bims-camemi Biomed News
on Mitochondrial metabolism in cancer
Issue of 2025–06–01
47 papers selected by
Christian Frezza, Universität zu Köln
  1. PRPS activity tunes redox homeostasis in Myc-driven lymphoma.
  2. The diverse roles of the circadian clock in cancer.
  3. Disulfide-mediated tetramerization of TRAP1 fosters its antioxidant and pro-neoplastic activities.
  4. Genetically encoded fluorescent reporter for polyamines.
  5. Structural and systems characterization of phosphorylation on metabolic enzymes identifies sex-specific metabolic reprogramming in obesity.
  6. WNK1 signalling regulates amino acid transport and mTORC1 activity to sustain acute myeloid leukaemia growth.
  7. Reverse electron transport drives metabolic changes in obesity.
  8. CoQ imbalance drives reverse electron transport to disrupt liver metabolism.
  9. Mechanisms of heme transport in the mitochondria.
  10. The mitochondrial intermembrane space - a permanently proteostasis-challenged compartment.
  11. Cross-organ metabolite production and consumption in healthy and atherogenic conditions.
  12. Sphingosine-1-phosphate signalling activates E-Syt1 to facilitate HDL-derived cholesterol transport.
  13. Nonhypermutator Cancers Access Driver Mutations Through Reversals in Germline Mutational Bias.
  14. The power of connections: Recent advances in understanding the regulation of mitochondrial dynamics by membrane contact sites.
  15. CRISPR screen reveals a simultaneous targeted mechanism to reduce cancer cell selenium and increase lipid oxidation to induce ferroptosis.
  16. Mitochondrial calcium signaling regulates branched-chain amino acid catabolism in fibrolamellar carcinoma.
  17. Inhibition of mitochondrial protein import and proteostasis by a pro-apoptotic lipid.
  18. Mitochondrial DNA transfer between malignant cells and T lymphocytes shapes the cancer-immunity dialogue.
  19. Tegavivint triggers TECR-dependent nonapoptotic cancer cell death.
  20. Dual phosphorylation of glycogen synthase kinase 3β differentially integrates metabolic programs to determine T cell immunity across vertebrates.
  21. The metabolic code of ferroptosis: nutritional regulators of cell death.
  22. Restoring calcium crosstalk between ER and mitochondria promotes intestinal stem cell rejuvenation through autophagy in aged Drosophila.
  23. Stable 13C-glutamine Tracing Resolved Metabolomics for Cancer Metabolism Study.
  24. Multi-organ metabolome biological age implicates cardiometabolic conditions and mortality risk.
  25. Cross-tissue coordination between SLC nucleoside transporters regulates reproduction in Caenorhabditis elegans.
  26. Metabolic flux analysis of glioblastoma neural stem cells reveals distinctive metabolic phenotypes in ketogenic conditions.
  27. FOXA2 promotes metastatic competence in small cell lung cancer.
  28. Ferroptosis-activating metabolite acrolein antagonizes necroptosis and anti-cancer therapeutics.
  29. Cocrystal structure reveals the mechanism of FSP1 inhibition by FSEN1.
  30. Mitochondrial clonal mosaicism encodes a biphasic molecular clock of aging.
  31. ARID1A and Its Impact Across the Hallmarks of Cancer.
  32. Polyamine acetylation mediates crosstalk between cancer cells and myeloid cells to promote mesenchymal/plurimetabolic states in glioblastoma.
  33. Cross-tissue multicellular coordination and its rewiring in cancer.
  34. Remodeling and retooling metabolism.
  35. Lysine acetylation modulates s-OPA1 GTPase activity and oligomerization in mitochondrial membrane remodeling.
  36. YTHDF1 differentiates the contributing roles of mTORC1 in aging.
  37. GPR55 senses lactate to sustain motility in prostate cancer cells.
  38. Enabling pan-repository reanalysis for big data science of public metabolomics data.
  39. The geroprotectors trametinib and rapamycin combine additively to extend mouse healthspan and lifespan.
  40. Tipping the balance: innate and adaptive immunity in mitochondrial disease.
  41. MLN4924 suppresses tumor metabolism and growth of clear cell renal cell carcinoma by stabilizing nuclear FBP1.
  42. Kinetic modules are sources of concentration robustness in biochemical networks.
  43. Post-translational modifications and the reprogramming of tumor metabolism.
  44. High KYNU Expression Is Associated with Poor Prognosis, KEAP1/STK11 Mutations, and Immunosuppressive Metabolism in Patient-Derived but Not Murine Lung Adenocarcinomas.
  45. Reactivity-based metabolomics reveal cysteine has glyoxalase 1-like and glyoxalase 2-like activities.
  46. Base editing of trinucleotide repeats that cause Huntington's disease and Friedreich's ataxia reduces somatic repeat expansions in patient cells and in mice.
  47. Immunoproteasome-specific subunit alterations as a potential therapeutic target for mitochondriopathies.
  1. Redox Biol. 2025 Apr 25. pii: S2213-2317(25)00162-4. [Epub ahead of print]84 103649
    PRPS activity tunes redox homeostasis in Myc-driven lymphoma.
    Austin C MacMillan, Bibek Karki, Juechen Yang, Karmela R Gertz, Samantha Zumwalde, Jay G Patel, 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.
    Keywords:  Enzymatic regulation; Mitochondrial respiration; Oxidative/reductive stress; Pentose phosphate pathway; Purine metabolism; Redox metabolism
    DOI:  https://doi.org/10.1016/j.redox.2025.103649
  2. Nat Cancer. 2025 May;6(5): 753-767
    The diverse roles of the circadian clock in cancer.
    Bridget M Fortin, Alisa L Mahieu, Rachel C Fellows, Yi Kang, Amber N Lewis, Aya S Ead, Katja A Lamia, Yin Cao, Nicholas R Pannunzio, Selma Masri.
