bims-camemi 2025-02-02 papers

bims-camemi

Biomed News

on Mitochondrial metabolism in cancer

Issue of 2025–02–02
47 papers selected by
Christian Frezza, Universität zu Köln

Ferroptosis triggers mitochondrial fragmentation via Drp1 activation.
Subcellular mitochondrial heterogeneity enables opposing metabolic demands.
Epstein-Barr virus-driven cardiolipin synthesis sustains metabolic remodeling during B cell transformation.
Epigenetic modification increases skeletal muscle resilience to metabolic stress.
Multiomics reveals that triacylglycerol mobilization helps drive recovery from mitochondrial stress.
BET inhibition induces GDH1-dependent glutamine metabolic remodeling and vulnerability in liver cancer.
Spatial metabolomics to unravel cellular metabolism.
SLC25A38 is required for mitochondrial pyridoxal 5'-phosphate (PLP) accumulation.
PRPS activity tunes redox homeostasis in Myc-driven lymphoma.
The histone modification regulator, SIN3, plays a role in the cellular response to changes in glycolytic flux.
TRIM28-dependent developmental heterogeneity determines cancer susceptibility through distinct epigenetic states.
Emerging insights into the impact of systemic metabolic changes on tumor-immune interactions.
Fluorescence lifetime imaging microscopy for metabolic analysis of LDHB inhibition in triple negative breast cancer.
A genetically encoded fluorescent biosensor for visualization of acetyl-CoA in live cells.
Rewiring cancer: 3D genome determinants of cancer hallmarks.
SLC29A1 and SLC29A2 are human nicotinamide cell membrane transporters.
The Role of Mitochondrial Solute Carriers SLC25 in Cancer Metabolic Reprogramming: Current Insights and Future Perspectives.
Metabolic adaptations to acute glucose uptake inhibition converge upon mitochondrial respiration for leukemia cell survival.
The spatial landscape of cancer hallmarks reveals patterns of tumor ecological dynamics and drug sensitivity.
SLC25A1 and ACLY maintain cytosolic acetyl-CoA and regulate ferroptosis susceptibility via FSP1 acetylation.
PAX3-FOXO1 drives targetable cell state-dependent metabolic vulnerabilities in rhabdomyosarcoma.
Mitochondrial KMT9 methylates DLAT to control pyruvate dehydrogenase activity and prostate cancer growth.
FAM43A coordinates mtDNA replication and mitochondrial biogenesis in response to mtDNA depletion.
A multimodal imaging pipeline to decipher cell-specific metabolic functions and tissue microenvironment dynamics.
Redirecting glucose flux during in vitro expansion generates epigenetically and metabolically superior T cells for cancer immunotherapy.
Electrical homeostasis of the inner mitochondrial membrane potential.
Tissue-specific effects of dietary protein on cellular senescence are mediated by branched-chain amino acids.
Mitochondrial cristae: lung cancer metabolism architects.
Metabolic Reprogramming at the Edge of Redox: Connections Between Metabolic Reprogramming and Cancer Redox State.
Microenvironmental determinants of endothelial cell heterogeneity.
Flux measurements of the tricarboxylic acid cycle in the tumors of mice.
Splicing accuracy varies across human introns, tissues, age and disease.
Placental mitochondrial metabolic adaptation maintains cellular energy balance in pregnancy complicated by gestational hypoxia.
Methanol transfer supports metabolic syntrophy between bacteria and archaea.
A compendium of Amplification-Related Gain Of Sensitivity genes in human cancer.
Ketogenesis supports hepatic polyunsaturated fatty acid homeostasis via fatty acid elongation.
Cancer evolution: from Darwin to the Extended Evolutionary Synthesis.
Arginine metabolism in myeloid cells in health and disease.
Nutrient control of splice site selection contributes to methionine addiction of cancer.
A Call for a Neoadjuvant Kidney Cancer Consortium: Lessons Learned from Other Cancer Types.
Reproducibility and transparency: what's going on and how can we help.
Sub-organellar mitochondrial hydrogen peroxide observed using a SNAP tag targeted coumarin-based fluorescent reporter.
The 40S ribosomal subunit recycling complex modulates mitochondrial dynamics and endoplasmic reticulum - mitochondria tethering at mitochondrial fission/fusion hotspots.
Using DIMet for Differential Analysis of Labeled Metabolomics Data: A Step-by-step Guide Showcasing the Glioblastoma Metabolism.
Sphingolipid metabolism orchestrates establishment of the hair follicle stem cell compartment.
The protection of UCK2 protein stability by GART maintains pyrimidine salvage synthesis for HCC growth under glucose limitation.
A mitochondria-to-nucleus regulation mediated by the nuclear-translocated mitochondrial lncRNAs.

Cell Death Dis. 2025 Jan 25. 16(1): 40

Ferroptosis triggers mitochondrial fragmentation via Drp1 activation.

Lohans Pedrera, Laura Prieto Clemente, Alina Dahlhaus, Sara Lotfipour Nasudivar, Sofya Tishina, Daniel Olmo González, Jenny Stroh, Fatma Isil Yapici, Randhwaj Pratap Singh, Nils Grotehans, Thomas Langer, Ana J García-Sáez, Silvia von Karstedt.

Constitutive mitochondrial dynamics ensure quality control and metabolic fitness of cells, and their dysregulation has been implicated in various human diseases. The large GTPase Dynamin-related protein 1 (Drp1) is intimately involved in mediating constitutive mitochondrial fission and has been implicated in mitochondrial cell death pathways. During ferroptosis, a recently identified type of regulated necrosis driven by excessive lipid peroxidation, mitochondrial fragmentation has been observed. Yet, how this is regulated and whether it is involved in ferroptotic cell death has remained unexplored. Here, we provide evidence that Drp1 is activated upon experimental induction of ferroptosis and promotes cell death execution and mitochondrial fragmentation. Using time-lapse microscopy, we found that ferroptosis induced mitochondrial fragmentation and loss of mitochondrial membrane potential, but not mitochondrial outer membrane permeabilization. Importantly, Drp1 accelerated ferroptotic cell death kinetics. Notably, this function was mediated by the regulation of mitochondrial dynamics, as overexpression of Mitofusin 2 phenocopied the effect of Drp1 deficiency in delaying ferroptosis cell death kinetics. Mechanistically, we found that Drp1 is phosphorylated and activated after induction of ferroptosis and that it translocates to mitochondria. Further activation at mitochondria through the phosphatase PGAM5 promoted ferroptotic cell death. Remarkably, Drp1 depletion delayed mitochondrial and plasma membrane lipid peroxidation. These data provide evidence for a functional role of Drp1 activation and mitochondrial fragmentation in the acceleration of ferroptotic cell death, with important implications for targeting mitochondrial dynamics in diseases associated with ferroptosis.

DOI: https://doi.org/10.1038/s41419-024-07312-2
Trends Endocrinol Metab. 2025 Jan 28. pii: S1043-2760(25)00003-7. [Epub ahead of print]

Subcellular mitochondrial heterogeneity enables opposing metabolic demands.

Brandon Chen, Yatrik M Shah, Costas A Lyssiotis.

  Mitochondria perform essential metabolic processes that sustain cellular bioenergetics and biosynthesis. In a recent article, Ryu et al. explored how mitochondria coordinate biochemical reactions with opposing redox demands within the same cell. They demonstrate that subcellular mitochondrial heterogeneity enables metabolic compartmentalization to permit concurrent oxidative ATP production and reductive proline biosynthesis.

Keywords:  metabolic compartmentalization; mitochondria dynamics; mitochondrial ultrastructure; organelle communication; proline metabolism

DOI:  https://doi.org/10.1016/j.tem.2025.01.003
Sci Adv. 2025 Jan 31. 11(5): eadr8837

Epstein-Barr virus-driven cardiolipin synthesis sustains metabolic remodeling during B cell transformation.

Haixi You, Larissa Havey, Zhixuan Li, Yin Wang, John M Asara, Rui Guo.

The Epstein-Barr virus (EBV) infects nearly 90% of adults globally and is linked to over 200,000 annual cancer cases. Immunocompromised individuals from conditions such as primary immune disorders, HIV, or posttransplant immunosuppressive therapies are particularly vulnerable because of EBV's transformative capability. EBV remodels B cell metabolism to support energy, biosynthetic precursors, and redox equivalents necessary for transformation. Most EBV-driven metabolic pathways center on mitochondria. However, how EBV regulates B cell mitochondrial function and metabolic fluxes remains unclear. Here, we show that EBV boosts cardiolipin (CL) biosynthesis, essential for mitochondrial cristae biogenesis, via EBV nuclear antigen 2/MYC-induced CL enzyme transactivation. Pharmacological and CRISPR genetic analyses underscore the essentiality of CL biosynthesis in EBV-transformed B cells. Metabolomic and isotopic tracing highlight CL's role in sustaining respiration, one-carbon metabolism, and aspartate synthesis. Disrupting CL biosynthesis destabilizes mitochondrial matrix enzymes pivotal to these pathways. We demonstrate EBV-induced CL metabolism as a therapeutic target, offering synthetic lethal strategies against EBV-associated B cell malignancies.

