the expression of CPT2. Collectively, our data reveal a critical oncogenic role of SLC25A42 in GCs and suggest that SLC25A42 represent a promising therapeutic target for GC.

DOI: https://doi.org/10.1038/s41419-025-07644-7
bioRxiv. 2025 Apr 04. pii: 2025.04.03.645994. [Epub ahead of print]

A non-canonical cGAS-STING pathway drives cellular and organismal aging.

Rafael Cancado de Faria, Lilian Silva, Barbara Teodoro-Castro, Kyle S McCommis, Elena V Shashkova, Susana Gonzalo.

Accumulation of cytosolic DNA has emerged as a hallmark of aging, inducing sterile inflammation. STING (Stimulator of Interferon Genes) protein translates the sensing of cytosolic DNA by cGAS (cyclic-GMP-AMP synthase) into an inflammatory response. However, the molecular mechanisms whereby cytosolic DNA-induced cGAS-STING pathway leads to aging remain poorly understood. We show that STING does not follow the canonical pathway of activation in human fibroblasts passaged (aging) in culture, senescent fibroblasts, or progeria fibroblasts (from Hutchinson Gilford Progeria Syndrome patients). Despite cytosolic DNA buildup, features of the canonical cGAS-STING pathway like increased cGAMP production, STING phosphorylation, and STING trafficking to perinuclear compartment are not observed in progeria/senescent/aging fibroblasts. Instead, STING localizes at endoplasmic reticulum, nuclear envelope, and chromatin. Despite the non-conventional STING behavior, aging/senescent/progeria cells activate inflammatory programs such as the senescence-associated secretory phenotype (SASP) and the interferon (IFN) response, in a cGAS and STING-dependent manner, revealing a non-canonical pathway in aging. Importantly, progeria/aging/senescent cells are hindered in their ability to activate the canonical cGAS-STING pathway with synthetic DNA, compared to young cells. This deficiency is rescued by activating vitamin D receptor signaling, unveiling new mechanisms regulating the cGAS-STING pathway in aging. Significantly, in HGPS, inhibition of the non-canonical cGAS-STING pathway ameliorates cellular hallmarks of aging, reduces tissue degeneration, and extends the lifespan of progeria mice. Our study reveals that a new feature of aging is the progressively reduced ability to activate the canonical cGAS-STING pathway in response to cytosolic DNA, triggering instead a non-canonical pathway that drives senescence/aging phenotypes.
Significance Statement: Our study provides novel insights into the mechanisms driving sterile inflammation in aging and progeria. We reveal a previously unrecognized characteristic of aging cells: the progressive loss of ability to activate the canonical response to foreign or self-DNA at the cytoplasm. Instead, aging, senescent, and progeria cells activate inflammatory programs via a non-conventional pathway driven by cGAS and the adaptor protein STING. Importantly, pharmacological inhibition of the non-canonical cGAS-STING pathway ameliorates cellular, tissue and organismal decline in a devastating accelerated aging disease (Hutchinson Gilford Progeria Syndrome), highlighting it as a promising therapeutic target for age-related pathologies.

DOI: https://doi.org/10.1101/2025.04.03.645994
Nat Commun. 2025 Apr 19. 16(1): 3710

Epithelial cell competition is promoted by signaling from immune cells.

Yilun Zhu, Zeba Wunderlich, Arthur D Lander.

In epithelial tissues, juxtaposition of cells of different phenotypes can trigger cell competition, a process whereby one type of cell drives death and extrusion of another. During growth and homeostasis, cell competition is thought to serve a quality control function, eliminating cells that are "less fit". Tissues may also attack and eliminate newly arising tumor cells, exploiting mechanisms shared with other instances of cell competition, but that differ, reportedly, in the involvement of the immune system. Whereas immune cells have been shown to play a direct role in killing tumor cells, this has not been observed in other cases of cell competition, suggesting that tissues recognize and handle cancer cells differently. Here, we challenge this view, showing that, in the fruit fly Drosophila, innate immune cells play similar roles in cell killing during classical cell competition as in eliminating tumors. These findings suggest that immune suppression of cancer may exploit the same mechanisms as are involved in promoting phenotypic uniformity among epithelial cells.

DOI: https://doi.org/10.1038/s41467-025-59130-5
Nat Commun. 2025 Apr 17. 16(1): 3401

Mitochondrial complexity is regulated at ER-mitochondria contact sites via PDZD8-FKBP8 tethering.