      A growing part of the human population is affected by circadian misalignment caused by deregulated sleep, increased nighttime light exposure and erratic eating patterns. Thus, circadian rhythms are a key research area, with compelling links to cancer. Here, we review the circadian regulation of critical cellular processes, including immunity, metabolism, cell cycle control and DNA repair, under physiological homeostasis and in cancer. We discuss the divergent evidence indicating tissue-specific roles of the circadian clock in different cancer types and the potential link between circadian misalignment and early-onset cancers. Finally, we outline how understanding the circadian clock can improve cancer prevention and chronomedicine-based therapies.
    DOI:  https://doi.org/10.1038/s43018-025-00981-8
  3. Redox Biol. 2025 May 13. pii: S2213-2317(25)00190-9. [Epub ahead of print]84 103677
    Disulfide-mediated tetramerization of TRAP1 fosters its antioxidant and pro-neoplastic activities.
    Fiorella Faienza, Claudio Laquatra, Matteo Castelli, Gianmarco Matrullo, Salvatore Rizza, Federica Guarra, Azam Roshani Dashtmian, Alessia Magro, Paola Giglio, Chiara Pecorari, Lavinia Ferrone, Elisabetta Moroni, Francesca Pacello, Andrea Battistoni, Giorgio Colombo, Andrea Rasola, Giuseppe Filomeni.
      The mitochondrial chaperone TRAP1 exerts protective functions under diverse stress conditions. It induces metabolic rewiring and safeguards cancer cells from oxidative insults, thereby contributing to neoplastic progression. TRAP1 works as a homodimer, but recent evidence indicated that it forms tetramers whose effects remain elusive. Here, we find that TRAP1 generates redox-sensitive tetramers via disulfide bonds involving cysteines 261 and 573. TRAP1 tetramerization is elicited by oxidative stress and abrogated upon expression of the double C261S/C573R mutant. In cancer cells, the TRAP1 C261S/C573R mutant is unable to inhibit the activity of its client succinate dehydrogenase and to confer protection against oxidative insults, thus hampering the invasiveness of aggressive sarcoma cells. Overall, our findings indicate that TRAP1 undergoes tetramerization in response to oxidative stress and identify C261 and C573 as critical for TRAP1 structural rearrangement and functions.
    Keywords:  Cysteine; Metabolism; Mitochondria; Oxidative stress; Tumorigenesis
    DOI:  https://doi.org/10.1016/j.redox.2025.103677
  4. Nat Commun. 2025 May 27. 16(1): 4921
    Genetically encoded fluorescent reporter for polyamines.
    Pushkal Sharma, Colin Y Kim, Heather R Keys, Shinya Imada, Alex B Joseph, Luke Ferro, Tenzin Kunchok, Rachel Anderson, Yulin Sun, Ömer H Yilmaz, Jing-Ke Weng, Ankur Jain.
      Polyamines are abundant and evolutionarily conserved metabolites that are essential for life. Dietary polyamine supplementation extends life-span and health-span. Dysregulation of polyamine homeostasis is linked to Parkinson's disease and cancer, driving interest in therapeutically targeting this pathway. However, measuring cellular polyamine levels, which vary across cell types and states, remains challenging. We introduce a genetically encoded polyamine reporter for real-time measurement of polyamine concentrations in single living cells. This reporter utilizes the polyamine-responsive ribosomal frameshift motif from the OAZ1 gene. We demonstrate broad applicability of this approach and reveal dynamic changes in polyamine levels in response to genetic and pharmacological perturbations. Using this reporter, we conduct a genome-wide CRISPR screen and uncover an unexpected link between mitochondrial respiration and polyamine import, which are both risk factors for Parkinson's disease. By offering a lens to examine polyamine biology, this reporter may advance our understanding of these ubiquitous metabolites and accelerate therapy development.
    DOI:  https://doi.org/10.1038/s41467-025-60147-z
  5. Mol Cell. 2025 May 21. pii: S1097-2765(25)00412-5. [Epub ahead of print]
    Structural and systems characterization of phosphorylation on metabolic enzymes identifies sex-specific metabolic reprogramming in obesity.
    Tigist Y Tamir, Shreya Chaudhary, Annie X Li, Sonia E Trojan, Cameron T Flower, Paula Vo, Yufei Cui, Jeffrey C Davis, Rachit Mukkamala, Francesca N Venditti, Alissandra L Hillis, Alex Toker, Matthew G Vander Heiden, Jessica B Spinelli, Norman J Kennedy, Roger J Davis, Forest M White.
      Coordination of adaptive metabolism through signaling networks is essential for cellular bioenergetics and homeostasis. Phosphorylation of metabolic enzymes provides a rapid, efficient, and dynamic mechanism to regulate metabolic networks. Our structural analysis stratified phosphosites on metabolic enzymes based on proximity to functional and dimerization domains. Most phosphosites occur on oxidoreductases and are enriched near substrate, cofactor, active sites, or dimer interfaces. Despite low stoichiometry, phosphotyrosine (pY) is overrepresented in functional domains. Using high-fat diet (HFD)-induced obesity in C57BL/6J mice and multiomics, we measured HFD-induced sex-specific dysregulation of pY and metabolites, which was reversible with the antioxidant butylated hydroxyanisole (BHA). Computational modeling revealed predictive pY sites for HFD- or BHA-induced metabolite changes. We characterized functional roles for predictive pY sites on glutathione S-transferase pi 1 (GSTP1), isocitrate dehydrogenase 1 (IDH1), and uridine monophosphate synthase (UMPS) using CRISPR interference (CRISPRi) rescue and stable isotope tracing. Our findings reveal mechanisms whereby cellular signaling fine-tunes enzyme activity and metabolism.
    Keywords:  GSTP1; IDH1; UMPS; cell signaling; computational modelling; metabolism; metabolomics; obesity; oxidative stress response; phosphoproteomics
    DOI:  https://doi.org/10.1016/j.molcel.2025.05.007
  6. Nat Commun. 2025 May 27. 16(1): 4920
    WNK1 signalling regulates amino acid transport and mTORC1 activity to sustain acute myeloid leukaemia growth.