DOI: https://doi.org/10.1126/sciadv.adr8837
Nat Metab. 2025 Jan 27.

Epigenetic modification increases skeletal muscle resilience to metabolic stress.

DOI: https://doi.org/10.1038/s42255-024-01211-8
Nat Cell Biol. 2025 Jan 24.

Multiomics reveals that triacylglycerol mobilization helps drive recovery from mitochondrial stress.

DOI: https://doi.org/10.1038/s41556-024-01603-8
Life Metab. 2024 Aug;3(4): loae016

BET inhibition induces GDH1-dependent glutamine metabolic remodeling and vulnerability in liver cancer.

Wen Mi, Jianwei You, Liucheng Li, Lingzhi Zhu, Xinyi Xia, Li Yang, Fei Li, Yi Xu, Junfeng Bi, Pingyu Liu, Li Chen, Fuming Li.

  Bromodomain and extra-terminal domain (BET) proteins, which function partly through MYC proto-oncogene (MYC), are critical epigenetic readers and emerging therapeutic targets in cancer. Whether and how BET inhibition simultaneously induces metabolic remodeling in cancer cells remains unclear. Here we find that even transient BET inhibition by JQ-1 and other pan-BET inhibitors (pan-BETis) blunts liver cancer cell proliferation and tumor growth. BET inhibition decreases glycolytic gene expression but enhances mitochondrial glucose and glutamine oxidative metabolism revealed by metabolomics and isotope labeling analysis. Specifically, BET inhibition downregulates miR-30a to upregulate glutamate dehydrogenase 1 (GDH1) independent of MYC, which produces α-ketoglutarate for mitochondrial oxidative phosphorylation (OXPHOS). Targeting GDH1 or OXPHOS is synthetic lethal to BET inhibition, and combined BET and OXPHOS inhibition therapeutically prevents liver tumor growth in vitro and in vivo. Together, we uncover an important epigenetic-metabolic crosstalk whereby BET inhibition induces MYC-independent and GDH1-dependent glutamine metabolic remodeling that can be exploited for innovative combination therapy of liver cancer.

Keywords:  BET; glutamate dehydrogenase 1; glutamine metabolism; oxidative phosphorylation; synthetic lethality

DOI:  https://doi.org/10.1093/lifemeta/loae016
Nat Rev Genet. 2025 Jan 28.

Spatial metabolomics to unravel cellular metabolism.

Arafath K Najumudeen, Johan Vande Voorde.

DOI: https://doi.org/10.1038/s41576-025-00817-2
Nat Commun. 2025 Jan 24. 16(1): 978

SLC25A38 is required for mitochondrial pyridoxal 5'-phosphate (PLP) accumulation.

Izabella A Pena, Jeffrey S Shi, Sarah M Chang, Jason Yang, Samuel Block, Charles H Adelmann, Heather R Keys, Preston Ge, Shveta Bathla, Isabella H Witham, Grzegorz Sienski, Angus C Nairn, David M Sabatini, Caroline A Lewis, Nora Kory, Matthew G Vander Heiden, Myriam Heiman.

Many essential proteins require pyridoxal 5'-phosphate, the active form of vitamin B6, as a cofactor for their activity. These include enzymes important for amino acid metabolism, one-carbon metabolism, polyamine synthesis, erythropoiesis, and neurotransmitter metabolism. A third of all mammalian pyridoxal 5'-phosphate-dependent enzymes are localized in the mitochondria; however, the molecular machinery involved in the regulation of mitochondrial pyridoxal 5'-phosphate levels in mammals remains unknown. In this study, we used a genome-wide CRISPR interference screen in erythroleukemia cells and organellar metabolomics to identify the mitochondrial inner membrane protein SLC25A38 as a regulator of mitochondrial pyridoxal 5'-phosphate. Loss of SLC25A38 causes depletion of mitochondrial, but not cellular, pyridoxal 5'-phosphate, and impairs cellular proliferation under both physiological and low vitamin B6 conditions. Metabolic changes associated with SLC25A38 loss suggest impaired mitochondrial pyridoxal 5'-phosphate-dependent enzymatic reactions, including serine to glycine conversion catalyzed by serine hydroxymethyltransferase-2 as well as ornithine aminotransferase. The proliferation defect of SLC25A38-null K562 cells in physiological and low vitamin B6 media can be explained by the loss of serine hydroxymethyltransferase-2-dependent production of one-carbon units and downstream de novo nucleotide synthesis. Our work points to a role for SLC25A38 in mitochondrial pyridoxal 5'-phosphate accumulation and provides insights into the pathology of congenital sideroblastic anemia.

DOI: https://doi.org/10.1038/s41467-025-56130-3
bioRxiv. 2025 Jan 13. pii: 2025.01.08.632009. [Epub ahead of print]

PRPS activity tunes redox homeostasis in Myc-driven lymphoma.

Austin C MacMillan, Bibek Karki, Juechen Yang, Karmela R Gertz, Samantha Zumwalde, Maria F Czyzyk-Krzeska, Jarek Meller, John T Cunningham.

Myc hyperactivation coordinately regulates numerous metabolic processes to drive lymphomagenesis. Here, we elucidate the temporal and functional relationships between the medley of pathways, factors, and mechanisms that cooperate to control redox homeostasis in Myc-overexpressing B cell lymphomas. We find that Myc overexpression rapidly stimulates the oxidative pentose phosphate pathway (oxPPP), nucleotide synthesis, and mitochondrial respiration, which collectively steers cellular equilibrium to a more oxidative state. We identify Myc-dependent hyperactivation of the phosphoribosyl pyrophosphate synthetase (PRPS) enzyme as a primary regulator of redox status in lymphoma cells. Mechanistically, we show that genetic inactivation of the PRPS2 isozyme, but not PRPS1, in Myc-driven lymphoma cells leads to elevated NADPH levels and reductive stress-mediated death. Employing a pharmacological screen, we demonstrate how targeting PRPS1 or PRPS2 elicits opposing sensitivity or resistance, respectively, to chemotherapeutic agents affecting the thioredoxin and glutathione network, thus providing a therapeutic blueprint for treating Myc-driven lymphomas.

DOI: https://doi.org/10.1101/2025.01.08.632009
bioRxiv. 2025 Jan 15. pii: 2025.01.15.633193. [Epub ahead of print]

The histone modification regulator, SIN3, plays a role in the cellular response to changes in glycolytic flux.

Imad Soukar, Anindita Mitra, Linh Vo, Melanie Rofoo, Miriam L Greenberg, Lori A Pile.

Epigenetic regulation and metabolism are connected. Epigenetic regulators, like the SIN3 complex, affect the expression of a wide range of genes, including those encoding metabolic enzymes essential for central carbon metabolism. The idea that epigenetic modifiers can sense and respond to metabolic flux by regulating gene expression has long been proposed. In support of this cross-talk, we provide data linking SIN3 regulatory action on a subset of metabolic genes with the cellular response to changes in metabolic flux. Furthermore, we show that loss of SIN3 is linked to decreases in mitochondrial respiration and the cellular response to mitochondrial and glycolytic stress. Data presented here provide evidence that SIN3 is important for the cellular response to metabolic flux change.

DOI: https://doi.org/10.1101/2025.01.15.633193
Nat Cancer. 2025 Jan 24.

TRIM28-dependent developmental heterogeneity determines cancer susceptibility through distinct epigenetic states.

PERMUTE

Mutations in cancer risk genes increase susceptibility, but not all carriers develop cancer. Indeed, while DNA mutations are necessary drivers of cancer, only a small subset of mutated cells go on to cause the disease. To date, the mechanisms underlying individual cancer susceptibility remain unclear. Here, we took advantage of a unique mouse model of intrinsic developmental heterogeneity (Trim28+/D9) to investigate whether early-life epigenetic variation influences cancer susceptibility later in life. We found that heterozygosity of Trim28 is sufficient to generate two distinct early-life epigenetic states associated with differing cancer susceptibility. These developmentally primed states exhibit differential methylation patterns at typically silenced heterochromatin, detectable as early as 10 days of age. The differentially methylated loci are enriched for genes with known oncogenic potential, frequently mutated in human cancers and correlated with poor prognosis. This study provides genetic evidence that intrinsic developmental heterogeneity can prime individual, lifelong cancer susceptibility.

DOI: https://doi.org/10.1038/s43018-024-00900-3
Cell Rep. 2025 Jan 23. pii: S2211-1247(25)00005-1. [Epub ahead of print]44(2): 115234

Emerging insights into the impact of systemic metabolic changes on tumor-immune interactions.

Andrea L Cote, Chad J Munger, Alison E Ringel.

