bims-camemi 2025-04-13 papers

bims-camemi

Biomed News

on Mitochondrial metabolism in cancer

Issue of 2025–04–13
47 papers selected by
Christian Frezza, Universität zu Köln

Recommendations for robust and reproducible research on ferroptosis.
PAX translocations remodel mitochondrial metabolism through altered leucine usage in rhabdomyosarcoma.
UPRmt controls the mesenchymal-to-epithelial transition.
Cancer cell-derived arginine fuels polyamine biosynthesis in tumor-associated macrophages to promote immune evasion.
ARMC1 partitions between distinct complexes and assembles MIRO with MTFR to control mitochondrial distribution.
Somatic mutations in the stomach.
Metabolite tunes MDV pathway to maintain mitochondrial fitness.
Radiotherapy promotes cuproptosis and synergizes with cuproptosis inducers to overcome tumor radioresistance.
How does cancer affect motivation?
Natural killer cells' functional impairment drives the immune escape of pre-malignant clones in early-stage myelodysplastic syndromes.
Alternative start codon selection shapes mitochondrial function during evolution, homeostasis, and disease.
Peripheral positioning of lysosomes supports melanoma aggressiveness.
The Warburg hypothesis and the emergence of the mitochondrial metabolic theory of cancer.
Histone H3 cysteine 110 enhances iron metabolism and modulates replicative life span in Saccharomyces cerevisiae.
Small molecules restore mutant mitochondrial DNA polymerase activity.
The regulation and function of post-transcriptional RNA splicing.
Inhibition of mitochondrial complex I induces mitochondrial ferroptosis by regulating CoQH2 levels in cancer.
Blocking cholesterol biosynthesis to clean out cancer.
Cells are swapping their mitochondria. What does this mean for our health?
A redefined InDel taxonomy provides insights into mutational signatures.
Multiple roles of branched-chain amino acid metabolism in tumour progression.
Mitochondria and cell death signalling.
STING mediates lysosomal quality control and recovery through its proton channel function and TFEB activation in lysosomal storage disorders.
Tumor acidosis supports cancer cell lipid uptake via a rapid, transporter-independent mechanism.
Pre-existing intratumoral stem-like CD8+ T cells drive radiotherapy-induced tumor immunity.
TMEM65 regulates and is required for NCLX-dependent mitochondrial calcium efflux.
Glycolysis model shows that allostery maintains high ATP and limits accumulation of intermediates.
Unraveling the nexus: Genomic instability and metabolism in cancer.
Mitochondrial fatty acid synthesis and MECR regulate CD4+ T cell function and oxidative metabolism.
The Futile Creatine Cycle powers UCP1-independent thermogenesis in classical BAT.
Amino acids in cancer: Understanding metabolic plasticity and divergence for better therapeutic approaches.
Compression of morbidity by interventions that steepen the survival curve.
Dietary patterns and healthy ageing.
Horizontal acquisition of prokaryotic hopanoid biosynthesis reorganizes membrane physiology driving lifestyle innovation in a eukaryote.
Acute myeloid leukemia mitochondria hydrolyze ATP to support oxidative metabolism and resist chemotherapy.
RNA G-quadruplexes control mitochondria-localized mRNA translation and energy metabolism.
Succinate-loaded tumor cell-derived microparticles reprogram tumor-associated macrophage metabolism.
Intergenerational metabolic effects of cold exposure.
Y12C mutation disrupts IMPDH cytoophidia and alters cancer metabolism.
Regulation of plant glycolysis and the tricarboxylic acid cycle by posttranslational modifications.
TMEM65 joins the mitochondrial Ca2+ club.
Timing is everything.
Revisiting insulin-stimulated hydrogen peroxide dynamics reveals a cytosolic reductive shift in skeletal muscle.
NK cell-derived IFNγ mobilizes free fatty acids from adipose tissue to promote early B cell activation during viral infection.
Emerging roles of lysine lactyltransferases and lactylation.
Hijacking the powerhouse: Mitochondrial transfer and mitophagy as emerging mechanisms of immune evasion.
Metabolites are not genes - avoiding the misuse of pathway analysis in metabolomics.

Nat Rev Mol Cell Biol. 2025 Apr 09.

Recommendations for robust and reproducible research on ferroptosis.

Eikan Mishima, Toshitaka Nakamura, Sebastian Doll, Bettina Proneth, Maria Fedorova, Derek A Pratt, José Pedro Friedmann Angeli, Scott J Dixon, Adam Wahida, Marcus Conrad.

Ferroptosis is a necrotic, non-apoptotic cell death modality triggered by unrestrained iron-dependent lipid peroxidation. By unveiling the regulatory mechanisms of ferroptosis and its relevance to various diseases, research over the past decade has positioned ferroptosis as a promising therapeutic target. The rapid growth of this research field presents challenges, associated with potentially inadequate experimental approaches that may lead to misinterpretations in the assessment of ferroptosis. Typical examples include assessing whether an observed phenotype is indeed linked to ferroptosis, and selecting appropriate animal models and small-molecule modulators of ferroptotic cell death. This Expert Recommendation outlines state-of-the-art methods and tools to reliably study ferroptosis and increase the reproducibility and robustness of experimental results. We present highly validated compounds and animal models, and discuss their advantages and limitations. Furthermore, we provide an overview of the regulatory mechanisms and the best-studied players in ferroptosis regulation, such as GPX4, FSP1, SLC7A11 and ACSL4, discussing frequent pitfalls in experimental design and relevant guidance. These recommendations are intended for researchers at all levels, including those entering the expanding and exciting field of ferroptosis research.

DOI: https://doi.org/10.1038/s41580-025-00843-2
Cell. 2025 Apr 01. pii: S0092-8674(25)00281-8. [Epub ahead of print]

PAX translocations remodel mitochondrial metabolism through altered leucine usage in rhabdomyosarcoma.

Bhargab Kalita, Gerard Martinez-Cebrian, Justina McEvoy, Melody Allensworth, Michelle Knight, Alessandro Magli, Rita C R Perlingeiro, Michael A Dyer, Elizabeth Stewart, Brian David Dynlacht.

  Alveolar rhabdomyosarcoma (ARMS) patients harboring paired-box fusion proteins (PAX3/7-FOXO1) exhibit a greater incidence of tumor relapse, metastasis, and poor survival outcome, thereby underscoring the urgent need to develop effective therapies to treat this subtype of childhood cancer. To uncover mechanisms that contribute to tumor initiation, we develop a muscle progenitor model and use epigenomic approaches to unravel genome rewiring events mediated by PAX3/7 fusion proteins. Among the key targets of PAX3/7 fusion proteins, we identify a cohort of oncogenes, fibroblast growth factor (FGF) receptors, tRNA-modifying enzymes, and genes essential for mitochondrial metabolism and protein translation, which we successfully targeted in preclinical trials. We identify leucine usage as a key factor driving the growth of aggressive PAX-fusion tumors, as limiting its bioavailability impaired oxidative phosphorylation and mitochondrial metabolism, delaying tumor progression and improving survival in vivo. Our data provide a compelling list of actionable targets and suggest promising new strategies to treat this tumor.

Keywords:  3D/2D-adapted PDX models; Leucine; MYCN; TRMT5; alveolar rhabdomyosarcoma; mitochondrial metabolism; myogenic progenitors; roblitinib; tRNA modifications; tigecycline

DOI:  https://doi.org/10.1016/j.cell.2025.03.008
Nat Metab. 2025 Apr 09.

UPRmt controls the mesenchymal-to-epithelial transition.

Marine Barthez, Danica Chen.

DOI: https://doi.org/10.1038/s42255-025-01260-7
Cancer Cell. 2025 Apr 01. pii: S1535-6108(25)00116-3. [Epub ahead of print]

Cancer cell-derived arginine fuels polyamine biosynthesis in tumor-associated macrophages to promote immune evasion.

Yinghua Zhu, Ziwei Zhou, Xin Du, Xiaorong Lin, Zhi-Mei Liang, Si Chen, Yiwei Sun, Yue Wang, Zhenkun Na, Zhiyong Wu, Jiaxin Zhong, Beinan Han, Xiangping Zhu, Wenkui Fu, Hongde Li, Man-Li Luo, Hai Hu.