    Shunlei Duan, Karl Agger, Jan-Erik Messling, Koutarou Nishimura, Xuerui Han, Isabel Peña-Rømer, Pavel Shliaha, Helene Damhofer, Max Douglas, Manas Kohli, Akos Pal, Yasmin Asad, Aaron Van Dyke, Raquel Reilly, Robert Köchl, Victor L J Tybulewicz, Ronald C Hendrickson, Florence I Raynaud, Paolo Gallipoli, George Poulogiannis, Kristian Helin.
      The lack of curative therapies for acute myeloid leukaemia (AML) remains an ongoing challenge despite recent advances in the understanding of the molecular basis of the disease. Here we identify the WNK1-OXSR1/STK39 pathway as a previously uncharacterised dependency in AML. We show that genetic depletion and pharmacological inhibition of WNK1 or its downstream phosphorylation targets OXSR1 and STK39 strongly reduce cell proliferation and induce apoptosis in leukaemia cells in vitro and in vivo. Furthermore, we show that the WNK1-OXSR1/STK39 pathway controls mTORC1 signalling via regulating amino acid uptake through a mechanism involving the phosphorylation of amino acid transporters, such as SLC38A2. Our findings underscore an important role of the WNK1-OXSR1/STK39 pathway in regulating amino acid uptake and driving AML progression.
    DOI:  https://doi.org/10.1038/s41467-025-59969-8
  7. Nature. 2025 May 28.
    Reverse electron transport drives metabolic changes in obesity.
      
    Keywords:  Metabolism; Obesity; Physiology
    DOI:  https://doi.org/10.1038/d41586-025-01621-y
  8. Nature. 2025 May 28.
    CoQ imbalance drives reverse electron transport to disrupt liver metabolism.
    Renata L S Goncalves, Zeqiu Branden Wang, Jillian K Riveros, Güneş Parlakgül, Karen E Inouye, Grace Yankun Lee, Xiaorong Fu, Jani Saksi, Clement Rosique, Sheng Tony Hui, Mar Coll, Ana Paula Arruda, Shawn C Burgess, Isabel Graupera, Gökhan S Hotamışlıgil.
      Mitochondrial reactive oxygen species (mROS) are central to physiology1,2. Excess mROS production has been associated with several disease states2,3; however, the precise sources, regulation and mechanism of generation in vivo remain unclear, which limits translational efforts. Here we show that in obesity, hepatic coenzyme Q (CoQ) synthesis is impaired, which increases the CoQH2 to CoQ (CoQH2/CoQ) ratio and drives excessive mROS production through reverse electron transport (RET) from site IQ in complex I. Using multiple complementary genetic and pharmacological models in vivo, we demonstrate that RET is crucial for metabolic health. In patients with steatosis, the hepatic CoQ biosynthetic program is also suppressed, and the CoQH2/CoQ ratio positively correlates with disease severity. Our data identify a highly selective mechanism for pathological mROS production in obesity, which can be targeted to protect metabolic homeostasis.
    DOI:  https://doi.org/10.1038/s41586-025-09072-1
  9. Biochem Soc Trans. 2025 May 29. pii: BST20253013. [Epub ahead of print]
    Mechanisms of heme transport in the mitochondria.
    Saieeda Fabia Ali, Adrianna E White, Amy Medlock, Oleh Khalimonchuk.
      Heme is a vital but highly reactive compound that is synthesized in mitochondria and subsequently distributed to a variety of subcellular compartments for utilization. The transport of heme is essential for normal cellular metabolism, growth, and development. Despite the vital importance of heme transport within the cell, data are lacking about how newly synthesized heme is shuttled within the mitochondrion or exported from the organelle. Here, we briefly summarize current knowledge about the process of mitochondrial heme distribution and discuss the current unresolved questions pertinent to this process.
    Keywords:  heme; heme biosynthesis; hemoproteins; membrane transporters; mitochondria
    DOI:  https://doi.org/10.1042/BST20253013
  10. Biol Chem. 2025 May 27.
    The mitochondrial intermembrane space - a permanently proteostasis-challenged compartment.
    Matthias Weith, Konstantin Weiss, Dylan Stobbe, Jan Riemer.
      The mitochondrial intermembrane space (IMS) houses proteins essential for redox regulation, protein import, signaling, and energy metabolism. Protein import into the IMS is mediated by dedicated pathways, including the disulfide relay pathway for oxidative folding. In addition, various IMS-traversing import pathways potentially expose unfolded proteins, representing threats to proteostasis. This trafficking of precursors coincides with unique biophysical challenges in the IMS, including a confined volume, elevated temperature, variable pH and high levels of reactive oxygen species. Ultrastructural properties and import supercomplex formation ameliorate these challenges. Nonetheless, IMS proteostasis requires constant maintenance by chaperones, folding catalysts, and proteases to counteract misfolding and aggregation. The IMS plays a key role in stress signaling, where proteostasis disruptions trigger responses including the integrated stress response (ISR) activated by mitochondrial stress (ISRmt) and responses to cytosolic accumulation of mitochondrial protein precursors. This review explores the biology and mechanisms governing IMS proteostasis, presents models, which have been employed to decipher IMS-specific stress responses, and discusses open questions.
    Keywords:  IMS; mitochondria; protein import; proteostasis; stress responses
    DOI:  https://doi.org/10.1515/hsz-2025-0108
  11. Cell. 2025 May 20. pii: S0092-8674(25)00512-4. [Epub ahead of print]
    Cross-organ metabolite production and consumption in healthy and atherogenic conditions.