Koki Nakamura, Saeko Aoyama-Ishiwatari, Takahiro Nagao, Mohammadreza Paaran, Christopher J Obara, Yui Sakurai-Saito, Jake Johnston, Yudan Du, Shogo Suga, Masafumi Tsuboi, Makoto Nakakido, Kouhei Tsumoto, Yusuke Kishi, Yukiko Gotoh, Chulhwan Kwak, Hyun-Woo Rhee, Jeong Kon Seo, Hidetaka Kosako, Clint Potter, Bridget Carragher, Jennifer Lippincott-Schwartz, Franck Polleux, Yusuke Hirabayashi.

Mitochondria-ER membrane contact sites (MERCS) represent a fundamental ultrastructural feature underlying unique biochemistry and physiology in eukaryotic cells. The ER protein PDZD8 is required for the formation of MERCS in many cell types, however, its tethering partner on the outer mitochondrial membrane (OMM) is currently unknown. Here we identify the OMM protein FKBP8 as the tethering partner of PDZD8 using a combination of unbiased proximity proteomics, CRISPR-Cas9 endogenous protein tagging, Cryo-electron tomography, and correlative light-electron microscopy. Single molecule tracking reveals highly dynamic diffusion properties of PDZD8 along the ER membrane with significant pauses and captures at MERCS. Overexpression of FKBP8 is sufficient to narrow the ER-OMM distance, whereas independent versus combined deletions of these two proteins demonstrate their interdependence for MERCS formation. Furthermore, PDZD8 enhances mitochondrial complexity in a FKBP8-dependent manner. Our results identify a novel ER-mitochondria tethering complex that regulates mitochondrial morphology in mammalian cells.

DOI: https://doi.org/10.1038/s41467-025-58538-3
Biol Chem. 2025 Apr 14.

The proteostasis burden of aneuploidy.

Prince Saforo Amponsah, Zuzana Storchová.

  Aneuploidy refers to chromosome number abnormality that is not an exact multiple of the haploid chromosome set. Aneuploidy has largely negative consequences in cells and organisms, manifested as so-called aneuploidy-associated stresses. A major consequence of aneuploidy is proteotoxic stress due to abnormal protein expression from imbalanced chromosome numbers. Recent advances have improved our understanding of the nature of the proteostasis imbalance caused by aneuploidy and highlighted their relevance with respect to organellar homeostasis, dosage compensation, or mechanisms employed by cells to mitigate the detrimental stress. In this review, we highlight the recent findings and outline questions to be addressed in future research.

Keywords:  SQSTM1/p62; aging; aneuploidy; cancer; mitochondria; proteostasis

DOI:  https://doi.org/10.1515/hsz-2024-0163
Nat Commun. 2025 Apr 16. 16(1): 3306

Elevated mitochondrial membrane potential is a therapeutic vulnerability in Dnmt3a-mutant clonal hematopoiesis.

Kira A Young, Mohsen Hosseini, Jayna J Mistry, Claudia Morganti, Taylor S Mills, Xiurong Cai, Brandon T James, Griffin J Nye, Natalie R Fournier, Veronique Voisin, Ali Chegini, Aaron D Schimmer, Gary D Bader, Grace Egan, Marc R Mansour, Grant A Challen, Eric M Pietras, Kelsey H Fisher-Wellman, Keisuke Ito, Steven M Chan, Jennifer J Trowbridge.

The competitive advantage of mutant hematopoietic stem and progenitor cells (HSPCs) underlies clonal hematopoiesis (CH). Drivers of CH include aging and inflammation; however, how CH-mutant cells gain a selective advantage in these contexts is an unresolved question. Using a murine model of CH (Dnmt3aR878H/+), we discover that mutant HSPCs sustain elevated mitochondrial respiration which is associated with their resistance to aging-related changes in the bone marrow microenvironment. Mutant HSPCs have DNA hypomethylation and increased expression of oxidative phosphorylation gene signatures, increased functional oxidative phosphorylation capacity, high mitochondrial membrane potential (Δψm), and greater dependence on mitochondrial respiration compared to wild-type HSPCs. Exploiting the elevated Δψm of mutant HSPCs, long-chain alkyl-TPP molecules (MitoQ, d-TPP) selectively accumulate in the mitochondria and cause reduced mitochondrial respiration, mitochondrial-driven apoptosis and ablate the competitive advantage of HSPCs ex vivo and in vivo in aged recipient mice. Further, MitoQ targets elevated mitochondrial respiration and the selective advantage of human DNMT3A-knockdown HSPCs, supporting species conservation. These data suggest that mitochondrial activity is a targetable mechanism by which CH-mutant HSPCs gain a selective advantage over wild-type HSPCs.