  Tumors are inherently embedded in systemic physiology, which contributes metabolites, signaling molecules, and immune cells to the tumor microenvironment. As a result, any systemic change to host metabolism can impact tumor progression and response to therapy. In this review, we explore how factors that affect metabolic health, such as diet, obesity, and exercise, influence the interplay between cancer and immune cells that reside within tumors. We also examine how metabolic diseases influence cancer progression, metastasis, and treatment. Finally, we consider how metabolic interventions can be deployed to improve immunotherapy. The overall goal is to highlight how metabolic heterogeneity in the human population shapes the immune response to cancer.

Keywords:  CP: Cancer; CP: Metabolism; anti-tumor immunity; systemic metabolism; tumor microenvironment

DOI:  https://doi.org/10.1016/j.celrep.2025.115234
bioRxiv. 2025 Jan 18. pii: 2025.01.13.632864. [Epub ahead of print]

Fluorescence lifetime imaging microscopy for metabolic analysis of LDHB inhibition in triple negative breast cancer.

A Galloway, B Ter Hofstede, Alex J Walsh.

Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer with no targeted treatments currently available. TNBC cells participate in metabolic symbiosis, a process that optimizes tumor growth by balancing metabolic processes between glycolysis and oxidative phosphorylation through increased activity by the enzyme lactate dehydrogenase B (LDHB). Metabolic symbiosis allows oxidative cancer cells to function at a similar rate as glycolytic cancer cells, increasing overall metabolic activity and proliferation. Here, fluorescence lifetime imaging microscopy (FLIM) is used to analyze the metabolism of TNBC cells with inhibition of LDHB using a multiphoton microscope to measure the fluorescent lifetimes of two metabolic coenzymes, NAD(P)H and FAD. LDHB is inhibited via an indole derivative known as AXKO-0046 in varying concentrations. Understanding how TNBC cell metabolism changes due to LDHB inhibition will provide further insight into metabolic symbiosis and potential new TNBC treatment options.

DOI: https://doi.org/10.1101/2025.01.13.632864
Cell Chem Biol. 2025 Jan 21. pii: S2451-9456(25)00002-9. [Epub ahead of print]

A genetically encoded fluorescent biosensor for visualization of acetyl-CoA in live cells.

Joseph J Smith, Taylor R Valentino, Austin H Ablicki, Riddhidev Banerjee, Adam R Colligan, Debra M Eckert, Gabrielle A Desjardins, Katharine L Diehl.

  Acetyl-coenzyme A is a central metabolite that participates in many cellular pathways. Evidence suggests that acetyl-CoA metabolism is highly compartmentalized in mammalian cells. Yet methods to measure acetyl-CoA in living cells are lacking. Herein, we engineered an acetyl-CoA biosensor from the bacterial protein PanZ and circularly permuted green fluorescent protein (cpGFP). The sensor, "PancACe," has a maximum change of ∼2-fold and a response range of ∼10 μM-2 mM acetyl-CoA. We demonstrated that the sensor has a greater than 7-fold selectivity over coenzyme A, butyryl-CoA, malonyl-CoA, and succinyl-CoA, and a 2.3-fold selectivity over propionyl-CoA. We expressed the sensor in E. coli and showed that it enables detection of rapid changes in acetyl-CoA levels. By localizing the sensor to either the cytoplasm, nucleus, or mitochondria in human cells, we showed that it enables subcellular detection of changes in acetyl-CoA levels, the magnitudes of which agreed with an orthogonal PicoProbe assay.

Keywords:  acetyl-CoA; biosensor; coenzyme A; metabolism; metabolite; protein engineering

DOI:  https://doi.org/10.1016/j.chembiol.2025.01.002
Curr Opin Genet Dev. 2025 Jan 24. pii: S0959-437X(24)00156-4. [Epub ahead of print]91 102307

Rewiring cancer: 3D genome determinants of cancer hallmarks.

Maria E Amodeo, Christine E Eyler, Sarah E Johnstone.

In modern cancer biology, Hanahan and Weinberg's classic depiction of the Hallmarks of Cancer serves as a heuristic for understanding malignant phenotypes [1]. Genetic determinants of these phenotypes promote cancer induction and progression, and these mutations drive current approaches to understanding and treating cancer. Meanwhile, for over a century, pathologists have noted that profound alterations of nuclear structure accompany transformation, integrating these changes into diagnostic classifications (Figure 1). Nevertheless, the relationship of nuclear organization to malignant phenotypes has lagged. Recent advances yield profound insight into the 3D genome's relationship with cancer phenotypes, suggesting that spatial genome organization influences many, if not all, of these malignant features. Here, we highlight recent discoveries elucidating connections between 3D genome organization and cancer phenotypes.

DOI: https://doi.org/10.1016/j.gde.2024.102307
Nat Commun. 2025 Jan 30. 16(1): 1181

SLC29A1 and SLC29A2 are human nicotinamide cell membrane transporters.

Mingyang Chen, Luexiang Yuan, Binxin Chen, Hui Chang, Jun Luo, Hengbin Zhang, Zhongjian Chen, Jiao Kong, Yaodong Yi, Mengru Bai, Minlei Dong, Hui Zhou, Huidi Jiang.

Nicotinamide (NAM), a main precursor of NAD+, is essential for cellular fuel respiration, energy production, and other cellular processes. Transporters for other precursors of NAD+ such as nicotinic acid and nicotinamide mononucleotide (NMN) have been identified, but the cellular transporter of nicotinamide has not been elucidated. Here, we demonstrate that equilibrative nucleoside transporter 1 and 2 (ENT1 and 2, encoded by SLC29A1 and 2) drive cellular nicotinamide uptake and establish nicotinamide metabolism homeostasis. In addition, ENT1/2 exhibits a strong capacity to change the cellular metabolite composition and the transcript, especially those related to nicotinamide. We further observe that ENT1/2 regulates cellular respiration and senescence, contributing by altering the NAD+ pool level and mitochondrial status. Changes to cellular respiration, mitochondrial status and senescence by ENT1/2 knockdown are reversed by NMN supplementation. Together, ENT1 and ENT2 act as both cellular nicotinamide-level keepers and nicotinamide biological regulators through their NAM transport functions.

DOI: https://doi.org/10.1038/s41467-025-56402-y
Int J Mol Sci. 2024 Dec 26. pii: 92. [Epub ahead of print]26(1):

The Role of Mitochondrial Solute Carriers SLC25 in Cancer Metabolic Reprogramming: Current Insights and Future Perspectives.

Amer Ahmed, Giorgia Natalia Iaconisi, Daria Di Molfetta, Vincenzo Coppola, Antonello Caponio, Ansu Singh, Aasia Bibi, Loredana Capobianco, Luigi Palmieri, Vincenza Dolce, Giuseppe Fiermonte.

  Cancer cells undergo remarkable metabolic changes to meet their high energetic and biosynthetic demands. The Warburg effect is the most well-characterized metabolic alteration, driving cancer cells to catabolize glucose through aerobic glycolysis to promote proliferation. Another prominent metabolic hallmark of cancer cells is their increased reliance on glutamine to replenish tricarboxylic acid (TCA) cycle intermediates essential for ATP production, aspartate and fatty acid synthesis, and maintaining redox homeostasis. In this context, mitochondria, which are primarily used to maintain energy homeostasis and support balanced biosynthesis in normal cells, become central organelles for fulfilling the heightened biosynthetic and energetic demands of proliferating cancer cells. Mitochondrial coordination and metabolite exchange with other cellular compartments are crucial. The human SLC25 mitochondrial carrier family, comprising 53 members, plays a pivotal role in transporting TCA intermediates, amino acids, vitamins, nucleotides, and cofactors across the inner mitochondrial membrane, thereby facilitating this cross-talk. Numerous studies have demonstrated that mitochondrial carriers are altered in cancer cells, actively contributing to tumorigenesis. This review comprehensively discusses the role of SLC25 carriers in cancer pathogenesis and metabolic reprogramming based on current experimental evidence. It also highlights the research gaps that need to be addressed in future studies. Understanding the involvement of these carriers in tumorigenesis may provide valuable novel targets for drug development.

Keywords:  cancer; metabolic reprogramming; metabolism; mitochondria; mitochondrial carriers

DOI:  https://doi.org/10.3390/ijms26010092
Cell Commun Signal. 2025 Jan 25. 23(1): 47

Metabolic adaptations to acute glucose uptake inhibition converge upon mitochondrial respiration for leukemia cell survival.

Monika Komza, Jesminara Khatun, Jesse D Gelles, Andrew P Trotta, Ioana Abraham-Enachescu, Juan Henao, Ahmed Elsaadi, Andriana G Kotini, Cara Clementelli, JoAnn Arandela, Sebastian El Ghaity-Beckley, Agneesh Barua, Yiyang Chen, Mirela Berisa, Bridget K Marcellino, Eirini P Papapetrou, Masha V Poyurovsky, Jerry Edward Chipuk.