    Hosung Bae, Sunhee Jung, Johnny Le, Ian Tamburini, Joohwan Kim, Eric Wang, Won-Suk Song, Wonsuk Choi, Ki-Hong Jang, Taekyung Kang, Miranda L Lopez, Cuauhtemoc Ramirez, Ipsita Mohanty, Miranda E Kelly, Jessie Kim, Raymond Kim, Sang Hee Park, Jongwon Baek, Bryan Mendez, Paul Petrus, Thomas Q de Aguiar Vallim, Dequina A Nicholas, Quinton Smith, Gina Lee, Marcus Seldin, Cholsoon Jang.
      Mammalian organs continuously produce and consume circulating metabolites for organismal health and survival. However, the landscape of this fundamental process and its perturbation by diet and disease is unknown. Using arteriovenous metabolomics, tissue transcriptomics, and hormone arrays in multiple pathophysiological conditions in pigs, we generated an atlas of 10 cross-organ metabolite production and consumption during fasting/feeding, Western diet, and cardiovascular disease progression induced by low-density lipoprotein receptor (LDLR) deficiency. We discovered numerous instances of feeding-dependent and -independent metabolite production and consumption by organs and proposed mechanisms by which these are disrupted by Western diet via altered metabolite concentration gradients and hormones. Both Western diet and LDLR deficiency trigger the release of bile acids (BAs) by extra-hepatic organs, likely contributing to abnormally elevated circulating BA levels and consequent vascular inflammation and atherosclerosis development. These resources reveal intricate inter-organ metabolic crosstalk across pathophysiological conditions, offering biochemical insights into diet effects and cardiometabolic diseases.
    Keywords:  arteriovenous metabolomics; bile acid metabolism; cardiovascular disease; circulating metabolite; flux; inter-organ exchange; isotope tracing; low-density lipoprotein receptor; metabolomics; western diet
    DOI:  https://doi.org/10.1016/j.cell.2025.05.001
  12. Nat Cell Biol. 2025 May 28.
    Sphingosine-1-phosphate signalling activates E-Syt1 to facilitate HDL-derived cholesterol transport.
    Zizhen Xu, Ying Meng, Jonathan St-Germain, Arezoo Afshari, Charneal L Dixon, Saskia Heybrock, Qiang Zhao, Xialian Weng, Jishun Chen, Richard Collins, Hu Hu, Quan Zhou, Qiming Sun, Pinglong Xu, Wei Liu, Paul Saftig, Brian Raught, Gregory D Fairn, Dante Neculai.
      Cholesterol derived from high-density lipoprotein (HDL) is rapidly redistributed to intracellular compartments in steroidogenic and bile-producing cells, but the molecular mechanisms governing this essential transport process remain poorly understood. Here we uncover a signalling cascade coordinating HDL-derived cholesterol transport through membrane contact sites between the endoplasmic reticulum (ER) and plasma membrane (PM). We find that HDL-resident sphingosine-1-phosphate (S1P) activates S1P receptor 3 and its associated G protein αq, leading to phospholipase-C-β3-mediated hydrolysis of phosphatidylinositol 4,5-bisphosphate and an elevation in cytosolic calcium. This calcium signal triggers the rapid recruitment of Extended-Synaptotagmin 1 to ER-PM membrane contact sites. Genetic or pharmacological disruption of this pathway impairs the non-vesicular transfer of HDL-derived cholesterol to intracellular compartments. Our findings reveal how HDL binding to the cell surface alters ER-PM membrane contact site dynamics through S1P signalling. This ensures efficient offloading and redistribution of HDL cholesterol to support steroid and bile acid synthesis.
    DOI:  https://doi.org/10.1038/s41556-025-01665-2
  13. Mol Biol Evol. 2025 Apr 30. pii: msaf105. [Epub ahead of print]42(5):
    Nonhypermutator Cancers Access Driver Mutations Through Reversals in Germline Mutational Bias.
    Marwa Z Tuffaha, David Castellano, Claudia Serrano Colomé, Ryan N Gutenkunst, Lindi M Wahl.
      Cancer is an evolutionary disease driven by mutations in asexually reproducing somatic cells. In asexual microbes, bias reversals in the mutation spectrum can speed adaptation by increasing access to previously undersampled beneficial mutations. By analyzing tumors from 20 tissues, along with normal tissue and the germline, we demonstrate this effect in cancer. Nonhypermutated tumors reverse the germline mutation bias and have consistent spectra across tissues. These spectra changes carry the signature of hypoxia, and they facilitate positive selection in cancer genes. Hypermutated and nonhypermutated tumors thus acquire driver mutations differently: hypermutated tumors by higher mutation rates and nonhypermutated tumors by changing the mutation spectrum to reverse the germline mutation bias.
    Keywords:  cancer; hypermutator; hypoxia; mutation bias; mutation spectrum; positive selection
    DOI:  https://doi.org/10.1093/molbev/msaf105
  14. Curr Opin Cell Biol. 2025 May 28. pii: S0955-0674(25)00073-0. [Epub ahead of print]95 102535
    The power of connections: Recent advances in understanding the regulation of mitochondrial dynamics by membrane contact sites.
    Jason C Casler, Laura L Lackner.
      The continuous remodeling of the mitochondrial network through fusion, fission, transport, and turnover events, collectively known as mitochondrial dynamics, is essential for the maintenance of mitochondrial metabolic and genomic health. While the primary molecular machines that mediate these processes were discovered decades ago, the regulation of mitochondrial dynamics clearly involves additional factors. A major breakthrough came from the discovery that sites of close apposition between organelles, known as membrane contact sites (MCSs), serve as critical regulators of organelle function. MCSs between mitochondria and the ER are now universally recognized as important regulatory hubs of mitochondrial dynamics. Despite this, there are still many unknowns pertaining to the mechanisms by which MCSs influence mitochondrial dynamics. In this review, we describe recent progress identifying novel protein and lipid components that regulate mitochondrial dynamics and emphasize clear gaps in our understanding of how mitochondrial dynamics are coordinated at MCSs. Finally, we conclude by discussing progress towards defining the highly biomedically relevant, but enigmatic, role of mitochondrial dynamics in the preservation of mitochondrial DNA integrity.