  Arginine metabolism reshapes the tumor microenvironment (TME) into a pro-tumor niche through complex metabolic cross-feeding among various cell types. However, the key intercellular metabolic communication that mediates the collective effects of arginine metabolism within the TME remains unclear. Here, we reveal that the metabolic interplay between cancer cells and macrophages plays a dominant role in arginine-driven breast cancer progression. Within the TME, breast cancer cells serve as the primary source of arginine, which induces a pro-tumor polarization of tumor-associated macrophages (TAMs), thereby suppressing the anti-tumor activity of CD8+ T cells. Notably, this cancer cell-macrophage interaction overrides the arginine-mediated enhancement of CD8+ T cell anti-tumor activity. Mechanistically, polyamines derived from arginine metabolism enhance pro-tumor TAM polarization via thymine DNA glycosylase (TDG)-mediated DNA demethylation, regulated by p53 signaling. Importantly, targeting the arginine-polyamine-TDG axis between cancer cells and macrophages significantly suppresses breast cancer growth, highlighting its therapeutic potential.

Keywords:  arginine; breast cancer; metabolic communication; polyamine; tumor microenvironment; tumor-associated macrophages

DOI:  https://doi.org/10.1016/j.ccell.2025.03.015
Sci Adv. 2025 Apr 11. 11(15): eadu5091

ARMC1 partitions between distinct complexes and assembles MIRO with MTFR to control mitochondrial distribution.

Michael J McKenna, Felix Kraus, João P L Coelho, Muskaan Vasandani, Jiuchun Zhang, Benjamin M Adams, Joao A Paulo, J Wade Harper, Sichen Shao.

Maintaining an optimal mitochondrial distribution is critical to ensure an adequate supply of energy and metabolites to support important cellular functions. How cells balance dynamic mitochondrial processes to achieve homeostasis is incompletely understood. Here, we show that ARMC1 partitioning between distinct mitochondrial protein complexes is a key determinant of mitochondrial distribution. In one complex, the mitochondrial trafficking adaptor MIRO recruits ARMC1, which mediates the assembly of a mitochondrial fission regulator (MTFR). MTFR stability depends on ARMC1, and MIRO-MTFR complexes specifically antagonize retrograde mitochondrial movement. In another complex, DNAJC11 facilitates ARMC1 release from mitochondria. Disrupting MIRO-MTFR assembly fails to rescue aberrant mitochondrial distributions clustered in the perinuclear area observed with ARMC1 deletion, while disrupting ARMC1 interaction with DNAJC11 leads to excessive mitochondrially localized ARMC1 and distinct mitochondrial defects. Thus, the abundance and trafficking impact of MIRO-MTFR complexes require ARMC1, whose mito-cytoplasmic shuttling balanced by DNAJC11 tunes steady-state mitochondrial distributions.

DOI: https://doi.org/10.1126/sciadv.adu5091
Nat Genet. 2025 Apr;57(4): 774

Somatic mutations in the stomach.

Safia Danovi.

DOI: https://doi.org/10.1038/s41588-025-02181-7
Mol Cell. 2025 Apr 03. pii: S1097-2765(25)00189-3. [Epub ahead of print]85(7): 1253-1255

Metabolite tunes MDV pathway to maintain mitochondrial fitness.

Shiori Sekine, Yusuke Sekine.

In this issue of Molecular Cell, Tang et al.1 demonstrate that the ketone body β-hydroxybutyrate (BHB) promotes the biogenesis of mitochondrial-derived vesicles (MDVs) via lysine β-hydroxybutyrylation (Kbhb) on SNX9, revealing a way to fine-tune the mitochondrial quality control pathway with metabolites.

DOI: https://doi.org/10.1016/j.molcel.2025.02.027
Cancer Cell. 2025 Apr 07. pii: S1535-6108(25)00132-1. [Epub ahead of print]

Radiotherapy promotes cuproptosis and synergizes with cuproptosis inducers to overcome tumor radioresistance.

Guang Lei, Mingchuang Sun, Jun Cheng, Rui Ye, Zhengze Lu, Amber Horbath, David Huo, Shengrong Wu, Anagha Alapati, Sadhna Aggarwal, Zhihao Xu, Chao Mao, Yuelong Yan, Jun Yao, Qidong Li, Xiong Chen, Hyemin Lee, Li Zhuang, Dadi Jiang, Apar Pataer, Jack A Roth, Nicholas Navin, Albert C Koong, Mingjian James You, Steven H Lin, Boyi Gan.

  Cuproptosis is a recently identified form of copper-dependent cell death. Here, we reveal that radiotherapy (RT) induces cuproptosis in cancer cells, independent of apoptosis and ferroptosis, and depletes lipoylated proteins and iron-sulfur (Fe-S) cluster proteins-both hallmarks of cuproptosis-in patient tumors. Mechanistically, RT elevates mitochondrial copper levels by upregulating copper transporter 1 (CTR1) and depleting mitochondrial glutathione, a copper chelator, thereby triggering cuproptosis. Integrated analyses of RNA sequencing (RNA-seq) from radioresistant esophageal cancer cells and single-cell RNA-seq from esophageal tumors of patients unresponsive to RT link radioresistance to the downregulation of BTB and CNC homology 1 (BACH1). This downregulation de-represses the expression of copper-sequestering metallothionein (MT) 1E/X, thereby mitigating cuproptosis and contributing to radioresistance. Copper ionophore treatment sensitizes radioresistant cancer cells and cell line- and patient-derived xenografts to RT by potentiating cuproptosis. Our findings unveil a link between RT and cuproptosis and inform a therapeutic strategy to overcome tumor radioresistance by targeting cuproptosis.

Keywords:  copper; cuproptosis; metallothionein; radioresistance; radiotherapy

DOI:  https://doi.org/10.1016/j.ccell.2025.03.031
Science. 2025 Apr 11. 388(6743): 150-151

How does cancer affect motivation?

Jeffrey W Dalley, Mary-Ellen Lynall.

Inflammatory cytokines hijack a brain circuit to cause apathy in cancer.

DOI: https://doi.org/10.1126/science.adw8833
Nat Commun. 2025 Apr 11. 16(1): 3450

Natural killer cells' functional impairment drives the immune escape of pre-malignant clones in early-stage myelodysplastic syndromes.

Juan Jose Rodriguez-Sevilla, Irene Ganan-Gomez, Bijender Kumar, Natthakan Thongon, Feiyang Ma, Kelly S Chien, Yi J Kim, Hui Yang, Sanam Loghavi, Roselyn Tan, Vera Adema, Zongrui Li, Tomoyuki Tanaka, Hidetaka Uryu, Rashmi Kanagal-Shamanna, Gheath Al-Atrash, Rafael Bejar, Pinaki Prosad Banerjee, Sophia Lynn Cha, Guillermo Montalban-Bravo, Max Dougherty, Maria Claudina Fernandez Laurita, Noelle Wheeler, Baosen Jia, Eirini P Papapetrou, Franco Izzo, Daniela E Dueñas, Salome McAllen, Yiqian Gu, Gabriele Todisco, Francesca Ficara, Matteo Giovanni Della Porta, Abhinav Jain, Koichi Takahashi, Karen Clise-Dwyer, Stephanie Halene, Maria Teresa Sabrina Bertilaccio, Guillermo Garcia-Manero, May Daher, Simona Colla.

Dissecting the preneoplastic disease states' biological mechanisms that precede tumorigenesis can lead to interventions that can slow down disease progression and/or mitigate disease-related comorbidities. Myelodysplastic syndromes (MDS) cannot be cured by currently available pharmacological therapies, which fail to eradicate aberrant hematopoietic stem cells (HSCs), most of which are mutated by the time of diagnosis. Here, we sought to elucidate how MDS HSCs evade immune surveillance and expand in patients with clonal cytopenias of undetermined significance (CCUS), the pre-malignant stage of MDS. We used multi-omic single-cell approaches and functional in vitro studies to show that immune escape at disease initiation is mainly mediated by mutant, dysfunctional natural killer (NK) cells with impaired cytotoxic capability against cancer cells. Preclinical in vivo studies demonstrated that injecting NK cells from healthy donors efficiently depleted CCUS mutant cells while allowing normal cells to regenerate hematopoiesis. Our findings suggest that early intervention with adoptive cell therapy can prevent or delay the development of MDS.