  One hallmark of cancer is the upregulation and dependency on glucose metabolism to fuel macromolecule biosynthesis and rapid proliferation. Despite significant pre-clinical effort to exploit this pathway, additional mechanistic insights are necessary to prioritize the diversity of metabolic adaptations upon acute loss of glucose metabolism. Here, we investigated a potent small molecule inhibitor to Class I glucose transporters, KL-11743, using glycolytic leukemia cell lines and patient-based model systems. Our results reveal that while several metabolic adaptations occur in response to acute glucose uptake inhibition, the most critical is increased mitochondrial oxidative phosphorylation. KL-11743 treatment efficiently blocks the majority of glucose uptake and glycolysis, yet markedly increases mitochondrial respiration via enhanced Complex I function. Compared to partial glucose uptake inhibition, dependency on mitochondrial respiration is less apparent suggesting robust blockage of glucose uptake is essential to create a metabolic vulnerability. When wild-type and oncogenic RAS patient-derived induced pluripotent stem cell acute myeloid leukemia (AML) models were examined, KL-11743 mediated induction of mitochondrial respiration and dependency for survival associated with oncogenic RAS. Furthermore, we examined the therapeutic potential of these observations by treating a cohort of primary AML patient samples with KL-11743 and witnessed similar dependency on mitochondrial respiration for sustained cellular survival. Together, these data highlight conserved adaptations to acute glucose uptake inhibition in diverse leukemic models and AML patient samples, and position mitochondrial respiration as a key determinant of treatment success.

Keywords:  Adaptations; Bioenergetics; Cancer; Chemotherapy; Glucose; Leukemia; Metabolism; Mitochondria; Oncogenes; Stem cells

DOI:  https://doi.org/10.1186/s12964-025-02044-y
Cell Rep. 2025 Jan 24. pii: S2211-1247(24)01580-8. [Epub ahead of print]44(2): 115229

The spatial landscape of cancer hallmarks reveals patterns of tumor ecological dynamics and drug sensitivity.

DUTRENEO Study Investigators

  Tumors are complex ecosystems of interacting cell types. The concept of cancer hallmarks distills this complexity into underlying principles that govern tumor growth. Here, we explore the spatial distribution of cancer hallmarks across 63 primary untreated tumors from 10 cancer types using spatial transcriptomics. We show that hallmark activity is spatially organized, with the cancer compartment contributing to the activity of seven out of 13 hallmarks, while the tumor microenvironment (TME) contributes to the activity of the rest. Additionally, we discover that genomic distance between tumor subclones correlates with differences in hallmark activity, even leading to clone-hallmark specialization. Finally, we demonstrate interdependent relationships between hallmarks at the junctions of TME and cancer compartments and how they relate to sensitivity to different neoadjuvant treatments in 33 bladder cancer patients from the DUTRENEO trial. In conclusion, our findings may improve our understanding of tumor ecology and help identify new drug biomarkers.

Keywords:  CP: cancer; cancer hallmarks; drug sensitivity; ecosystem; intratumoral heterogeneity; spatial transcriptomics; tumor microenvironment

DOI:  https://doi.org/10.1016/j.celrep.2024.115229
EMBO J. 2025 Jan 29.

SLC25A1 and ACLY maintain cytosolic acetyl-CoA and regulate ferroptosis susceptibility via FSP1 acetylation.

Wei Li, Jing Han, Bin Huang, Tengteng Xu, Yihong Wan, Dan Luo, Weiyao Kong, Ying Yu, Lei Zhang, Yong Nian, Bo Chu, Chengqian Yin.

  Ferroptosis, an iron-dependent form of programmed cell death characterized by excessive lipid hydroperoxides accumulation, emerges as a promising target in cancer therapy. Among the solute carrier (SLC) superfamily, the cystine/glutamate transporter system antiporter components SLC3A2 and SLC7A11 are known to regulate ferroptosis by facilitating cystine import for ferroptosis inhibition. However, the contribution of additional SLC superfamily members to ferroptosis remains poorly understood. Here, we use a targeted CRISPR-Cas9 screen of the SLC superfamily to identify SLC25A1 as a critical ferroptosis regulator in human cancer cells. SLC25A1 drives citrate export from the mitochondria to the cytosol, where it fuels acetyl-CoA synthesis by ATP citrate lyase (ACLY). This acetyl-CoA supply sustains FSP1 acetylation and prevents its degradation by the proteasome via K29-linked ubiquitin chains. K168 is the primary site of FSP1 acetylation and deacetylation by KAT2B and HDAC3, respectively. Pharmacological inhibition of SLC25A1 and ACLY significantly enhances cancer cell susceptibility to ferroptosis both in vitro and in vivo. Targeting the SLC25A1-ACLY axis is therefore a potential therapeutic strategy for ferroptosis-targeted cancer intervention.

Keywords:  ACLY; Acetylation; FSP1; Ferroptosis; SLC25A1

DOI:  https://doi.org/10.1038/s44318-025-00369-5
bioRxiv. 2025 Jan 19. pii: 2025.01.15.633227. [Epub ahead of print]

PAX3-FOXO1 drives targetable cell state-dependent metabolic vulnerabilities in rhabdomyosarcoma.

Katrina I Paras, Julia S Brunner, Jacob A Boyer, Angela M Montero, Benjamin T Jackson, Sangita Chakraborty, Abigail Xie, Kristina Guillan, Armaan Siddiquee, Lourdes Pajuelo Torres, Joshua D Rabinowitz, Andrew Kung, Daoqi You, Filemon Dela Cruz, Lydia W S Finley.

PAX3-FOXO1, an oncogenic transcription factor, drives a particularly aggressive subtype of rhabdomyosarcoma (RMS) by enforcing gene expression programs that support malignant cell states. Here we show that PAX3-FOXO1 + RMS cells exhibit altered pyrimidine metabolism and increased dependence on enzymes involved in de novo pyrimidine synthesis, including dihydrofolate reductase (DHFR). Consequently, PAX3-FOXO1 + cells display increased sensitivity to inhibition of DHFR by the chemotherapeutic drug methotrexate, and this dependence is rescued by provision of pyrimidine nucleotides. Methotrexate treatment mimics the metabolic and transcriptional impact of PAX3-FOXO1 silencing, reducing expression of genes related to PAX3-FOXO1-driven malignant cell states. Accordingly, methotrexate treatment slows growth of multiple PAX3-FOXO1 + tumor xenograft models, but not fusion-negative counterparts. Taken together, these data demonstrate that PAX3-FOXO1 induces cell states characterized by altered pyrimidine dependence and nominate methotrexate as an addition to the current therapeutic arsenal for treatment of these malignant pediatric tumors.

DOI: https://doi.org/10.1101/2025.01.15.633227
Nat Commun. 2025 Jan 30. 16(1): 1191

Mitochondrial KMT9 methylates DLAT to control pyruvate dehydrogenase activity and prostate cancer growth.

Yanhan Jia, Sheng Wang, Sylvia Urban, Judith M Müller, Manuela Sum, Qing Wang, Helena Bauer, Uwe Schulte, Heike Rampelt, Nikolaus Pfanner, Katrin M Schüle, Axel Imhof, Ignasi Forné, Christopher Berlin, August Sigle, Christian Gratzke, Holger Greschik, Eric Metzger, Roland Schüle.

Prostate cancer (PCa) growth depends on de novo lipogenesis controlled by the mitochondrial pyruvate dehydrogenase complex (PDC). In this study, we identify lysine methyltransferase (KMT)9 as a regulator of PDC activity. KMT9 is localized in mitochondria of PCa cells, but not in mitochondria of other tumor cell types. Mitochondrial KMT9 regulates PDC activity by monomethylation of its subunit dihydrolipoamide transacetylase (DLAT) at lysine 596. Depletion of KMT9 compromises PDC activity, de novo lipogenesis, and PCa cell proliferation, both in vitro and in a PCa mouse model. Finally, in human patients, levels of mitochondrial KMT9 and DLAT K596me1 correlate with Gleason grade. Together, we present a mechanism of PDC regulation and an example of a histone methyltransferase with nuclear and mitochondrial functions. The dependency of PCa cells on mitochondrial KMT9 allows to develop therapeutic strategies to selectively fight PCa.

DOI: https://doi.org/10.1038/s41467-025-56492-8
J Cell Biol. 2025 Mar 03. pii: e202311082. [Epub ahead of print]224(3):

FAM43A coordinates mtDNA replication and mitochondrial biogenesis in response to mtDNA depletion.

Alva G Sainz, Gladys R Rojas, Alexandra G Moyzis, Matthew P Donnelly, Kailash C Mangalhara, Melissa A Johnson, Pau B Esparza-Moltó, Kym J Grae, Reuben J Shaw, Gerald S Shadel.