    DOI:  https://doi.org/10.1016/j.ceb.2025.102535
  15. Proc Natl Acad Sci U S A. 2025 Jun 03. 122(22): e2502876122
    CRISPR screen reveals a simultaneous targeted mechanism to reduce cancer cell selenium and increase lipid oxidation to induce ferroptosis.
    Sophia M Lamperis, Kaylin M McMahon, Andrea E Calvert, Jonathan S Rink, Karthik Vasan, Madhura R Pandkar, Eliana U Crentsil, Zachary R Chalmers, Natalie R McDonald, Cameron J Kosmala, Marcelo G Bonini, Daniela Matei, Leo I Gordon, Navdeep S Chandel, C Shad Thaxton.
      Ferroptosis is a cell death mechanism distinguished by its dependence on iron-mediated lipid oxidation. Cancer cells highly resistant to conventional therapies often demonstrate lipid metabolic and redox vulnerabilities that sensitize them to cell death by ferroptosis. These include a unique dependency on the lipid antioxidant selenoenzyme, glutathione peroxidase 4 (GPx4), that acts as a ferroptosis inhibitor. Synthetic high-density lipoprotein-like nanoparticle (HDL NP) targets the high-affinity HDL receptor scavenger receptor class B type 1 (SR-B1) and regulates cell and cell membrane lipid metabolism. Recently, we reported that targeting cancer cell SR-B1 with HDL NP depleted cell GPx4, which is accompanied by increased cell membrane lipid peroxidation and cancer cell death. These data suggest that HDL NP may induce ferroptosis. Thus, we conducted an unbiased CRISPR-based positive selection screen and target validation studies in ovarian clear cell carcinoma (OCCC) cell lines to ascertain the mechanism through which HDL NP regulates GPx4 and kills cancer cells. The screen revealed two genes, acyl-CoA synthetase long chain family member 4 (ACSL4) and thioredoxin reductase 1 (TXNRD1), whose loss conferred resistance to HDL NP. Validation of ACSL4 supports that HDL NP induces ferroptosis as the predominant mechanism of cell death, while validation of TXNRD1 revealed that HDL NP reduces cellular selenium and selenoprotein production, most notably, GPx4. Accordingly, we define cancer cell metabolic targets that can be simultaneously actuated by a multifunctional, synthetic HDL NP ligand of SR-B1 to kill cancer cells by ferroptosis.
    Keywords:  cancer; cell death; ferroptosis; lipids; nanoparticles
    DOI:  https://doi.org/10.1073/pnas.2502876122
  16. Sci Adv. 2025 May 30. 11(22): eadu9512
    Mitochondrial calcium signaling regulates branched-chain amino acid catabolism in fibrolamellar carcinoma.
    Nicole M Marsh, Melissa J S MacEwen, Jane Chea, Heidi L Kenerson, Albert A Kwong, Timothy M Locke, Francisco Javier Miralles, Tanmay Sapre, Natasha Gozali, Madeleine L Hart, Theo K Bammler, James W MacDonald, Lucas B Sullivan, G Ekin Atilla-Gokcumen, Shao-En Ong, John D Scott, Raymond S Yeung, Yasemin Sancak.
      Metabolic adaptations are essential for survival. The mitochondrial calcium uniporter plays a key role in coordinating metabolic homeostasis by regulating mitochondrial metabolic pathways and calcium signaling. However, a comprehensive analysis of uniporter-regulated mitochondrial pathways has remained unexplored. Here, we investigate consequences of uniporter loss and gain of function using uniporter knockout cells and fibrolamellar carcinoma (FLC), which we demonstrate to have elevated mitochondrial calcium levels. We find that branched-chain amino acid (BCAA) catabolism and the urea cycle are uniporter-regulated pathways. Reduced uniporter function boosts expression of BCAA catabolism genes and the urea cycle enzyme ornithine transcarbamylase. In contrast, high uniporter activity in FLC suppresses their expression. This suppression is mediated by the transcription factor KLF15, a master regulator of liver metabolism. Thus, the uniporter plays a central role in FLC-associated metabolic changes, including hyperammonemia. Our study identifies an important role for the uniporter in metabolic adaptation through transcriptional regulation of metabolism and elucidates its importance for BCAA and ammonia metabolism.
    DOI:  https://doi.org/10.1126/sciadv.adu9512
  17. Elife. 2025 May 30. pii: RP93621. [Epub ahead of print]13
    Inhibition of mitochondrial protein import and proteostasis by a pro-apoptotic lipid.
    Josep Fita-Torró, José Luis Garrido-Huarte, Lucía López-Gil, Agnès H Michel, Benoit Kornmann, Amparo Pascual-Ahuir, Markus Proft.
      Mitochondria-mediated cell death is critically regulated by bioactive lipids derived from sphingolipid metabolism. The lipid aldehyde trans-2-hexadecenal (t-2-hex) induces mitochondrial dysfunction from yeast to humans. Here, we apply unbiased transcriptomic, functional genomics, and chemoproteomic approaches in the yeast model to uncover the principal mechanisms and biological targets underlying this lipid-induced mitochondrial inhibition. We find that loss of Hfd1 fatty aldehyde dehydrogenase function efficiently sensitizes cells for t-2-hex inhibition and apoptotic cell death. Excess of t-2-hex causes a profound transcriptomic response with characteristic hallmarks of impaired mitochondrial protein import, like activation of mitochondrial and cytosolic chaperones or proteasomal function and severe repression of translation. We confirm that t-2-hex stress induces rapid accumulation of mitochondrial pre-proteins and protein aggregates and subsequent activation of Hsf1- and Rpn4-dependent gene expression. By saturated transposon mutagenesis, we find that t-2-hex tolerance requires an efficient heat shock response and specific mitochondrial and ER functions and that mutations in ribosome, protein, and amino acid biogenesis are beneficial upon t-2-hex stress. We further show that genetic and pharmacological inhibition of protein translation causes t-2-hex resistance, indicating that loss of proteostasis is the predominant consequence of the pro-apoptotic lipid. Several TOM subunits, including the central Tom40 channel, are lipidated by t-2-hex in vitro and mutation of accessory subunits Tom20 or Tom70 confers t-2-hex tolerance. Moreover, the Hfd1 gene dose determines the strength of t-2-hex mediated inhibition of mitochondrial protein import, and Hfd1 co-purifies with Tom70. Our results indicate that the transport of mitochondrial precursor proteins through the outer mitochondrial membrane is sensitively inhibited by the pro-apoptotic lipid and thus represents a hotspot for pro- and anti-apoptotic signaling.