DOI: https://doi.org/10.1038/s41467-025-58662-0
bioRxiv. 2025 Mar 27. pii: 2025.03.27.645657. [Epub ahead of print]

Alternative start codon selection shapes mitochondrial function during evolution, homeostasis, and disease.

Jimmy Ly, Yi Fei Tao, Matteo Di Bernardo, Ekaterina Khalizeva, Christopher J Giuliano, Sebastian Lourido, Mark D Fleming, Iain M Cheeseman.

Mitochondrial endosymbiosis was a pivotal event in eukaryotic evolution, requiring core proteins to adapt to function both within the mitochondria and in the host cell. Here, we systematically profile the localization of protein isoforms generated by alternate start codon selection during translation. We identify hundreds of pairs of differentially-localized protein isoforms, many of which affect mitochondrial targeting and are essential for mitochondrial function. The emergence of dual-localized mitochondrial protein isoforms coincides with mitochondrial acquisition during early eukaryotic evolution. We further reveal that eukaryotes use diverse mechanisms-such as leaky ribosome scanning, alternative transcription, and paralog duplication-to maintain the production of dual-localized isoforms. Finally, we identify multiple isoforms that are specifically dysregulated by rare disease patient mutations and demonstrate how these mutations can help explain unique clinical presentations. Together, our findings illuminate the evolutionary and pathological relevance of alternative translation initiation, offering new insights into the molecular underpinnings of mitochondrial biology.

DOI: https://doi.org/10.1101/2025.03.27.645657
Nat Commun. 2025 Apr 09. 16(1): 3375

Peripheral positioning of lysosomes supports melanoma aggressiveness.

Katerina Jerabkova-Roda, Marina Peralta, Kuang-Jing Huang, Antoine Mousson, Clara Bourgeat Maudru, Louis Bochler, Ignacio Busnelli, Rabia Karali, Hélène Justiniano, Lucian-Mihai Lisii, Philippe Carl, Vincent Mittelheisser, Nandini Asokan, Annabel Larnicol, Olivier Lefebvre, Hugo Lachuer, Angélique Pichot, Tristan Stemmelen, Anne Molitor, Léa Scheid, Quentin Frenger, Frédéric Gros, Aurélie Hirschler, François Delalande, Emilie Sick, Raphaël Carapito, Christine Carapito, Dan Lipsker, Kristine Schauer, Philippe Rondé, Vincent Hyenne, Jacky G Goetz.

Emerging evidence suggests that the function and position of organelles are pivotal for tumor cell dissemination. Among them, lysosomes stand out as they integrate metabolic sensing with gene regulation and secretion of proteases. Yet, how their function is linked to their position and how this controls metastasis remains elusive. Here, we analyze lysosome subcellular distribution in patient-derived melanoma cells and patient biopsies and show that lysosome spreading scales with melanoma aggressiveness. Peripheral lysosomes promote matrix degradation and cell invasion which is directly linked to the lysosomal and cell transcriptional programs. Using chemo-genetical control of lysosome positioning, we demonstrate that perinuclear clustering impairs lysosome secretion, matrix degradation and invasion. Impairing lysosome spreading significantly reduces invasive outgrowth in two in vivo models, mouse and zebrafish. Our study provides a direct demonstration that lysosome positioning controls cell invasion, illustrating the importance of organelle adaptation in carcinogenesis and suggesting its potential utility for diagnosis of metastatic melanoma.

DOI: https://doi.org/10.1038/s41467-025-58528-5
J Bioenerg Biomembr. 2025 Apr 08.

The Warburg hypothesis and the emergence of the mitochondrial metabolic theory of cancer.

Thomas N Seyfried, Derek C Lee, Tomas Duraj, Nathan L Ta, Purna Mukherjee, Michael Kiebish, Gabriel Arismendi-Morillo, Christos Chinopoulos.

  Otto Warburg originally proposed that cancer arose from a two-step process. The first step involved a chronic insufficiency of mitochondrial oxidative phosphorylation (OxPhos), while the second step involved a protracted compensatory energy synthesis through lactic acid fermentation. His extensive findings showed that oxygen consumption was lower while lactate production was higher in cancerous tissues than in non-cancerous tissues. Warburg considered both oxygen consumption and extracellular lactate as accurate markers for ATP production through OxPhos and glycolysis, respectively. Warburg's hypothesis was challenged from findings showing that oxygen consumption remained high in some cancer cells despite the elevated production of lactate suggesting that OxPhos was largely unimpaired. New information indicates that neither oxygen consumption nor lactate production are accurate surrogates for quantification of ATP production in cancer cells. Warburg also did not know that a significant amount of ATP could come from glutamine-driven mitochondrial substrate level phosphorylation in the glutaminolysis pathway with succinate produced as end product, thus confounding the linkage of oxygen consumption to the origin of ATP production within mitochondria. Moreover, new information shows that cytoplasmic lipid droplets and elevated aerobic lactic acid fermentation are both biomarkers for OxPhos insufficiency. Warburg's original hypothesis can now be linked to a more complete understanding of how OxPhos insufficiency underlies dysregulated cancer cell growth. These findings can also address several questionable assumptions regarding the origin of cancer thus allowing the field to advance with more effective therapeutic strategies for a less toxic metabolic management and prevention of cancer.

Keywords:  Cardiolipin; Lactate; Lipid droplets; Oxidative phosphorylation; Oxygen consumption; Somatic mutations; Substrate level phosphorylation; Succinate

DOI:  https://doi.org/10.1007/s10863-025-10059-w
Sci Adv. 2025 Apr 11. 11(15): eadv4082

Histone H3 cysteine 110 enhances iron metabolism and modulates replicative life span in Saccharomyces cerevisiae.

Chen Cheng, Brenna S McCauley, Nedas Matulionis, Maria Vogelauer, Dimitrios Camacho, Heather R Christofk, Weiwei Dang, Nicholas A T Irwin, Siavash K Kurdistani.

The discovery of histone H3 copper reductase activity provides a novel metabolic framework for understanding the functions of core histone residues, which, unlike N-terminal residues, have remained largely unexplored. We previously demonstrated that histone H3 cysteine 110 (H3C110) contributes to cupric (Cu2+) ion binding and its reduction to the cuprous (Cu1+) form. However, this residue is absent in Saccharomyces cerevisiae, raising questions about its evolutionary and functional significance. Here, we report that H3C110 has been lost in many fungal lineages despite near-universal conservation across eukaryotes. Introduction of H3C110 into S. cerevisiae increased intracellular Cu1+ levels and ameliorated the iron homeostasis defects caused by inactivation of the Cup1 metallothionein or glutathione depletion. Enhanced histone copper reductase activity also extended replicative life span under oxidative growth conditions but reduced it under fermentative conditions. Our findings suggest that a trade-off between histone copper reductase activity, iron metabolism, and life span may underlie the loss or retention of H3C110 across eukaryotes.

DOI: https://doi.org/10.1126/sciadv.adv4082
Nature. 2025 Apr 09.

Small molecules restore mutant mitochondrial DNA polymerase activity.

Sebastian Valenzuela, Xuefeng Zhu, Bertil Macao, Mattias Stamgren, Carol Geukens, Paul S Charifson, Gunther Kern, Emily Hoberg, Louise Jenninger, Anja V Gruszczyk, Seoeun Lee, Katarina A S Johansson, Javier Miralles Fusté, Yonghong Shi, S Jordan Kerns, Laleh Arabanian, Gabriel Martinez Botella, Sofie Ekström, Jeremy Green, Andrew M Griffin, Carlos Pardo-Hernández, Thomas A Keating, Barbara Küppers-Munther, Nils-Göran Larsson, Cindy Phan, Viktor Posse, Juli E Jones, Xie Xie, Simon Giroux, Claes M Gustafsson, Maria Falkenberg.