DOI: https://doi.org/10.1038/s41467-025-57238-2
Trends Cancer. 2025 Apr 17. pii: S2405-8033(25)00093-7. [Epub ahead of print]

A macrophage-neutrophil program drives mammary carcinogenesis.

Lukas Bolini, Simon R V Knott, Lorenzo Galluzzi.

  The molecular and cellular pathways through which breast cancer evades immunosurveillance remain poorly understood. Recent data from Camargo et al. demonstrate that - on recruitment to the tumor microenvironment by ductal macrophages - a heterogeneous population of neutrophils can establish physical contacts with malignant cells within spatial niches that sustain mammary oncogenesis.

Keywords:  CCL3; MMTV-PyMT; angiogenesis; endothelial cells; three Cs; γδ T cells

DOI:  https://doi.org/10.1016/j.trecan.2025.04.001
J Biol Chem. 2025 Apr 16. pii: S0021-9258(25)00359-X. [Epub ahead of print] 108510

MitoSNO inhibits mitochondrial hydrogen peroxide (mtH2O2) generation by α-ketoglutarate dehydrogenase (KGDH).

Olivia Chalifoux, Samantha Sterman, Ben Faerman, Meijing Li, Stephanie Trezza, Marek Michalak, Luis B Agellon, Ryan J Mailloux.

Here, we demonstrate mitochondrial hydrogen peroxide (mtH2O2) production by α-ketoglutarate dehydrogenase (KGDH) can be inhibited by MitoSNO, alleviating lipotoxicity. MitoSNO in the nanomolar range inhibits mtH2O2 by ∼50% in isolated liver mitochondria without disrupting respiration, whereas the mitochondria-selective derivative used to synthesize MitoSNO, mitochondria-selective N-acetyl-penicillamine (MitoNAP), had no effect on either mtH2O2 generation or oxidative phosphorylation (OxPhos). Additionally, mtH2O2 generation in isolated liver mitochondria was almost abolished when MitoSNO was administered in the low micromolar range. The potent inhibitory effect of MitoSNO was comparable to 2-keto-3-methyl-valeric acid (KMV) and valproic acid (VA), selective inhibitors for KGDH-mediate mH2O2 production. S1QEL 1.1 (S1) and S3QEL (S3), which are known to selectively suppress mtH2O2 genesis through inhibition of complex I and complex III respectively, without disrupting respiration, had little to no effect on mtH2O2 production by liver mitochondria. We also identified it was a major mtH2O2 source as well but MitoSNO and MitoNAP did not affect mtH2O2 production by this ETC-linked enzyme. The MitoSNO also suppressed mtH2O2 production and partially rescued mitochondrial respiration in Huh-7 cells subjected to palmitate (PA) and fructose (Fruc) induced lipotoxicity. MitoSNO also prevented cell death and abrogated intrahepatic lipid accumulation in these Huh-7 cells. MitoSNO nullified mtH2O2 overgeneration and partially rescued OxPhos in liver mitochondria from mice fed a high fat diet (HFD). Our findings demonstrate that MitoSNO interferes with mtH2O2 production through KGDH S-nitrosation and may be useful in alleviating non-alcoholic fatty liver disease (NAFLD).

DOI: https://doi.org/10.1016/j.jbc.2025.108510
Cell Rep. 2025 Apr 16. pii: S2211-1247(25)00362-6. [Epub ahead of print]44(5): 115591

Simultaneous in vivo multi-organ fluxomics reveals divergent metabolic adaptations in liver, heart, and skeletal muscle during obesity.

Mohsin Rahim, Tomasz K Bednarski, Clinton M Hasenour, Deveena R Banerjee, Irina Trenary, Jamey D Young.

  We present an isotope-based metabolic flux analysis (MFA) approach to simultaneously quantify metabolic fluxes in the liver, heart, and skeletal muscle of individual mice. The platform was scaled to examine metabolic flux adaptations in age-matched cohorts of mice exhibiting varying levels of chronic obesity. We found that severe obesity increases hepatic gluconeogenesis and citric acid cycle flux, accompanied by elevated glucose oxidation in the heart that compensates for impaired fatty acid oxidation. In contrast, skeletal muscle fluxes exhibit an overall reduction in substrate oxidation. These findings demonstrate the dichotomy in fuel utilization between cardiac and skeletal muscle during worsening metabolic disease and demonstrate the divergent effects of obesity on metabolic fluxes in different organs. This multi-tissue MFA technology can be extended to address important questions about in vivo regulation of metabolism and its dysregulation in disease, which cannot be fully answered through studies of single organs or isolated cells/tissues.