    Keywords:  S. cerevisiae; apoptosis; biochemistry; chemical biology; genetics; genomics; lipid signaling; mitochondrial protein import; proteostasis; sphingolipid metabolism; yeast
    DOI:  https://doi.org/10.7554/eLife.93621
  18. Oncoimmunology. 2025 Dec;14(1): 2512109
    Mitochondrial DNA transfer between malignant cells and T lymphocytes shapes the cancer-immunity dialogue.
    Liwei Zhao, Peng Liu, Oliver Kepp, Guido Kroemer.
      Nonmutated mitochondrial DNA (mtDNA) from T lymphocytes can be incorporated into cancer cells bearing mutated mtDNA to repair their bioenergetic deficiency. However, a recent paper by Ikeda et al. indicates that mutated mtDNA from malignant cells can also be transferred into tumor-infiltrating T lymphocytes to subvert their function in cancer immunosurveillance.
    Keywords:  Immune checkpoint inhibition; Immunotherapy; immunosuppression
    DOI:  https://doi.org/10.1080/2162402X.2025.2512109
  19. Nat Chem Biol. 2025 May 26.
    Tegavivint triggers TECR-dependent nonapoptotic cancer cell death.
    Logan Leak, Ziwei Wang, Alby J Joseph, Brianna Johnson, Alyssa A Chan, Cassandra M Decosto, Leslie Magtanong, Pin-Joe Ko, Weaverly Colleen Lee, Joan Ritho, Sophia Manukian, Alec Millner, Shweta Chitkara, Jennifer J Salinas, Rachid Skouta, Matthew G Rees, Melissa M Ronan, Jennifer A Roth, Chad L Myers, Jason Moffat, Charles Boone, Steven J Bensinger, David A Nathanson, G Ekin Atilla-Gokcumen, Everett J Moding, Scott J Dixon.
      Small molecules that induce nonapoptotic cell death are of fundamental mechanistic interest and may be useful to treat certain cancers. Here we report that tegavivint, a drug candidate undergoing human clinical trials, can activate a unique mechanism of nonapoptotic cell death in sarcomas and other cancer cells. This lethal mechanism is distinct from ferroptosis, necroptosis and pyroptosis and requires the lipid metabolic enzyme trans-2,3-enoyl-CoA reductase (TECR). TECR is canonically involved in the synthesis of very-long-chain fatty acids but appears to promote nonapoptotic cell death in response to CIL56 and tegavivint via the synthesis of the saturated long-chain fatty acid palmitate. These findings outline a lipid-dependent nonapoptotic cell death mechanism that can be induced by a drug candidate currently being tested in humans.
    DOI:  https://doi.org/10.1038/s41589-025-01913-4
  20. Cell Mol Life Sci. 2025 May 28. 82(1): 218
    Dual phosphorylation of glycogen synthase kinase 3β differentially integrates metabolic programs to determine T cell immunity across vertebrates.
    Wei Liang, Ming Geng, Wenzhuo Rao, Kang Li, Yating Zhu, Yuying Zheng, Xiumei Wei, Jialong Yang.
      The integration of metabolic programs with T cell signaling establishes a molecular foundation for immune metabolism. As a key metabolic regulator, GSK3β's activity is dynamically modulated by phosphorylation at Ser9 and Tyr216. However, the contribution of these phosphorylation sites on metabolism-driven T cell response remains unclear. Using tilapia and mouse models, we investigated the regulation of GSK3β on T cell metabolism and its evolutionary variation. In tilapia, T cell activation induces GSK3β signaling, linking to both glycolysis and oxidative phosphorylation (OXPHOS). Tyr216 phosphorylation preferentially promotes glycolysis, facilitating T cell activation, proliferation, and antibacterial immunity; while inhibition of Ser9 phosphorylation specifically enhances OXPHOS to sustain T cell responses. Differently, Tyr216 phosphorylation supports both glycolysis and OXPHOS in mouse, ensuring CD4+ T and CD8+ T cell activation, proliferation, and cytokine production. Although Ser9 phosphorylation controls OXPHOS, its inhibition impairs rather than enhances OXPHOS and CD4+ T cell responses in mouse. We thus revealed a previously unknown mechanism underlying T cell metabolism and proposed that, through evolution, GSK3β has restructured the regulatory strategy, enabling bidirectional control of T cell metabolism and immunity in mammals and enhancing the flexibility of the adaptive immune system.
    Keywords:  Evolution; Fish; GSK3β; Immunometabolism; T cells
    DOI:  https://doi.org/10.1007/s00018-025-05746-1
  21. Trends Biochem Sci. 2025 May 28. pii: S0968-0004(25)00104-5. [Epub ahead of print]
    The metabolic code of ferroptosis: nutritional regulators of cell death.
    Juliane Tschuck, Vera Skafar, José Pedro Friedmann Angeli, Kamyar Hadian.