Mammalian mitochondrial DNA (mtDNA) is replicated by DNA polymerase γ (POLγ), a heterotrimeric complex consisting of a catalytic POLγA subunit and two accessory POLγB subunits1. More than 300 mutations in POLG, the gene encoding the catalytic subunit, have been linked to severe, progressive conditions with high rates of morbidity and mortality, for which no treatment exists2. Here we report on the discovery and characterization of PZL-A, a first-in-class small-molecule activator of mtDNA synthesis that is capable of restoring function to the most common mutant variants of POLγ. PZL-A binds to an allosteric site at the interface between the catalytic POLγA subunit and the proximal POLγB subunit, a region that is unaffected by nearly all disease-causing mutations. The compound restores wild-type-like activity to mutant forms of POLγ in vitro and activates mtDNA synthesis in cells from paediatric patients with lethal POLG disease, thereby enhancing biogenesis of the oxidative phosphorylation machinery and cellular respiration. Our work demonstrates that a small molecule can restore function to mutant DNA polymerases, offering a promising avenue for treating POLG disorders and other severe conditions linked to depletion of mtDNA.

DOI: https://doi.org/10.1038/s41586-025-08856-9
Nat Rev Genet. 2025 Apr 11.

The regulation and function of post-transcriptional RNA splicing.

Karine Choquet, Ines L Patop, L Stirling Churchman.

Eukaryotic RNA transcripts undergo extensive processing before becoming functional messenger RNAs, with splicing being a critical and highly regulated step that occurs both co-transcriptionally and post-transcriptionally. Recent analyses have revealed, with unprecedented spatial and temporal resolution, that up to 40% of mammalian introns are retained after transcription termination and are subsequently removed largely while transcripts remain chromatin-associated. Post-transcriptional splicing has emerged as a key layer of gene expression regulation during development, stress response and disease progression. The control of post-transcriptional splicing regulates protein production through delayed splicing and nuclear export, or nuclear retention and degradation of specific transcript isoforms. Here, we review current methodologies for detecting post-transcriptional splicing, discuss the mechanisms controlling the timing of splicing and examine how this temporal regulation affects gene expression programmes in healthy cells and in disease states.

DOI: https://doi.org/10.1038/s41576-025-00836-z
Cell Death Dis. 2025 Apr 05. 16(1): 254

Inhibition of mitochondrial complex I induces mitochondrial ferroptosis by regulating CoQH2 levels in cancer.

Ru Deng, Lingyi Fu, Haoyu Liang, Xixiong Ai, Fangyi Liu, Nai Li, Liyan Wu, Shuo Li, Xia Yang, Yansong Lin, Yuhua Huang, Jingping Yun.

Ferroptosis, a novel form of regulated cell death induced by the excessive accumulation of lipid peroxidation products, plays a pivotal role in the suppression of tumorigenesis. Two prominent mitochondrial ferroptosis defense systems are glutathione peroxidase 4 (GPX4) and dihydroorotate dehydrogenase (DHODH), both of which are localized within the mitochondria. However, the existence of supplementary cellular defense mechanisms against mitochondrial ferroptosis remains unclear. Our findings unequivocally demonstrate that inactivation of mitochondrial respiratory chain complex I (MCI) induces lipid peroxidation and consequently invokes ferroptosis across GPX4 low-expression cancer cells. However, in GPX4 high expression cancer cells, the MCI inhibitor did not induce ferroptosis, but increased cell sensitivity to ferroptosis induced by the GPX4 inhibitor. Overexpression of the MCI alternative protein yeast NADH-ubiquinone reductase (NDI1) not only quells ferroptosis induced by MCI inhibitors but also confers cellular protection against ferroptosis inducers. Mechanically, MCI inhibitors actuate an elevation in the NADH level while concomitantly diminishing the CoQH2 level. The manifestation of MCI inhibitor-induced ferroptosis can be reversed by supplementation with mitochondrial-specific analogues of CoQH2. Notably, MCI operates in parallel with mitochondrial-localized GPX4 and DHODH to inhibit mitochondrial ferroptosis, but independently of cytosolically localized GPX4 or ferroptosis suppressor protein 1(FSP1). The MCI inhibitor IACS-010759, is endowed with the ability to induce ferroptosis while concurrently impeding tumor proliferation in vivo. Our results identified a ferroptosis defense mechanism mediated by MCI within the mitochondria and suggested a therapeutic strategy for targeting ferroptosis in cancer treatment.

DOI: https://doi.org/10.1038/s41419-025-07510-6
Nat Rev Cancer. 2025 Apr 04.

Blocking cholesterol biosynthesis to clean out cancer.

Daniela Senft.

DOI: https://doi.org/10.1038/s41568-025-00816-9
Nature. 2025 Apr;640(8058): 302-304

Cells are swapping their mitochondria. What does this mean for our health?

Gemma Conroy.



Keywords:  Cancer; Cell biology; Diseases

DOI:  https://doi.org/10.1038/d41586-025-01064-5
Nat Genet. 2025 Apr 10.

A redefined InDel taxonomy provides insights into mutational signatures.

Gene Ching Chiek Koh, Arjun Scott Nanda, Giuseppe Rinaldi, Soraya Boushaki, Andrea Degasperi, Cherif Badja, Andrew Marcel Pregnall, Salome Jingchen Zhao, Lucia Chmelova, Daniella Black, Laura Heskin, João Dias, Jamie Young, Yasin Memari, Scott Shooter, Jan Czarnecki, Matthew Arthur Brown, Helen Ruth Davies, Xueqing Zou, Serena Nik-Zainal.

Despite their deleterious effects, small insertions and deletions (InDels) have received far less attention than substitutions. Here we generated isogenic CRISPR-edited human cellular models of postreplicative repair dysfunction (PRRd), including individual and combined gene edits of DNA mismatch repair (MMR) and replicative polymerases (Pol ε and Pol δ). Unique, diverse InDel mutational footprints were revealed. However, the prevailing InDel classification framework was unable to discriminate these InDel signatures from background mutagenesis and from each other. To address this, we developed an alternative InDel classification system that considers flanking sequences and informative motifs (for example, longer homopolymers), enabling unambiguous InDel classification into 89 subtypes. Through focused characterization of seven tumor types from the 100,000 Genomes Project, we uncovered 37 InDel signatures; 27 were new. In addition to unveiling previously hidden biological insights, we also developed PRRDetect-a highly specific classifier of PRRd status in tumors, with potential implications for immunotherapies.

DOI: https://doi.org/10.1038/s41588-025-02152-y
J Biomed Sci. 2025 Apr 09. 32(1): 41

Multiple roles of branched-chain amino acid metabolism in tumour progression.

Lin Wang, Feng Shi, Ya Cao, Longlong Xie.

  Metabolic reprogramming enables tumour cells to sustain their continuous proliferation and adapt to the ever-changing microenvironment. Branched-chain amino acids (BCAAs) and their metabolites are involved in intracellular protein synthesis and catabolism, signal transduction, epigenetic modifications, and the maintenance of oxidative homeostasis. Alterations in BCAA metabolism can influence the progression of various tumours. However, how BCAA metabolism is dysregulated differs among depending on tumour type; for example, it can manifest as decreased BCAA metabolism leading to BCAA accumulation, or as enhanced BCAA uptake and increased catabolism. In this review, we describe the role of BCAA metabolism in the progression of different tumours. As well as discuss how BCAA metabolic reprogramming drives tumour therapy resistance and evasion of the antitumour immune response, and how these pro-cancer effects are achieved in part by activating the mTORC signalling pathway. In-depth investigations into the potential mechanisms by which BCAA metabolic reprogramming affects tumorigenesis and tumour progression can enhance our understanding of the relationship between metabolism and cancer and provide new strategies for cancer therapy.

Keywords:  BCAA metabolism; Metabolic reprogramming; Tumour immunity; Tumour progression; Tumour resistance; mTORC signalling pathway

DOI:  https://doi.org/10.1186/s12929-025-01132-y
Curr Opin Cell Biol. 2025 Apr 10. pii: S0955-0674(25)00048-1. [Epub ahead of print]94 102510

Mitochondria and cell death signalling.

Ella Hall-Younger, Stephen Wg Tait.

Mitochondria are essential organelles in the life and death of a cell. During apoptosis, mitochondrial outer membrane permeabilisation (MOMP) engages caspase activation and cell death. Under nonlethal apoptotic stress, some mitochondria undergo permeabilisation, termed minority MOMP. Nonlethal apoptotic signalling impacts processes including genome stability, senescence and innate immunity. Recent studies have shown that upon MOMP, mitochondria and consequent signalling can trigger inflammation. We discuss how this occurs, and how mitochondrial inflammation might be targeted to increase tumour immunogenicity. Finally, we highlight how mitochondria contribute to other types of cell death including pyroptosis and ferroptosis. Collectively, these studies reveal critical new insights into how mitochondria regulate cell death, highlighting that mitochondrial signals engaged under nonlethal apoptotic stress have wide-ranging biological functions.