Mitochondrial retrograde signaling (MRS) pathways relay the functional status of mitochondria to elicit homeostatic or adaptive changes in nuclear gene expression. Budding yeast have "intergenomic signaling" pathways that sense the amount of mitochondrial DNA (mtDNA) independently of oxidative phosphorylation (OXPHOS), the primary function of genes encoded by mtDNA. However, MRS pathways that sense the amount of mtDNA in mammalian cells remain poorly understood. We found that mtDNA-depleted IMR90 cells can sustain OXPHOS for a significant amount of time, providing a robust model system to interrogate human intergenomic signaling. We identified FAM43A, a largely uncharacterized protein, as a CHK2-dependent early responder to mtDNA depletion. Depletion of FAM43A activates a mitochondrial biogenesis program, resulting in an increase in mitochondrial mass and mtDNA copy number via CHK2-mediated upregulation of the p53R2 form of ribonucleotide reductase. We propose that FAM43A performs a checkpoint-like function to limit mitochondrial biogenesis and turnover under conditions of mtDNA depletion or replication stress.

DOI: https://doi.org/10.1083/jcb.202311082
Nat Protoc. 2025 Jan 29.

A multimodal imaging pipeline to decipher cell-specific metabolic functions and tissue microenvironment dynamics.

Sharavan Vishaan Venkateswaran, Peter Kreuzaler, Catherine Maclachlan, Greg McMahon, Gina Greenidge, Lucy Collinson, Josephine Bunch, Mariia Yuneva.

Tissue microenvironments are extremely complex and heterogeneous. It is challenging to study metabolic interaction between the different cell types in a tissue with the techniques that are currently available. Here we describe a multimodal imaging pipeline that allows cell type identification and nanoscale tracing of stable isotope-labeled compounds. This pipeline extends upon the principles of correlative light, electron and ion microscopy, by combining confocal microscopy reporter or probe-based fluorescence, electron microscopy, stable isotope labeling and nanoscale secondary ion mass spectrometry. We apply this method to murine models of hepatocellular and mammary gland carcinomas to study uptake of glucose derived carbon (13C) and glutamine derived nitrogen (15N) by tumor-associated immune cells. In vivo labeling with fluorescent-tagged antibodies (B220, CD3, CD8a, CD68) in tandem with confocal microscopy allows for the identification of specific cell types (B cells, T cells and macrophages) in the tumor microenvironment. Subsequent image correlation with electron microscopy offers the contrast and resolution to image membranes and organelles. Nanoscale secondary ion mass spectrometry tracks the enrichment of stable isotopes within these intracellular compartments. The whole protocol described here would take ~6 weeks to perform from start to finish. Our pipeline caters to a broad spectrum of applications as it can easily be adapted to trace the uptake and utilization of any stable isotope-labeled nutrient, drug or a probe by defined cellular populations in any tissue in situ.

DOI: https://doi.org/10.1038/s41596-024-01118-4
Cell Metab. 2025 Jan 24. pii: S1550-4131(24)00489-3. [Epub ahead of print]

Redirecting glucose flux during in vitro expansion generates epigenetically and metabolically superior T cells for cancer immunotherapy.

Andrew T Frisch, Yiyang Wang, Bingxian Xie, Aaron Yang, B Rhodes Ford, Supriya Joshi, Katarzyna M Kedziora, Ronal Peralta, Drew Wilfahrt, Steven J Mullett, Kellie Spahr, Konstantinos Lontos, Jessica A Jana, Victoria G Dean, William G Gunn, Stacy Gelhaus, Amanda C Poholek, Dayana B Rivadeneira, Greg M Delgoffe.

  Cellular therapies are living drugs whose efficacy depends on persistence and survival. Expansion of therapeutic T cells employs hypermetabolic culture conditions to promote T cell expansion. We show that typical in vitro expansion conditions generate metabolically and functionally impaired T cells more reliant on aerobic glycolysis than those expanding in vivo. We used dichloroacetate (DCA) to modulate glycolytic metabolism during expansion, resulting in elevated mitochondrial capacity, stemness, and improved antitumor efficacy in murine T cell receptor (TCR)-Tg and human CAR-T cells. DCA-conditioned T cells surprisingly show no elevated intratumoral effector function but rather have improved engraftment. DCA conditioning decreases reliance on glucose, promoting usage of serum-prevalent physiologic carbon sources. Further, DCA conditioning promotes metabolic flux from mitochondria to chromatin, resulting in increased histone acetylation at key longevity genes. Thus, hyperglycemic culture conditions promote expansion at the expense of metabolic flexibility and suggest pharmacologic metabolic rewiring as a beneficial strategy for improvement of cellular immunotherapies.

Keywords:  CAR-T; Immunometabolism; T cell; cell therapy; epigenetics; glucose; immunotherapy; longevity; metabolism; mitochondria

DOI:  https://doi.org/10.1016/j.cmet.2024.12.007
Phys Biol. 2025 Jan 31. 22(2):

Electrical homeostasis of the inner mitochondrial membrane potential.

Peyman Fahimi, Lázaro A M Castanedo, P Thomas Vernier, Chérif F Matta.

  The electric potential across the inner mitochondrial membrane must be maintained within certain bounds for the proper functioning of the cell. A feedback control mechanism for the homeostasis of this membrane potential is proposed whereby an increase in the electric field decreases the rate-limiting steps of the electron transport chain (ETC). An increase in trans-membrane electric field limits the rate of proton pumping to the inter-membrane gap by slowing the ETC reactions and by intrinsically induced electroporation that depolarizes the inner membrane. The proposed feedback mechanism is akin to a Le Chatelier's-type principle of trans-membrane potential feedback control.

Keywords:  chemiosmotic theory; electrical feedback control in biological systems; mitochondrial biophysics; mitochondrial electric potential; mitochondrial homeostasis

DOI:  https://doi.org/10.1088/1478-3975/adaa47
bioRxiv. 2025 Jan 16. pii: 2025.01.13.632607. [Epub ahead of print]

Tissue-specific effects of dietary protein on cellular senescence are mediated by branched-chain amino acids.

Mariah F Calubag, Ismail Ademi, Isaac Grunow, Lucia Breuer, Reji Babygirija, Penelope Lialios, Sandra Le, Dennis Minton, Michelle M Sonsalla, Julia Illiano, Bailey A Knopf, Fan Xiao, Adam R Konopka, David A Harris, Dudley W Lamming.

Dietary protein is a key regulator of healthy aging in both mice and humans. In mice, reducing dietary levels of the branched-chain amino acids (BCAAs) recapitulates many of the benefits of a low protein diet; BCAA-restricted diets extend lifespan, reduce frailty, and improve metabolic health, while BCAA supplementation shortens lifespan, promotes obesity, and impairs glycemic control. Recently, high protein diets have been shown to promote cellular senescence, a hallmark of aging implicated in many age-related diseases, in the liver of mice. Here, we test the hypothesis that the effects of high protein diets on metabolic health and on cell senescence are mediated by BCAAs. We find that reducing dietary levels of BCAAs protects male and female mice from the negative metabolic consequences of both normal and high protein diets. Further, we identify tissue-specific effects of BCAAs on cellular senescence, with restriction of all three BCAAs - but not individual BCAAs - protecting from hepatic cellular senescence while potentiating cell senescence in white adipose tissue. We find that the effects of BCAAs on hepatic cellular senescence are cell-autonomous, with lower levels of BCAAs protecting cultured cells from antimycin-A induced senescence. Our results demonstrate a direct effect of a specific dietary component on a hallmark of aging and suggest that cellular senescence may be highly susceptible to dietary interventions.

DOI: https://doi.org/10.1101/2025.01.13.632607
Life Metab. 2023 Apr;2(2): load015

Mitochondrial cristae: lung cancer metabolism architects.

Masafumi Noguchi, Luca Scorrano.

DOI: https://doi.org/10.1093/lifemeta/load015
Int J Mol Sci. 2025 Jan 09. pii: 498. [Epub ahead of print]26(2):

Metabolic Reprogramming at the Edge of Redox: Connections Between Metabolic Reprogramming and Cancer Redox State.

José J Serrano, Miguel Ángel Medina.

  The importance of redox systems as fundamental elements in biology is now widely recognized across diverse fields, from ecology to cellular biology. Their connection to metabolism is particularly significant, as it plays a critical role in energy regulation and distribution within organisms. Over recent decades, metabolism has emerged as a relevant focus in studies of biological regulation, especially following its recognition as a hallmark of cancer. This shift has broadened cancer research beyond strictly genetic perspectives. The interaction between metabolism and redox systems in carcinogenesis involves the regulation of essential metabolic pathways, such as glycolysis and the Krebs cycle, as well as the involvement of redox-active components like specific amino acids and cofactors. The feedback mechanisms linking redox systems and metabolism in cancer highlight the development of redox patterns that enhance the flexibility and adaptability of tumor processes, influencing larger-scale biological phenomena such as circadian rhythms and epigenetics.

Keywords:  cancer; emergence; feedback; metabolism; redox; reprogramming

DOI:  https://doi.org/10.3390/ijms26020498
Nat Rev Mol Cell Biol. 2025 Jan 28.