      Ferroptosis is a distinctive form of regulated cell death driven by iron-dependent phospholipid peroxidation. Its initiation and suppression are finely tuned by metabolic pathways, transcription factors, and nuclear receptors that control lipid peroxidation levels. Significantly, nutrients such as vitamins and trace elements play a pivotal role in this regulation, directly linking diet and nutrients to cellular fate. This review conveys the latest insights into the metabolic components that influence ferroptosis. We highlight how metabolic and transcriptional regulators and key nutrients, micronutrients, and metabolites orchestrate this process. Charting these interactions will be essential for developing new avenues for therapeutic interventions targeting ferroptosis in various diseases.
    Keywords:  ferroptosis; lipid peroxidation; lipids; metabolites; nutrients; vitamins
    DOI:  https://doi.org/10.1016/j.tibs.2025.04.007
  22. Nat Commun. 2025 May 27. 16(1): 4909
    Restoring calcium crosstalk between ER and mitochondria promotes intestinal stem cell rejuvenation through autophagy in aged Drosophila.
    Yao Zhang, Peng Ma, Saifei Wang, Shuxin Chen, Hansong Deng.
      Breakdown of calcium network is closely associated with cellular aging. Previously, we found that cytosolic calcium (CytoCa2+) levels were elevated while mitochondrial calcium (MitoCa2+) levels were decreased and associated with metabolic shift in aged intestinal stem cells (ISCs) of Drosophila. How MitoCa2+ was decoupled from the intracellular calcium network and whether the reduction of MitoCa2+ drives ISC aging, however, remains unresolved. Here, we show that genetically restoring MitoCa2+ can reverse ISC functional decline and promote intestinal homeostasis by activating autophagy in aged flies. Further studies indicate that MitoCa2+ and Mitochondria-ER contacts (MERCs) form a positive feedback loop via IP3R to regulate autophagy independent of AMPK. Breakdown of this loop is responsible for MitoCa2+ reduction and ISC dysfunction in aged flies. Our results identify a regulatory module for autophagy initiation involving calcium crosstalk between the ER and mitochondria, providing a strategy to treat aging and age-related diseases.
    DOI:  https://doi.org/10.1038/s41467-025-60196-4
  23. Bio Protoc. 2025 May 20. 15(10): e5322
    Stable 13C-glutamine Tracing Resolved Metabolomics for Cancer Metabolism Study.
    Yaogang Zhong, Liqing He, Xinmin Yin, Logan Mazik, Xiang Zhang, Deliang Guo.
      Stable isotopes have frequently been used to study metabolic processes in live cells both in vitro and in vivo. Glutamine, the most abundant amino acid in human blood, plays multiple roles in cellular metabolism by contributing to the production of nucleotides, lipids, glutathione, and other amino acids. It also supports energy production via anaplerosis of tricarboxylic acid cycle intermediates. While 13C-glutamine has been extensively employed to study glutamine metabolism in various cell types, detailed analyses of specific lipids derived from 13C-glutamine via the reductive carboxylation pathway are limited. In this protocol, we present a detailed procedure to investigate glutamine metabolism in human glioblastoma (GBM) cells by conducting 13C-glutamine tracing coupled with untargeted metabolomics analysis using liquid chromatography-mass spectrometry (LC-MS/MS). The method includes step-by-step instructions for the extraction and detection of polar metabolites and long-chain fatty acids (LCFAs) derived from 13C-glutamine in GBM cells. Notably, this approach enables the distinction between isomers of two monounsaturated FAs with identical masses: palmitoleic acid (16:1n-7) (cis-9-hexadecenoic acid) and palmitelaidic acid (16:1n-7) (trans-9-hexadecenoic acid) derived from 13C-glutamine through the reductive carboxylation process. In addition, using this protocol, we also unveil previously unknown metabolic alterations in GBM cells following lysosome inhibition by the antipsychotic drug pimozide. Key features • Methods for analyzing the flux of the stable isotope 13C-glutamine in cancer cells and identifying its derived polar metabolites and long-chain fatty acids (LCFAs). • Distinguishes isomers of long-chain fatty acids, such as palmitoleic acid (16:1n-7) (cis-9-Hexadecenoic acid) and palmitelaidic acid (16:1n-7) (trans-9-Hexadecenoic acid), which share the exact same mass. • The method is utilized to investigate glutamine metabolism reprogramming in cancer cells following lysosome inhibition.
    Keywords:  13C-glutamine; GBM cells; LC–MS/MS; Long-chain fatty acids; Lysosome; Pimozide; Polar metabolites
    DOI:  https://doi.org/10.21769/BioProtoc.5322
  24. Nat Commun. 2025 May 26. 16(1): 4871
    Multi-organ metabolome biological age implicates cardiometabolic conditions and mortality risk.
    MULTI consortium
      Multi-organ biological aging clocks across different organ systems have been shown to predict human disease and mortality. Here, we extend this multi-organ framework to plasma metabolomics, developing five organ-specific metabolome-based biological age gaps (MetBAGs) using 107 plasma non-derivatized metabolites from 274,247 UK Biobank participants. Our age prediction models achieve a mean absolute error of approximately 6 years (0.25<r < 0.42). Crucially, including composite metabolites (e.g. sums or ratios of raw metabolites) results in poor generalizability to independent test data due to multicollinearity. Genome-wide associations identify 405 MetBAG-locus pairs (P < 5 × 10-8/5). Using SBayesS, we estimate the SNP-based heritability (0.09< hSNP2  < 0.18), negative selection signatures (-0.93 < S < -0.76), and polygenicity (0.001<Pi < 0.003) for the 5 MetBAGs. Genetic correlation and Mendelian randomization analyses reveal potential causal links between the 5 MetBAGs and cardiometabolic conditions (e.g., metabolic disorders and hypertension). Integrating multi-organ and multi-omics features improves disease category and mortality predictions. The 5 MetBAGs extend existing biological aging clocks to study human aging and disease across multiple biological scales. All results are publicly available at https://labs-laboratory.com/medicine/ .