DOI: https://doi.org/10.1016/j.ceb.2025.102510
Mol Cell. 2025 Mar 27. pii: S1097-2765(25)00201-1. [Epub ahead of print]

STING mediates lysosomal quality control and recovery through its proton channel function and TFEB activation in lysosomal storage disorders.

Zhen Tang, Cong Xing, Antonina Araszkiewicz, Kun Yang, Wanwan Huai, Devon Jeltema, Nicole Dobbs, Yihe Zhang, Lu O Sun, Nan Yan.

  Lysosomes are essential organelles for cellular homeostasis. Defective lysosomes are associated with diseases like lysosomal storage disorders (LSDs). How lysosomal defects are detected and lysosomal function restored remain incompletely understood. Here, we show that STING mediates a neuroinflammatory gene signature in three distinct LSD mouse models, Galctwi/twi, Ppt1-/-, and Cln7-/-. Transcriptomic analysis of Galctwi/twi mouse brain tissue revealed that STING also mediates the expression of lysosomal genes that are regulated by transcriptional factor EB (TFEB). Immunohistochemical and single-nucleus RNA-sequencing (snRNA-seq) analysis show that STING regulates lysosomal gene expression in microglia. Mechanistically, we show that STING activation leads to TFEB dephosphorylation, nuclear translocation, and expression of lysosomal genes. This process requires STING's proton channel function, the V-ATPase-ATG5-ATG8 cascade, and is independent of immune signaling. Furthermore, we show that the STING-TFEB axis facilitates lysosomal repair. Together, our data identify STING-TFEB as a lysosomal quality control mechanism that responds to lysosomal dysfunction.

Keywords:  Krabbe disease; Niemann-Pick disease; STING; TFEB; innate immunity; lysosomal storage disorder; lysosome repair; neuroinflammation; non-canonical autophagy

DOI:  https://doi.org/10.1016/j.molcel.2025.03.008
J Cell Sci. 2025 Apr 07. pii: jcs.263688. [Epub ahead of print]

Tumor acidosis supports cancer cell lipid uptake via a rapid, transporter-independent mechanism.

Marc Severin, Rikke K Hansen, Michala G Rolver, Tove Hels, Kenji Maeda, Luis A Pardo, Stine F Pedersen.

  Tumor acidosis alters cancer cell metabolism and favors aggressive disease progression. Cancer cells in acidic environments increase lipid droplet (LD) accumulation and oxidative phosphorylation, characteristics of aggressive cancers. Here, we use live imaging, shotgun lipidomics, and immunofluorescence analyses of mammary and pancreatic cancer cells to demonstrate that both acute acidosis and adaptation to acidic growth drive rapid uptake of fatty acids (FA), which are converted to triacylglycerols (TAG) and stored in LDs. Consistent with its independence of de novo synthesis, TAG- and LD accumulation in acid-adapted cells is unaffected by FA-synthetase inhibitors. Macropinocytosis, which is upregulated in acid-adapted cells, partially contributes to FA uptake, which is independent of other protein-facilitated lipid uptake mechanisms, including CD36, FATP2, and caveolin- and clathrin-dependent endocytosis. We propose that a major mechanism by which tumor acidosis drives FA uptake is through neutralizing protonation of negatively charged FAs allowing their diffusive, transporter-independent uptake. We suggest that this could be a major factor triggering acidosis-driven metabolic rewiring.

Keywords:  CD36; FASN; Lipid diffusion; Macropinocytosis; Membrane contact sites; Protonation

DOI:  https://doi.org/10.1242/jcs.263688
Cell Rep. 2025 Apr 10. pii: S2211-1247(25)00337-7. [Epub ahead of print]44(4): 115566

Pre-existing intratumoral stem-like CD8+ T cells drive radiotherapy-induced tumor immunity.

Hakan Köksal, Michael Herbst, Paulo Perreira, Marc Nater, Nicola Regli, Cheïma Boudjeniba, Nese Erdem Borgoni, Virginia Cecconi, Maries van den Broek.

  CD8+ T cells are crucial for both spontaneous and therapy-induced restriction of tumor progression. Although many patients with cancer undergo radiotherapy, the precise effect of this genotoxic treatment on tumor-associated CD8+ T cells is insufficiently understood. Here, we investigated the influence of radiotherapy on intratumoral CD8+ T cells. We found that, although these CD8+ T cells initially decline following radiotherapy, they subsequently expand and are both essential and sufficient for early tumor control. In response to radiotherapy, stem-like CD8+ T cells proliferate and differentiate into effector CD8+ T cells, making them key drivers of tumor immunity. Our findings underscore the pivotal role of intratumoral stem-like CD8+ T cells in mediating radiotherapy-induced anti-tumor immunity and provide deeper insights into the dynamic behavior of CD8+ T cells during tumor control after radiotherapy.

Keywords:  CP: Cancer; CP: Immunology; TCF-1; cancer; radiotherapy; stem-like CD8(+) T cells

DOI:  https://doi.org/10.1016/j.celrep.2025.115566
Nat Metab. 2025 Apr 08.

TMEM65 regulates and is required for NCLX-dependent mitochondrial calcium efflux.

Joanne F Garbincius, Oniel Salik, Henry M Cohen, Carmen Choya-Foces, Adam S Mangold, Angelina D Makhoul, Anna E Schmidt, Dima Y Khalil, Joshua J Doolittle, Anya S Wilkinson, Emma K Murray, Michael P Lazaropoulos, Alycia N Hildebrand, Dhanendra Tomar, John W Elrod.

The balance between mitochondrial calcium (mCa2+) uptake and efflux is essential for ATP production and cellular homeostasis. The mitochondrial sodium-calcium exchanger, NCLX, is a critical route of mCa2+ efflux in excitable tissues, such as the heart and brain, and animal models support NCLX as a promising therapeutic target to limit pathogenic mCa2+ overload. However, the mechanisms that regulate NCLX activity are largely unknown. Using proximity biotinylation proteomic screening, we identify the mitochondrial inner membrane protein TMEM65 as an NCLX binding partner that enhances sodium (Na+)-dependent mCa2+ efflux. Mechanistically, acute pharmacological NCLX inhibition or genetic deletion of NCLX ablates the TMEM65-dependent increase in mCa2+ efflux, and loss-of-function studies show that TMEM65 is required for Na+-dependent mCa2+ efflux. In line with these findings, knockdown of Tmem65 in mice promotes mCa2+ overload in the heart and skeletal muscle and impairs both cardiac and neuromuscular function. Collectively, our results show that loss of TMEM65 function in excitable tissue disrupts NCLX-dependent mCa2+ efflux, causing pathogenic mCa2+ overload, cell death, and organ-level dysfunction. These findings demonstrate the essential role of TMEM65 in regulating NCLX-dependent mCa2+ efflux and suggest modulation of TMEM65 as a therapeutic strategy for a variety of diseases.

DOI: https://doi.org/10.1038/s42255-025-01250-9
Biophys J. 2025 Apr 03. pii: S0006-3495(25)00211-5. [Epub ahead of print]

Glycolysis model shows that allostery maintains high ATP and limits accumulation of intermediates.

Mangyu Choe, Tal Einav, Rob Phillips, Denis V Titov.

  Glycolysis is a conserved metabolic pathway that produces ATP and biosynthetic precursors. It is not well understood how the control of mammalian glycolytic enzymes through allosteric feedback and mass action accomplishes various tasks of ATP homeostasis, such as controlling the rate of ATP production, maintaining high and stable ATP levels, ensuring that ATP hydrolysis generates a net excess of energy, and maintaining glycolytic intermediate concentrations within physiological levels. To investigate these questions, we developed a biophysical model of glycolysis based on enzyme rate equations derived from in vitro kinetic data. This is the first biophysical model of human glycolysis that successfully recapitulates the above tasks of ATP homeostasis and predicts absolute concentrations of glycolytic intermediates and isotope tracing kinetics that align with experimental measurements in human cells. We use the model to show that mass action alone is sufficient to control the ATP production rate and maintain the high energy of ATP hydrolysis. Meanwhile, allosteric regulation of hexokinase (HK) and phosphofructokinase (PFK) by ATP, ADP, inorganic phosphate, and glucose-6-phosphate is required to maintain high ATP levels and to prevent uncontrolled accumulation of phosphorylated intermediates of glycolysis. Allosteric feedback achieves the latter by maintaining HK and PFK enzyme activity at one-half of ATP demand and, thus, inhibiting the reaction of Harden and Young, which otherwise converts glucose to supraphysiological levels of phosphorylated glycolytic intermediates at the expense of ATP. Our methodology provides a roadmap for a quantitative understanding of how metabolic homeostasis emerges from the activities of individual enzymes.