Microenvironmental determinants of endothelial cell heterogeneity.

Jesus M Gomez-Salinero, David Redmond, Shahin Rafii.

During development, endothelial cells (ECs) undergo an extraordinary specialization by which generic capillary microcirculatory networks spanning from arteries to veins transform into patterned organotypic zonated blood vessels. These capillary ECs become specialized to support the cellular and metabolic demands of each specific organ, including supplying tissue-specific angiocrine factors that orchestrate organ development, maintenance of organ-specific functions and regeneration of injured adult organs. Here, we illustrate the mechanisms by which microenvironmental signals emanating from non-vascular niche cells induce generic ECs to acquire specific inter-organ and intra-organ functional attributes. We describe how perivascular, parenchymal and immune cells dictate vascular heterogeneity and capillary zonation, and how this system is maintained through tissue-specific signalling activated by vasculogenic and angiogenic factors and deposition of matrix components. We also discuss how perturbation of organotypic vascular niche cues lead to erasure of EC signatures, contributing to the pathogenesis of disease processes. We also describe approaches that use reconstitution of tissue-specific signatures of ECs to promote regeneration of damaged organs.

DOI: https://doi.org/10.1038/s41580-024-00825-w
Life Metab. 2023 Jun;2(3): load020

Flux measurements of the tricarboxylic acid cycle in the tumors of mice.

Shiyu Liu, Jason W Locasale.

DOI: https://doi.org/10.1093/lifemeta/load020
Nat Commun. 2025 Jan 27. 16(1): 1068

Splicing accuracy varies across human introns, tissues, age and disease.

S García-Ruiz, D Zhang, E K Gustavsson, G Rocamora-Perez, M Grant-Peters, A Fairbrother-Browne, R H Reynolds, J W Brenton, A L Gil-Martínez, Z Chen, D C Rio, J A Botia, S Guelfi, L Collado-Torres, M Ryten.

Alternative splicing impacts most multi-exonic human genes. Inaccuracies during this process may have an important role in ageing and disease. Here, we investigate splicing accuracy using RNA-sequencing data from >14k control samples and 40 human body sites, focusing on split reads partially mapping to known transcripts in annotation. We show that splicing inaccuracies occur at different rates across introns and tissues and are affected by the abundance of core components of the spliceosome assembly and its regulators. We find that age is positively correlated with a global decline in splicing fidelity, mostly affecting genes implicated in neurodegenerative diseases. We find support for the latter by observing a genome-wide increase in splicing inaccuracies in samples affected with Alzheimer's disease as compared to neurologically normal individuals. In this work, we provide an in-depth characterisation of splicing accuracy, with implications for our understanding of the role of inaccuracies in ageing and neurodegenerative disorders.

DOI: https://doi.org/10.1038/s41467-024-55607-x
J Physiol. 2025 Jan 27.

Placental mitochondrial metabolic adaptation maintains cellular energy balance in pregnancy complicated by gestational hypoxia.

Wen Tong, Beth J Allison, Kirsty L Brain, Olga V Patey, Youguo Niu, Kimberley J Botting, Sage G Ford, Tess A Garrud, Peter F B Wooding, Qiang Lyu, Lin Zhang, Jin Ma, Alice P Sowton, Katie A O'Brien, Tereza Cindrova-Davies, Hong Wa Yung, Graham J Burton, Andrew J Murray, Dino A Giussani.

  The mechanisms that drive placental dysfunction in pregnancies complicated by hypoxia and fetal growth restriction remain poorly understood. Changes to mitochondrial respiration contribute to cellular dysfunction in conditions of hypoxia and have been implicated in the pathoaetiology of pregnancy complications, such as pre-eclampsia. We used bespoke isobaric hypoxic chambers and a combination of functional, molecular and imaging techniques to study cellular metabolism and mitochondrial dynamics in sheep undergoing hypoxic pregnancy. We show that hypoxic pregnancy in sheep triggers a shift in capacity away from β-oxidation and complex I-mediated respiration, while maintaining total oxidative phosphorylation capacity. There are also complex-specific changes to electron transport chain composition and a switch in mitochondrial dynamics towards fission. Hypoxic placentas show increased activation of the non-canonical mitochondrial unfolded protein response pathway and enhanced insulin like growth factor 2 signalling. Combined, therefore, the data show that the hypoxic placenta undergoes significant metabolic and morphological adaptations to maintain cellular energy balance. Chronic hypoxia during pregnancy in sheep activated placental mitochondrial stress pathways, leading to alterations in mitochondrial respiration, mitochondrial energy metabolism and mitochondrial dynamics, as seen in the placenta of women with pre-eclampsia. KEY POINTS: Hypoxia shifts mitochondrial respiration away from β-oxidation and complex I. Complex-specific changes occur in the electron transport chain composition. Activation of the non-canonical mitochondrial unfolded protein response pathway is heightened in hypoxic placentas. Enhanced insulin like growth factor 2 signalling is observed in hypoxic placentas. Hypoxic placentas undergo significant functional adaptations for energy balance.

Keywords:  chronic hypoxia; metabolic homeostasis; mitochondrial reactive oxygen species; mitochondrial respiration; non‐canonical mitochondrial unfolded protein response; placental metabolism

DOI:  https://doi.org/10.1113/JP287897
Nature. 2025 Jan 29.

Methanol transfer supports metabolic syntrophy between bacteria and archaea.

Yan Huang, Kensuke Igarashi, Laiyan Liu, Daisuke Mayumi, Tomomi Ujiie, Lin Fu, Min Yang, Yahai Lu, Lei Cheng, Souichiro Kato, Masaru K Nobu.

In subsurface methanogenic ecosystems, the ubiquity of methylated-compound-using archaea-methylotrophic methanogens1-4-implies that methylated compounds have an important role in the ecology and carbon cycling of such habitats. However, the origin of these chemicals remains unclear5,6 as there are no known energy metabolisms that generate methylated compounds de novo as a major product. Here we identified an energy metabolism in the subsurface-derived thermophilic anaerobe Zhaonella formicivorans7 that catalyses the conversion of formate to methanol, thereby producing methanol without requiring methylated compounds as an input. Cultivation experiments showed that formate-driven methanologenesis is inhibited by the accumulation of methanol. However, this limitation can be overcome through methanol consumption by a methylotrophic partner methanogen, Methermicoccus shengliensis. This symbiosis represents a fourth mode of mutualistic cross-feeding driven by thermodynamic necessity (syntrophy), previously thought to rely on transfer of hydrogen, formate or electrons8-10. The unusual metabolism and syntrophy provide insights into the enigmatic presence of methylated compounds in subsurface methanogenic ecosystems and demonstrate how organisms survive at the thermodynamic limit through metabolic symbiosis.

DOI: https://doi.org/10.1038/s41586-024-08491-w
Nat Commun. 2025 Jan 27. 16(1): 1077

A compendium of Amplification-Related Gain Of Sensitivity genes in human cancer.

Veronica Rendo, Michael Schubert, Nicholas Khuu, Maria F Suarez Peredo Rodriguez, Declan Whyte, Xiao Ling, Anouk van den Brink, Kaimeng Huang, Michelle Swift, Yizhou He, Johanna Zerbib, Ross Smith, Jonne Raaijmakers, Pratiti Bandopadhayay, Lillian M Guenther, Justin H Hwang, Amanda Iniguez, Susan Moody, Ji-Heui Seo, Elizabeth H Stover, Levi Garraway, William C Hahn, Kimberly Stegmaier, René H Medema, Dipanjan Chowdhury, Maria Colomé-Tatché, Uri Ben-David, Rameen Beroukhim, Floris Foijer.

While the effect of amplification-induced oncogene expression in cancer is known, the impact of copy-number gains on "bystander" genes is less understood. We create a comprehensive map of dosage compensation in cancer by integrating expression and copy number profiles from over 8000 tumors in The Cancer Genome Atlas and cell lines from the Cancer Cell Line Encyclopedia. Additionally, we analyze 17 cancer open reading frame screens to identify genes toxic to cancer cells when overexpressed. Combining these approaches, we propose a class of 'Amplification-Related Gain Of Sensitivity' (ARGOS) genes located in commonly amplified regions, yet expressed at lower levels than expected by their copy number, and toxic when overexpressed. We validate RBM14 as an ARGOS gene in lung and breast cancer cells, and suggest a toxicity mechanism involving altered DNA damage response and STING signaling. We additionally observe increased patient survival in a radiation-treated cancer cohort with RBM14 amplification.

DOI: https://doi.org/10.1038/s41467-025-56301-2
Sci Adv. 2025 Jan 31. 11(5): eads0535

Ketogenesis supports hepatic polyunsaturated fatty acid homeostasis via fatty acid elongation.