Keywords:  CP: Metabolism; cardiac metabolism; fluxomics; isotope labeling; liver metabolism; metabolic flux analysis; metabolomics; muscle metabolism; obesity; steatotic liver disease; systems biology

DOI:  https://doi.org/10.1016/j.celrep.2025.115591
Trends Biochem Sci. 2025 Apr 11. pii: S0968-0004(25)00056-8. [Epub ahead of print]

Emerging mechanisms of human mitochondrial translation regulation.

Michele Brischigliaro, Ahram Ahn, Seungwoo Hong, Flavia Fontanesi, Antoni Barrientos.

  Mitochondrial translation regulation enables precise control over the synthesis of hydrophobic proteins encoded by the organellar genome, orchestrating their membrane insertion, accumulation, and assembly into oxidative phosphorylation (OXPHOS) complexes. Recent research highlights regulation across all translation stages (initiation, elongation, termination, and recycling) through a complex interplay of mRNA structures, specialized translation factors, and unique regulatory mechanisms that adjust protein levels for stoichiometric assembly. Key discoveries include mRNA-programmed ribosomal pausing, frameshifting, and termination-dependent re-initiation, which fine-tune protein synthesis and promote translation of overlapping open reading frames (ORFs) in bicistronic transcripts. In this review, we examine these advances, which are significantly enhancing our understanding of mitochondrial gene expression.

Keywords:  RNA folding; mitochondrial translation; programmed ribosomal frameshifting; ribosome stalling; termination-reinitiation

DOI:  https://doi.org/10.1016/j.tibs.2025.03.007
Cell. 2025 Apr 10. pii: S0092-8674(25)00343-5. [Epub ahead of print]

Integrator loss leads to dsRNA formation that triggers the integrated stress response.

Apoorva Baluapuri, Nicole ChenCheng Zhao, Ryan J Marina, Kai-Lieh Huang, Anastasia Kuzkina, Maria E Amodeo, Chad B Stein, Lucie Y Ahn, Jordan S Farr, Ashleigh E Schaffer, Vikram Khurana, Eric J Wagner, Karen Adelman.

  Integrator (INT) is a metazoan-specific complex that targets promoter-proximally paused RNA polymerase II (RNAPII) for termination, preventing immature RNAPII from entering gene bodies and functionally attenuating transcription of stress-responsive genes. Mutations in INT subunits are associated with many human diseases, including cancer, ciliopathies, and neurodevelopmental disorders, but how reduced INT activity contributes to disease is unknown. Here, we demonstrate that the loss of INT-mediated termination in human cells triggers the integrated stress response (ISR). INT depletion causes upregulation of short genes such as the ISR transcription factor activating transcription factor 3 (ATF3). Further, immature RNAPII that escapes into genes upon INT depletion is prone to premature termination, generating incomplete pre-mRNAs with retained introns. Retroelements within retained introns form double-stranded RNA (dsRNA) that is recognized by protein kinase R (PKR), which drives ATF4 activation and prolonged ISR. Critically, patient cells with INT mutations exhibit dsRNA accumulation and ISR activation, thereby implicating chronic ISR in diseases caused by INT deficiency.

Keywords:  IR-Alu; Integrator; RNA polymerase II pausing; double-stranded RNA; gene regulation; integrated stress response; premature cleavage and polyadenylation; premature termination; protein kinase R

DOI:  https://doi.org/10.1016/j.cell.2025.03.025
Nat Rev Genet. 2025 Apr 16.

Emerging roles of transcriptional condensates as temporal signal integrators.

Kirstin Meyer, Bo Huang, Orion D Weiner.

Transcription factors relay information from the external environment to gene regulatory networks that control cell physiology. To confer signalling specificity, robustness and coordination, these signalling networks use temporal communication codes, such as the amplitude, duration or frequency of signals. Although much is known about how temporal information is encoded, a mechanistic understanding of how gene regulatory networks decode signalling dynamics is lacking. Recent advances in our understanding of phase separation of transcriptional condensates provide new biophysical frameworks for both temporal encoding and decoding mechanisms. In this Perspective, we summarize the mechanisms by which transcriptional condensates could enable temporal decoding through signal adaptation, memory and persistence. We further outline methods to probe and manipulate dynamic communication codes of transcription factors and condensates to rationally control gene activation.

DOI: https://doi.org/10.1038/s41576-025-00837-y