Keywords:  allosteric feedback; glycolysis; metabolism; modeling

DOI:  https://doi.org/10.1016/j.bpj.2025.03.037
Cell Rep. 2025 Apr 08. pii: S2211-1247(25)00311-0. [Epub ahead of print]44(4): 115540

Unraveling the nexus: Genomic instability and metabolism in cancer.

Vaibhavi Gujar, Haojian Li, Tanya T Paull, Carola A Neumann, Urbain Weyemi.

  The DNA-damage response (DDR) is a signaling network that enables cells to detect and repair genomic damage. Over the past three decades, inhibiting DDR has proven to be an effective cancer therapeutic strategy. Although cancer drugs targeting DDR have received approval for treating various cancers, tumor cells often develop resistance to these therapies, owing to their ability to undergo energetic metabolic reprogramming. Metabolic intermediates also influence tumor cells' ability to sense oxidative stress, leading to impaired redox metabolism, thus creating redox vulnerabilities. In this review, we summarize recent advances in understanding the crosstalk between DDR and metabolism. We discuss combination therapies that target DDR, metabolism, and redox vulnerabilities in cancer. We also outline potential obstacles in targeting metabolism and propose strategies to overcome these challenges.

Keywords:  CP: Cancer; DNA damage response; DNA repair; cancer therapy; metabolism; redox metabolism; therapy resistance

DOI:  https://doi.org/10.1016/j.celrep.2025.115540
J Immunol. 2025 Apr 09. pii: vkaf034. [Epub ahead of print]

Mitochondrial fatty acid synthesis and MECR regulate CD4+ T cell function and oxidative metabolism.

KayLee K Steiner, Arissa C Young, Andrew R Patterson, Ayaka Sugiura, McLane J Watson, Samuel E J Preston, Anton Zhelonkin, Erin Q Jennings, Channing Chi, Darren R Heintzman, Andrew P Pahnke, Yasmine T Toudji, Zaid Hatem, Matthew Z Madden, Emily N Arner, Allison E Sewell, Allison K Blount, Richmond Okparaugo, Emilia Fallman, Evan S Krystofiak, Ryan D Sheldon, Katherine N Gibson-Corley, Kelsey Voss, Sara M Nowinski, Russell G Jones, Denis A Mogilenko, Jeffrey C Rathmell.

  Imbalanced effector and regulatory CD4+ T cell subsets drive many inflammatory diseases. These T cell subsets rely on distinct metabolic programs, modulation of which differentially affects T cell fate and function. Lipid metabolism is fundamental yet remains poorly understood across CD4+ T cell subsets. Therefore, we performed targeted in vivo CRISPR/Cas9 screens to identify lipid metabolism genes and pathways essential for T cell functions. These screens established mitochondrial fatty acid synthesis genes Mecr, Mcat, and Oxsm as key metabolic regulators. Of these, the inborn error of metabolism gene Mecr was most dynamically regulated. Mecrfl/fl; Cd4cre mice had normal naïve CD4+ and CD8+ T cell numbers, demonstrating that MECR is not essential in homeostatic conditions. However, effector and memory T cells were reduced in Mecr knockout and MECR-deficient CD4+ T cells and proliferated, differentiated, and survived less well than control T cells. Interestingly, T cells ultimately showed signs of mitochondrial stress and dysfunction in the absence of MECR. Mecr-deficient T cells also had decreased mitochondrial respiration, reduced tricarboxylic acid intermediates, and accumulated intracellular iron, which appeared to contribute to increased cell death and sensitivity to ferroptosis. Importantly, MECR-deficient T cells exhibited fitness disadvantages and were less effective at driving disease in an in vivo model of inflammatory bowel disease. Thus, MECR-mediated metabolism broadly supports CD4+ T cell proliferation and survival in vivo. These findings may also provide insight to the immunological state of MECR- and other mitochondrial fatty acid synthesis-deficient patients.

Keywords:  CD4+ T cells; MECR; lipid metabolism; mtFAS

DOI:  https://doi.org/10.1093/jimmun/vkaf034
Nat Commun. 2025 Apr 04. 16(1): 3221

The Futile Creatine Cycle powers UCP1-independent thermogenesis in classical BAT.

Jakub Bunk, Mohammed F Hussain, Maria Delgado-Martin, Bozena Samborska, Mina Ersin, Abhirup Shaw, Janane F Rahbani, Lawrence Kazak.

Classical brown adipose tissue (BAT) is traditionally viewed as relying exclusively on uncoupling protein 1 (UCP1) for thermogenesis via inducible proton leak. However, the physiological significance of UCP1-independent mechanisms linking substrate oxidation to ATP turnover in classical BAT has remained unclear. Here, we identify the Futile Creatine Cycle (FCC), a mitochondrial-localized energy-wasting pathway involving creatine phosphorylation by creatine kinase b (CKB) and phosphocreatine hydrolysis by tissue-nonspecific alkaline phosphatase (TNAP), as a key UCP1-independent thermogenic mechanism in classical BAT. Reintroducing mitochondrial-targeted CKB exclusively into interscapular brown adipocytes in vivo restores thermogenesis and cold tolerance in mice lacking native UCP1 and CKB, in a TNAP-dependent manner. Furthermore, mice with inducible adipocyte-specific co-deletion of TNAP and UCP1 exhibit severe cold-intolerance. These findings challenge the view that BAT thermogenesis depends solely on UCP1 because of insufficient ATP synthase activity and establishes the FCC as a physiologically relevant thermogenic pathway in classical BAT.

DOI: https://doi.org/10.1038/s41467-025-58294-4
Cell Rep. 2025 Apr 05. pii: S2211-1247(25)00300-6. [Epub ahead of print]44(4): 115529

Amino acids in cancer: Understanding metabolic plasticity and divergence for better therapeutic approaches.

Linda K Do, Hyun Min Lee, Yun-Sok Ha, Chan-Hyeong Lee, Jiyeon Kim.

  Metabolic reprogramming is a hallmark of malignant transformation. While initial studies in the field of cancer metabolism focused on central carbon metabolism, the field has expanded to metabolism beyond glucose and glutamine and uncovered the important role of amino acids in tumorigenesis and tumor immunity as energy sources, signaling molecules, and precursors for (epi)genetic modification. As a result of the development and application of new technologies, a multifaceted picture has emerged, showing that context-dependent heterogeneity in amino acid metabolism exists between tumors and even within distinct regions of solid tumors. Understanding the complexity and flexibility of amino acid metabolism in cancer is critical because it can influence therapeutic responses and predict clinical outcomes. This overview discusses the current findings on the heterogeneity in amino acid metabolism in cancer and how understanding the metabolic diversity of amino acids can be translated into more clinically relevant therapeutic interventions.

Keywords:  CP: Cancer; CP: Metabolism; amino acids; cancer metabolism; metabolic heterogeneity

DOI:  https://doi.org/10.1016/j.celrep.2025.115529
Nat Commun. 2025 Apr 08. 16(1): 3340

Compression of morbidity by interventions that steepen the survival curve.

Yifan Yang, Avi Mayo, Tomer Levy, Naveh Raz, Ben Shenhar, Daniel F Jarosz, Uri Alon.

Longevity research aims to extend the healthspan while minimizing the duration of disability and morbidity, known as the sickspan. Most longevity interventions in model organisms extend healthspan, but it is not known whether they compress sickspan relative to the lifespan. Here, we present a theory that predicts which interventions compress relative sickspan, based on the shape of the survival curve. Interventions such as caloric restriction that extend mean lifespan while preserving the shape of the survival curve, are predicted to extend the sickspan proportionally, without compressing it. Conversely, a subset of interventions that extend lifespan and steepen the shape of the survival curve are predicted to compress the relative sickspan. We explain this based on the saturating-removal mathematical model of aging, and present evidence from longitudinal health data in mice, Caenorhabditis elegans and Drosophila melanogaster. We apply this theory to identify potential interventions for compressing the sickspan in mice, and to combinations of longevity interventions. This approach offers potential strategies for compressing morbidity and extending healthspan.