Eric D Queathem, Zahra Moazzami, David B Stagg, Alisa B Nelson, Kyle Fulghum, Abdirahman Hayir, Alisha Seay, Jacob R Gillingham, D André d'Avignon, Xianlin Han, Hai-Bin Ruan, Peter A Crawford, Patrycja Puchalska.

Ketogenesis is a dynamic metabolic conduit supporting hepatic fat oxidation particularly when carbohydrates are in short supply. Ketone bodies may be recycled into anabolic substrates, but a physiological role for this process has not been identified. Here, we use mass spectrometry-based 13C-isotope tracing and shotgun lipidomics to establish a link between hepatic ketogenesis and lipid anabolism. Unexpectedly, mouse liver and primary hepatocytes consumed ketone bodies to support fatty acid biosynthesis via both de novo lipogenesis (DNL) and polyunsaturated fatty acid (PUFA) elongation. While an acetoacetate intermediate was not absolutely required for ketone bodies to source DNL, PUFA elongation required activation of acetoacetate by cytosolic acetoacetyl-coenzyme A synthetase (AACS). Moreover, AACS deficiency diminished free and esterified PUFAs in hepatocytes, while ketogenic insufficiency depleted PUFAs and increased liver triacylglycerols. These findings suggest that hepatic ketogenesis influences PUFA metabolism, representing a molecular mechanism through which ketone bodies could influence systemic physiology and chronic diseases.

DOI: https://doi.org/10.1126/sciadv.ads0535
Trends Cancer. 2025 Jan 28. pii: S2405-8033(25)00001-9. [Epub ahead of print]

Cancer evolution: from Darwin to the Extended Evolutionary Synthesis.

Thomas Savy, Lucy Flanders, Thaneswari Karpanasamy, Min Sun, Marco Gerlinger.

  The fundamental evolutionary nature of cancer has been recognized for decades. Increasingly powerful genetic and single cell sequencing technologies, as well as preclinical models, continue to unravel the evolution of premalignant cells, and progression to metastatic stages and to drug-resistant end-stage disease. Here, we summarize recent advances and distil evolutionary principles and their relevance for the clinic. We reveal how cancer cell and microenvironmental plasticity are intertwined with Darwinian evolution and demonstrate the need for a conceptual framework that integrates these processes. This warrants the adoption of the recently developed Extended Evolutionary Synthesis (EES).

Keywords:  biomarkers; cancer evolution; cellular plasticity; drug resistance; macroevolution; metastasis; mutagenesis

DOI:  https://doi.org/10.1016/j.trecan.2025.01.001
Semin Immunopathol. 2025 Jan 25. 47(1): 11

Arginine metabolism in myeloid cells in health and disease.

Eleftheria Karadima, Triantafyllos Chavakis, Vasileia Ismini Alexaki.

  Metabolic flexibility is key for the function of myeloid cells. Arginine metabolism is integral to the regulation of myeloid cell responses. Nitric oxide (NO) production from arginine is vital for the antimicrobial and pro-inflammatory responses. Conversely, the arginase 1 (ARG1)-dependent switch between the branch of NO production and polyamine synthesis downregulates inflammation and promotes recovery of tissue homeostasis. Creatine metabolism is key for energy supply and proline metabolism is required for collagen synthesis. Myeloid ARG1 also regulates extracellular arginine availability and T cell responses in parasitic diseases and cancer. Cancer, surgery, sepsis and persistent inflammation in chronic inflammatory diseases, such as neuroinflammatory diseases or arthritis, are associated with dysregulation of arginine metabolism in myeloid cells. Here, we review current knowledge on arginine metabolism in different myeloid cell types, such as macrophages, neutrophils, microglia, osteoclasts, tumor-associated macrophages (TAMs), tumor-associated neutrophils (TANs) and myeloid-derived suppressor cells (MDSCs). A deeper understanding of the function of arginine metabolism in myeloid cells will improve our knowledge on the pathology of several diseases and may set the platform for novel therapeutic applications.

Keywords:  Arginine metabolism; Cancer; Infection; Inflammation; Myeloid cells; Sepsis-induced immune paralysis; Surgery

DOI:  https://doi.org/10.1007/s00281-025-01038-9
Mol Metab. 2025 Jan 23. pii: S2212-8778(25)00010-9. [Epub ahead of print]93 102103

Nutrient control of splice site selection contributes to methionine addiction of cancer.

Da-Wei Lin, Francisco G Carranza, Stacey Borrego, Linda Lauinger, Lucas Dantas de Paula, Harika R Pulipelli, Anna Andronicos, Klemens J Hertel, Peter Kaiser.

   OBJECTIVE: Many cancer cells depend on exogenous methionine for proliferation, whereas non-tumorigenic cells can divide in media supplemented with the metabolic precursor homocysteine. This phenomenon is known as methionine dependence of cancer or methionine addiction. The underlying mechanisms driving this cancer-specific metabolic addiction are poorly understood. Here we find that methionine dependence is associated with severe dysregulation of pre-mRNA splicing.
METHODS: We used triple-negative breast cancer cells and their methionine-independent derivatives R8 to compare RNA expression profiles in methionine and homocysteine growth media. The data set was also analyzed for alternative splicing.
RESULTS: When tumorigenic cells were cultured in homocysteine medium, cancer cells failed to efficiently methylate the spliceosomal snRNP component SmD1, which resulted in reduced binding to the Survival-of-Motor-Neuron protein SMN leading to aberrant splicing. These effects were specific for cancer cells as neither Sm protein methylation nor splicing fidelity was affected when non-tumorigenic cells were cultured in homocysteine medium. Sm protein methylation is catalyzed by Protein Arginine Methyl Transferase 5 (Prmt5). Reducing methionine concentrations in the culture medium sensitized cancer cells to Prmt5 inhibition supporting a mechanistic link between methionine dependence of cancer and splicing.
CONCLUSIONS: Our results link nutritional demands to splicing changes and thereby provide a link between the cancer-specific metabolic phenomenon, described as methionine addiction over 40 years ago, with a defined cellular pathway that contributes to cancer cell proliferation.

Keywords:  Methionine addiction; Methionine dependence of cancer; Methylation; Prmt5; Splicing

DOI:  https://doi.org/10.1016/j.molmet.2025.102103
Eur Urol. 2025 Jan 23. pii: S0302-2838(25)00018-1. [Epub ahead of print]

A Call for a Neoadjuvant Kidney Cancer Consortium: Lessons Learned from Other Cancer Types.

Axel Bex, Michael Jewett, Bryan Lewis, E Jason Abel, Laurence Albiges, Stephanie A Berg, Gennady Bratslavsky, David Braun, James Brugarolas, Toni K Choueiri, Antonio Finelli, Daniel George, Naomi B Haas, A Ari Hakimi, Hans Hammers, Michelle Hirsch, Eric Jonasch, Payal Kapur, W Marston Linehan, Viraj Master, Bradley McGregor, Rana R McKay, Rohit Mehra, Sumantha Pal, Susan Poteat, Thomas B Powles, Sabrina H Rossi, Daniel D Shapiro, Sabina Signoretti, Eric A Singer, Chuck Stravin, Nizar Tannir, Ulka Vaishampayan, Wenxin Xu, Grant D Stewart.

Neoadjuvant systemic treatment strategies have improved outcomes in several solid tumour types. This success has not yet been replicated in renal cell carcinoma (RCC). A consensus and international collaboration are urgently needed for the development of adaptive perioperative immunotherapy strategies for patients with RCC at high risk of recurrence.

DOI: https://doi.org/10.1016/j.eururo.2025.01.007
Nat Commun. 2025 Jan 27. 16(1): 1082

Reproducibility and transparency: what's going on and how can we help.

DOI: https://doi.org/10.1038/s41467-024-54614-2
Redox Biol. 2025 Jan 20. pii: S2213-2317(25)00015-1. [Epub ahead of print]80 103502

Sub-organellar mitochondrial hydrogen peroxide observed using a SNAP tag targeted coumarin-based fluorescent reporter.

Ross Eaglesfield, Erika Fernandez-Vizarra, Erik Lacko, Stuart T Caldwell, Nikki L Sloan, Daniel Siciarz, Richard C Hartley, Kostas Tokatlidis.

  Mitochondria are major sites of reactive oxygen species (ROS) production within cells. ROS are important signalling molecules, but excessive production can cause cellular damage and dysfunction. It is therefore crucial to accurately determine when, how and where ROS are produced within mitochondria. Previously, ROS detection involved various chemical probes and fluorescent proteins. These have limitations due to accumulation of the molecules only in the mitochondrial matrix, or the need for a new protein to be expressed for every different species. We report dynamic H2O2 flux changes within all mitochondrial sub-compartments with striking spatial resolution. We combined specific targeting of self-labeling proteins with novel H2O2-reactive probes. The approach is broad-ranging and flexible, with the same expressed proteins loadable with different dyes and sensors. It provides a framework for concomitant analysis of other chemical species, beyond ROS, whose dynamics within mitochondria are yet unknown, without needing to engineer new proteins.