DOI: https://doi.org/10.1038/s41467-025-57807-5
Nat Food. 2025 Apr 09.

Dietary patterns and healthy ageing.

Laurence Daoust.

DOI: https://doi.org/10.1038/s43016-025-01165-4
Nat Commun. 2025 Apr 07. 16(1): 3291

Horizontal acquisition of prokaryotic hopanoid biosynthesis reorganizes membrane physiology driving lifestyle innovation in a eukaryote.

Bhagyashree Dasari Rao, Elisa Gomez-Gil, Maria Peter, Gabor Balogh, Vanessa Nunes, James I MacRae, Qu Chen, Peter B Rosenthal, Snezhana Oliferenko.

Horizontal gene transfer is a source of metabolic innovation and adaptation to new environments. How new metabolic functionalities are integrated into host cell biology is largely unknown. Here, we probe this fundamental question using the fission yeast Schizosaccharomyces japonicus, which has acquired a squalene-hopene cyclase Shc1 through horizontal gene transfer. We show that Shc1-dependent production of hopanoids, mimics of eukaryotic sterols, allows S. japonicus to thrive in anoxia, where sterol biosynthesis is not possible. We demonstrate that glycerophospholipid fatty acyl asymmetry, prevalent in S. japonicus, is crucial for accommodating both sterols and hopanoids in membranes and explain how Shc1 functions alongside the sterol biosynthetic pathway to support membrane properties. Reengineering experiments in the sister species S. pombe show that hopanoids entail new traits in a naïve organism, but the acquisition of a new enzyme may trigger profound reorganization of the host metabolism and physiology.

DOI: https://doi.org/10.1038/s41467-025-58515-w
Sci Adv. 2025 Apr 11. 11(15): eadu5511

Acute myeloid leukemia mitochondria hydrolyze ATP to support oxidative metabolism and resist chemotherapy.

James T Hagen, McLane M Montgomery, Raphael T Aruleba, Brett R Chrest, Polina Krassovskaia, Thomas D Green, Emely A Pacheco, Miki Kassai, Tonya N Zeczycki, Cameron A Schmidt, Debajit Bhowmick, Su-Fern Tan, David J Feith, Charles E Chalfant, Thomas P Loughran, Darla Liles, Mark D Minden, Aaron D Schimmer, Md Salman Shakil, Matthew J McBride, Myles C Cabot, Joseph M McClung, Kelsey H Fisher-Wellman.

OxPhos inhibitors have struggled to show a clinical benefit because of their inability to distinguish healthy from cancerous mitochondria. Herein, we describe an actionable bioenergetic mechanism unique to acute myeloid leukemia (AML) mitochondria. Unlike healthy cells that couple respiration to ATP synthesis, AML mitochondria support inner-membrane polarization by consuming ATP. Matrix ATP consumption allows cells to survive bioenergetic stress. Thus, we hypothesized AML cells may resist chemotherapy-induced cell death by reversing the ATP synthase reaction. In support, BCL-2 inhibition with venetoclax abolished OxPhos flux without affecting mitochondrial polarization. In surviving AML cells, sustained mitochondrial polarization depended on matrix ATP consumption. Mitochondrial ATP consumption was further enhanced in AML cells made refractory to venetoclax, consequential to down-regulations in the endogenous F1-ATPase inhibitor ATP5IF1. Knockdown of ATP5IF1 conferred venetoclax resistance, while ATP5IF1 overexpression impaired F1-ATPase activity and heightened sensitivity to venetoclax. These data identify matrix ATP consumption as a cancer cell-intrinsic bioenergetic vulnerability actionable in the context of BCL-2 targeted chemotherapy.

DOI: https://doi.org/10.1126/sciadv.adu5511
Nat Commun. 2025 Apr 07. 16(1): 3292

RNA G-quadruplexes control mitochondria-localized mRNA translation and energy metabolism.

Leïla Dumas, Sauyeun Shin, Quentin Rigaud, Marie Cargnello, Beatriz Hernández-Suárez, Pauline Herviou, Nathalie Saint-Laurent, Marjorie Leduc, Morgane Le Gall, David Monchaud, Erik Dassi, Anne Cammas, Stefania Millevoi.

Cancer cells rely on mitochondria for their bioenergetic supply and macromolecule synthesis. Central to mitochondrial function is the regulation of mitochondrial protein synthesis, which primarily depends on the cytoplasmic translation of nuclear-encoded mitochondrial mRNAs whose protein products are imported into mitochondria. Despite the growing evidence that mitochondrial protein synthesis contributes to the onset and progression of cancer, and can thus offer new opportunities for cancer therapy, knowledge of the underlying molecular mechanisms remains limited. Here, we show that RNA G-quadruplexes (RG4s) regulate mitochondrial function by modulating cytoplasmic mRNA translation of nuclear-encoded mitochondrial proteins. Our data support a model whereby the RG4 folding dynamics, under the control of oncogenic signaling and modulated by small molecule ligands or RG4-binding proteins, modifies mitochondria-localized cytoplasmic protein synthesis. Ultimately, this impairs mitochondrial functions, affecting energy metabolism and consequently cancer cell proliferation.

DOI: https://doi.org/10.1038/s41467-025-58118-5
Sci Transl Med. 2025 Apr 09. 17(793): eadr4458

Succinate-loaded tumor cell-derived microparticles reprogram tumor-associated macrophage metabolism.

Shuya Lu, Jiexiao Li, Yonggang Li, Shichuan Liu, Yutong Liu, Yue Liang, Xifen Zheng, Yiyang Chen, Jinghui Deng, Huafeng Zhang, Jingwei Ma, Jiadi Lv, Yugang Wang, Bo Huang, Ke Tang.

The tumor microenvironment predominantly polarizes tumor-associated macrophages (TAMs) toward an M2-like phenotype, thereby inhibiting antitumor immune responses. This process is substantially affected by metabolic reprogramming; however, reeducating TAMs to enhance their antitumor capabilities through metabolic remodeling remains a challenge. Here, we show that tumor-derived microparticles loaded with succinate (SMPs) can remodel the metabolic state of TAMs. SMPs promote classical M1-like polarization of macrophages by enhancing glycolysis and attenuating the tricarboxylic acid (TCA) cycle in a protein succinylation-dependent manner. Mechanistically, succinate is delivered into the mitochondria and nucleus by SMPs, leading to succinylation of isocitrate dehydrogenase 2 (IDH2) and histone H3K122 within the lactate dehydrogenase A (Ldha) promoter region. Our findings provide a distinct approach for TAM polarization using cell membrane-derived microparticles loaded with endogenous metabolites, a platform that may be used more broadly for posttranslational modification-based tumor immunotherapy.

DOI: https://doi.org/10.1126/scitranslmed.adr4458
Nat Metab. 2025 Apr 07.

Intergenerational metabolic effects of cold exposure.

R Teperino.

DOI: https://doi.org/10.1038/s42255-025-01222-z
FEBS J. 2025 Apr 05.

Y12C mutation disrupts IMPDH cytoophidia and alters cancer metabolism.

Chia-Chun Chang, Min Peng, Gerson Dierley Keppeke, Li-Kuang Tsai, Ziheng Zhang, Li-Mei Pai, Li-Ying Sung, Ji-Long Liu.