Keywords:  Mitochondria; Oxidative stress; ROS; Redox signalling; Self-labeling proteins; Sub-cellular compartments

DOI:  https://doi.org/10.1016/j.redox.2025.103502
Nat Commun. 2025 Jan 25. 16(1): 1021

The 40S ribosomal subunit recycling complex modulates mitochondrial dynamics and endoplasmic reticulum - mitochondria tethering at mitochondrial fission/fusion hotspots.

Foozhan Tahmasebinia, Yinglu Tang, Rushi Tang, Yi Zhang, Will Bonderer, Maisa de Oliveira, Bretton Laboret, Songjie Chen, Ruiqi Jian, Lihua Jiang, Michael Snyder, Chun-Hong Chen, Yawei Shen, Qing Liu, Boxiang Liu, Zhihao Wu.

The 40S ribosomal subunit recycling pathway is an integral link in the cellular quality control network, occurring after translational errors have been corrected by the ribosome-associated quality control (RQC) machinery. Despite our understanding of its role, the impact of translation quality control on cellular metabolism remains poorly understood. Here, we reveal a conserved role of the 40S ribosomal subunit recycling (USP10-G3BP1) complex in regulating mitochondrial dynamics and function. The complex binds to fission-fusion proteins located at mitochondrial hotspots, regulating the functional assembly of endoplasmic reticulum-mitochondria contact sites (ERMCSs). Furthermore, it alters the activity of mTORC1/2 pathways, suggesting a link between quality control and energy fluctuations. Effective communication is essential for resolving proteostasis-related stresses. Our study illustrates that the USP10-G3BP1 complex acts as a hub that interacts with various pathways to adapt to environmental stimuli promptly. It advances our molecular understanding of RQC regulation and helps explain the pathogenesis of human proteostasis and mitochondrial dysfunction diseases.

DOI: https://doi.org/10.1038/s41467-025-56346-3
Bio Protoc. 2025 Jan 20. 15(2): e5168

Using DIMet for Differential Analysis of Labeled Metabolomics Data: A Step-by-step Guide Showcasing the Glioblastoma Metabolism.

Johanna Galvis, Joris Guyon, Thomas Daubon, Macha Nikolski.

  Stable-isotope resolved metabolomics (SIRM) is a powerful approach for characterizing metabolic states in cells and organisms. By incorporating isotopes, such as 13C, into substrates, researchers can trace reaction rates across specific metabolic pathways. Integrating metabolomics data with gene expression profiles further enriches the analysis, as we demonstrated in our prior study on glioblastoma metabolic symbiosis. However, the bioinformatics tools for analyzing tracer metabolomics data have been limited. In this protocol, we encourage the researchers to use SIRM and transcriptomics data and to perform the downstream analysis using our software tool DIMet. Indeed, DIMet is the first comprehensive tool designed for the differential analysis of tracer metabolomics data, alongside its integration with transcriptomics data. DIMet facilitates the analysis of stable-isotope labeling and metabolic abundances, offering a streamlined approach to infer metabolic changes without requiring complex flux analysis. Its pathway-based "metabologram" visualizations effectively integrate metabolomics and transcriptomics data, offering a versatile platform capable of analyzing corrected tracer datasets across diverse systems, organisms, and isotopes. We provide detailed steps for sample preparation and data analysis using DIMet through its intuitive, web-based Galaxy interface. To showcase DIMet's capabilities, we analyzed LDHA/B knockout glioblastoma cell lines compared to controls. Accessible to all researchers through Galaxy, DIMet is free, user-friendly, and open source, making it a valuable resource for advancing metabolic research. Key features • Glioblastoma tumor spheroids in vitro replicate tumors' three-dimensional structure and natural nutrient, metabolite, and gas gradients, providing a more realistic model of tumor biology. • Joint analysis of tracer metabolomics and transcriptomics datasets provides deeper insights into the metabolic states of cells. • DIMet is a web-based tool for differential analysis and seamless integration of metabolomics and transcriptomics data, making it accessible and user-friendly. • DIMet enables researchers to infer metabolic changes, offering intuitive and visually appealing "metabologram" outputs, surpassing conventional visual representations commonly used in the field.

Keywords:  Bioinformatics; Data integration; Differential analysis; Glioblastoma; Metabolomics; Transcriptomics

DOI:  https://doi.org/10.21769/BioProtoc.5168
J Cell Biol. 2025 Apr 07. pii: e202403083. [Epub ahead of print]224(4):

Sphingolipid metabolism orchestrates establishment of the hair follicle stem cell compartment.

Franziska Peters, Windie Höfs, Hunki Lee, Susanne Brodesser, Kai Kruse, Hannes C A Drexler, Jiali Hu, Verena K Raker, Dominika Lukas, Esther von Stebut, Martin Krönke, Carien M Niessen, Sara A Wickström.

Sphingolipids serve as building blocks of membranes to ensure subcellular compartmentalization and facilitate intercellular communication. How cell type-specific lipid compositions are achieved and what is their functional significance in tissue morphogenesis and maintenance has remained unclear. Here, we identify a stem cell-specific role for ceramide synthase 4 (CerS4) in orchestrating fate decisions in skin epidermis. Deletion of CerS4 prevents the proper development of the adult hair follicle bulge stem cell (HFSC) compartment due to altered differentiation trajectories. Mechanistically, HFSC differentiation defects arise from an imbalance of key ceramides and their derivate sphingolipids, resulting in hyperactivation of noncanonical Wnt signaling. This impaired HFSC compartment establishment leads to disruption of hair follicle architecture and skin barrier function, ultimately triggering a T helper cell 2-dominated immune infiltration resembling human atopic dermatitis. This work uncovers a fundamental role for a cell state-specific sphingolipid profile in stem cell homeostasis and in maintaining an intact skin barrier.

DOI: https://doi.org/10.1083/jcb.202403083
Oncogene. 2025 Jan 26.

The protection of UCK2 protein stability by GART maintains pyrimidine salvage synthesis for HCC growth under glucose limitation.

Nannan Sha, Bei Zhou, Guofang Hou, Zhifeng Xi, Wang Wang, Man Yan, Jing He, Yue Zhou, Qiang Xia, Yuhui Jiang, Qin Zhao.

Overexpression of uridine-cytidine kinase 2 (UCK2), a key enzyme in the pyrimidine salvage pathway, is implicated in human cancer development, while its regulation under nutrient stress remains to be investigated. Here, we show that under glucose limitation, AMPK phosphorylates glycinamide ribonucleotide formyltransferase (GART) at Ser440, and this modification facilitates its interaction with UCK2. Through its binding to UCK2, GART generates tetrahydrofolate (THF) and thus inhibits the activity of integrin-linked kinase associated phosphatase (ILKAP) for removing AKT1-mediated UCK2-Ser254 phosphorylation under glucose limitation, in which dephosphorylation of UCK2-Ser254 tends to cause Trim21-mediated UCK2 polyubiquitination and degradation. In this way, both UCK2 binding ability and THF producing catalytic activity of GART protect protein stability of UCK2 and pyrimidine salvage synthesis, and sustain tumor cell growth under glucose limitation. In addition, UCK2-Ser254 phosphorylation level displays a positive relationship with GART-Ser440 phosphorylation level and its enhancement is correlated with poor prognosis of human hepatocellular carcinoma (HCC) patients. These findings reveal a non-canonical role of GART in regulating pyrimidine salvage synthesis under nutrient stress, and raise the potential for alternative treatments in targeting pyrimidine salvage-dependent tumor growth.

DOI: https://doi.org/10.1038/s41388-025-03274-7
PLoS Genet. 2025 Jan 27. 21(1): e1011580

A mitochondria-to-nucleus regulation mediated by the nuclear-translocated mitochondrial lncRNAs.

Jia Li, Ruoling Bai, Yulian Zhou, Xu Song, Ling Li.

A bidirectional nucleus-mitochondria communication is essential for homeostasis and stress. By acting as critical molecules, the nuclear-encoded lncRNAs (nulncRNAs) have been implicated in the nucleus-to-mitochondria anterograde regulation. However, role of mitochondrial-derived lncRNAs (mtlncRNAs) in the mitochondria-to-nucleus retrograde regulation remains elusive. Here, we identify functional implication of the mtlncRNAs MDL1AS, lncND5 and lncCyt b in retrograde regulation. Mediated by HuR and PNPT1 proteins, the mtlncRNAs undergo a mitochondria-to-nucleus traveling and then regulate a network of nuclear genes. Moreover, as an example of the functional consequence, we showed that the nuclear-translocated lncCyt b cooperates with the splicing factor hnRNPA2B1 to influence several aspects of cell metabolism including glycolysis, possibly through their regulatory effect on the post-transcriptional processing of related nuclear genes. This study advances our knowledge in mitochondrial biology and provides new insights into the role of mtlncRNAs in mitochondria-nucleus communications.

DOI: https://doi.org/10.1371/journal.pgen.1011580