  Guanosine triphosphate (GTP) is a building block for DNA and RNA, and plays a pivotal role in various cellular functions, serving as an energy source, enzyme cofactor and a key component of signal transduction. The activity of the rate-limiting enzyme in de novo GTP synthesis, inosine monophosphate dehydrogenase (IMPDH), is regulated by nucleotide binding. Recent studies have illuminated that IMPDH octamers can assemble into linear polymers, adding another dimension to its enzymatic regulation. This polymerisation reduces IMPDH's sensitivity to the inhibitory effects of GTP binding, thereby augmenting its activity under conditions with elevated GTP levels. Within cells, IMPDH polymers may cluster to form the distinctive structure known as the cytoophidium, which is postulated to reflect the cellular demand for increased GTP concentrations. Nevertheless, the functional significance of IMPDH polymerisation in in vivo metabolic regulation remains unclear. In this study, we report the widespread presence of IMPDH cytoophidia in various human cancer tissues. Utilising the ABEmax base editor, we introduced a Y12C point mutation into IMPDH2 across multiple cancer cell lines. This mutation disrupts the polymerisation interface of IMPDH and prevents cytoophidium assembly. In some cancer xenografts, the absence of IMPDH polymers led to a downregulation of IMPDH, as well as the glycolytic and pentose phosphate pathways. Furthermore, mutant HeLa-cell-derived xenografts were notably smaller than their wild-type counterparts. Our data suggest that IMPDH polymerisation and cytoophidium assembly could be instrumental in modulating metabolic homeostasis in certain cancers, offering insights into the clinical relevance of IMPDH cytoophidium.

Keywords:  CRISPR base editor; IMPDH; cancer; cytoophidium; glycolysis; pentose phosphate pathway

DOI:  https://doi.org/10.1111/febs.70086
Plant J. 2025 Apr;122(1): e70142

Regulation of plant glycolysis and the tricarboxylic acid cycle by posttranslational modifications.

Ke Zheng, Maria Del Pilar Martinez, Maroua Bouzid, Manuel Balparda, Markus Schwarzländer, Veronica G Maurino.

  Plant glycolysis and the tricarboxylic acid (TCA) cycle are key pathways of central carbon metabolism. They facilitate energy transformation, provide redox balance, and supply the building blocks for biosynthetic processes that underpin plant survival, growth, and productivity. Yet, rather than acting as static pathways, the fluxes that are mediated by the enzymes involved form a branched network. Flux modes can change flexibly to match cellular demands and environmental fluctuations. Several of the enzymes involved in glycolysis and the TCA cycle have been identified as targets of posttranslational modifications (PTMs). PTMs can act as regulators to facilitate changes in flux by rapidly and reversibly altering enzyme organization and function. Consequently, PTMs enable plants to rapidly adjust their metabolic flux landscape, match energy and precursor provision with the changeable needs, and enhance overall metabolic flexibility. Here, we review the impact of different PTMs on glycolytic and TCA cycle enzymes, focusing on modifications that induce functional changes rather than the mere occurrence of PTMs at specific sites. By synthesizing recent findings, we provide a foundation for a system-level understanding of how PTMs choreograph the remarkable flexibility of plant central carbon metabolism.

Keywords:  central carbon metabolism; functional changes; glycolysis; posttranslational modifications; tricarboxylic acid cycle

DOI:  https://doi.org/10.1111/tpj.70142
Nat Metab. 2025 Apr 08.

TMEM65 joins the mitochondrial Ca2+ club.

Yasemin Sancak.

DOI: https://doi.org/10.1038/s42255-025-01271-4
Nat Cell Biol. 2025 Apr;27(4): 552

Timing is everything.

Angela R Parrish.

DOI: https://doi.org/10.1038/s41556-025-01659-0
Redox Biol. 2025 Mar 25. pii: S2213-2317(25)00120-X. [Epub ahead of print]82 103607

Revisiting insulin-stimulated hydrogen peroxide dynamics reveals a cytosolic reductive shift in skeletal muscle.

Carlos Henríquez-Olguín, Samantha Gallero, Anita Reddy, Kaspar W Persson, Farina L Schlabs, Christian T Voldstedlund, Gintare Valentinaviciute, Roberto Meneses-Valdés, Casper M Sigvardsen, Bente Kiens, Edward T Chouchani, Erik A Richter, Thomas E Jensen.

The intracellular redox state is crucial for insulin responses in peripheral tissues. Despite the longstanding belief that insulin signaling increases hydrogen peroxide (H2O2) production leading to reversible oxidation of cysteine thiols, evidence is inconsistent and rarely involves human tissues. In this study, we systematically investigated insulin-dependent changes in subcellular H2O2 levels and reversible cysteine modifications across mouse and human skeletal muscle models. Utilizing advanced redox tools-including genetically encoded H2O2 sensors and non-reducing immunoblotting-we consistently observed no increase in subcellular H2O2 levels following insulin stimulation. Instead, stoichiometric cysteine proteome analyses revealed a selective pro-reductive shift in cysteine modifications affecting insulin transduction related proteins, including Cys179 on GSK3β and Cys416 on Ras and Rab Interactor 2 (RIN2). Our findings challenge the prevailing notion that insulin promotes H2O2 generation in skeletal muscle and suggest that an insulin-stimulated pro-reductive shift modulates certain aspects of insulin signal transduction.

DOI: https://doi.org/10.1016/j.redox.2025.103607
Nat Metab. 2025 Apr 11.

NK cell-derived IFNγ mobilizes free fatty acids from adipose tissue to promote early B cell activation during viral infection.

Mia Krapić, Inga Kavazović, Sanja Mikašinović, Karlo Mladenić, Fran Krstanović, Gönül Seyhan, Sabine Helmrath, Elena Camerini, Ilija Brizić, Fleur S Peters, Marc Schmidt-Supprian, Bojan Polić, Tamara Turk Wensveen, Felix M Wensveen.

The immune system plays a major role in the regulation of adipose tissue homeostasis. Viral infection often drives fat loss, but how and why this happens is unclear. Here, we show that visceral adipose tissue transiently decreases adiposity following viral infection. Upon pathogen encounter, adipose tissue upregulates surface expression of ligands for activating receptors on natural killer cells, which drives IFNγ secretion. This cytokine directly stimulates adipocytes to shift their balance from lipogenesis to lipolysis, which leads to release of lipids in circulation, most notably of free fatty acids. The free fatty acid oleic acid stimulates early-activated B cells by promoting oxidative phosphorylation. Oleic acid promoted expression of co-stimulatory B7 molecules on B cells and promoted their ability to prime CD8+ T cells. Inhibiting lipid uptake by activated B cells impaired CD8+ T cell responses, causing an increase of viral replication in vivo. Our findings uncover a previously unappreciated mechanism of metabolic adaptation to infection and provide a better understanding of the interactions between immune cells and adipose tissue in response to inflammation.

DOI: https://doi.org/10.1038/s42255-025-01273-2
Nat Cell Biol. 2025 Apr;27(4): 563-574

Emerging roles of lysine lactyltransferases and lactylation.

Zhi Zong, Jiang Ren, Bing Yang, Long Zhang, Fangfang Zhou.

Given its various roles in cellular functions, lactate is no longer considered a waste product of metabolism and lactate sensing is a pivotal step in the transduction of lactate signals. Lysine lactylation is a recently identified post-translational modification that serves as an intracellular mechanism of lactate sensing and transfer. Although acetyltransferases such as p300 exhibit general acyl transfer activity, no bona fide lactyltransferases have been identified. Recently, the protein synthesis machinery, alanyl-tRNA synthetase 1 (AARS1), AARS2 and their Escherichia coli orthologue AlaRS, have been shown to be able to sense lactate and mediate lactyl transfer and are thus considered pan-lactyltransferases. Here we highlight the mechanisms and functions of these lactyltransferases and discuss potential strategies that could be exploited for the treatment of human diseases.

DOI: https://doi.org/10.1038/s41556-025-01635-8
Mol Cell. 2025 Apr 03. pii: S1097-2765(25)00188-1. [Epub ahead of print]85(7): 1258-1259

Hijacking the powerhouse: Mitochondrial transfer and mitophagy as emerging mechanisms of immune evasion.

Maria T Diaz-Meco, Juan F Linares, Jorge Moscat.

Cancer cells subvert the immune system by reprogramming their metabolism. In a recent study in Nature, Ikeda et al.1 show how cancer cells can directly transfer mitophagy-resistant mitochondria to tumor-infiltrating lymphocytes, promoting their homoplasmic replacement and undermining cancer immunity.

DOI: https://doi.org/10.1016/j.molcel.2025.02.026
Nat Metab. 2025 Apr 10.

Metabolites are not genes - avoiding the misuse of pathway analysis in metabolomics.

Kil Sun Lee, Xiaoyang Su, Tao Huan.

DOI: https://doi.org/10.1038/s42255-025-01283-0