    DOI:  https://doi.org/10.1038/s41467-025-59964-z
  25. PLoS Genet. 2025 May 30. 21(5): e1011425
    Cross-tissue coordination between SLC nucleoside transporters regulates reproduction in Caenorhabditis elegans.
    Youchen Guan, Yong Yu, Shihong M Gao, Lang Ding, Qian Zhao, Meng C Wang.
      Metabolism is fundamental to organism physiology and pathology. From the intricate network of metabolic reactions, diverse chemical molecules, collectively termed metabolites, are produced. In multicellular organisms, metabolite communication between different tissues is vital for maintaining homeostasis and adaptation. However, the molecular mechanisms mediating these metabolite communications remain poorly understood. Here, we focus on nucleosides and nucleotides, essential metabolites involved in multiple cellular processes, and report the pivotal role of the SLC29A family of transporters in mediating nucleoside coordination between the soma and the germline. Through genetic analysis, we discovered that two Caenorhabditis elegans homologs of SLC29A transporters, Equilibrative Nucleoside Transporter ENT-1 and ENT-2, act in the germline and the intestine, respectively, to regulate reproduction. Their knockdown synergistically results in sterility. Further single-cell transcriptomic and targeted metabolomic profiling revealed that the ENT double knockdown specifically affects genes in the purine biosynthesis pathway and reduces the ratio of guanosine to adenosine levels. Importantly, guanosine supplementation into the body cavity/pseudocoelom through microinjection rescued the sterility caused by the ENT double knockdown, whereas adenosine microinjection had no effect. Together, these studies support guanosine as a rate-limiting factor in the control of reproduction, uncover the previously unknown nucleoside/nucleotide communication between the soma and the germline essential for reproductive success, and highlight the significance of SLC-mediated cell-nonautonomous metabolite coordination in regulating organism physiology.
    DOI:  https://doi.org/10.1371/journal.pgen.1011425
  26. Sci Rep. 2025 May 28. 15(1): 18736
    Metabolic flux analysis of glioblastoma neural stem cells reveals distinctive metabolic phenotypes in ketogenic conditions.
    Anna Rushin, Aleezeh Shaikh, Callie Hardin, Loic P Deleyrolle, Matthew E Merritt.
      Glioblastomas (GBM) are the most prevalent primary brain tumors, affecting 5 in every 100,000 people. GBMs optimize proliferation through adaptive cellular metabolism, frequently exploiting the Warburg effect by increasing aerobic glycolysis and glucose utilization to facilitate rapid cell growth. This disproportionate reliance on glucose has driven interest in using the ketogenic diet (KD) as a treatment for GBM. In this study, we explored metabolic flux in three primary human GBM cell samples using a media simulating a KD. Flux analysis using a detailed metabolic modeling approach revealed three unique metabolic phenotypes in the patient GBMs that correlated with cell viability. Notably, these phenotypes are apparent in the flux modeling, but were not evidenced by changes in the metabolite pool sizes. This variability in metabolic flux may underlie the inconsistent results observed in preclinical and clinical studies using the KD as a treatment paradigm.
    Keywords:  Cancer biology; Glioblastoma; Isotopic analysis; Ketogenesis; Metabolism
    DOI:  https://doi.org/10.1038/s41598-025-02124-6
  27. Nat Commun. 2025 May 26. 16(1): 4865
    FOXA2 promotes metastatic competence in small cell lung cancer.
    Kenta Kawasaki, Sohrab Salehi, Yingqian A Zhan, Kevin Chen, Jun Ho Lee, Eralda Salataj, Hong Zhong, Parvathy Manoj, Dennis Kinyua, Barbara P Mello, Harsha Sridhar, Sam E Tischfield, Irina Linkov, Nicholas Ceglia, Matthew Zatzman, Eliyahu Havasov, Neil J Shah, Fanli Meng, Brian Loomis, Umesh K Bhanot, Esther Redin, Elisa de Stanchina, Pierre-Jacques Hamard, Richard P Koche, Andrew McPherson, Álvaro Quintanal-Villalonga, Sohrab P Shah, Joan Massagué, Charles M Rudin.
      Small cell lung cancer (SCLC) is known for its high metastatic potential, with most patients demonstrating clinically evident metastases in multiple organs at diagnosis. The factors contributing to this exceptional metastatic capacity have not been defined. To bridge this gap, we compare gene expression in SCLC patient samples who never experienced metastasis or relapse throughout their clinical course, versus primary SCLC patient samples from more typical patients who had metastatic disease at diagnosis. This analysis identifies FOXA2 as a transcription factor strongly associated with SCLC metastasis. Subsequent analyses in experimental models demonstrates that FOXA2 induces a fetal neuroendocrine gene expression program and promotes multi-site metastasis. Moreover, we identify ASCL1, a transcription factor known for its initiating role in SCLC tumorigenesis, as a direct binder of the FOXA2 promoter and regulator of FOXA2 expression. Taken together, these data define the ASCL1-FOXA2 axis as a critical driver of multiorgan SCLC metastasis.
    DOI:  https://doi.org/10.1038/s41467-025-60141-5
  28. Nat Commun. 2025 May 27. 16(1): 4919
    Ferroptosis-activating metabolite acrolein antagonizes necroptosis and anti-cancer therapeutics.
    Hyun Bae, Seonghyun Moon, Mengmeng Chang, Fenfen Zhang, Yeonseo Jang, Wonyoung Kim, Soyeon Kim, Minjie Fu, Jaemin Lim, Seongjun Park, Chirag N Patel, Raghvendra Mall, Min Zheng, Si Ming Man, Rajendra Karki.
      Dysregulated cell death leading to uncontrolled cell proliferation is a hallmark of cancer. Chemotherapy-induced cell death is critical for the success of cancer treatment but this process is impaired by metabolic byproducts. How these byproducts interfere with anti-cancer therapy is unclear. Here, we show that the metabolic byproduct acrolein derived from polyamines, tobacco smoke or fuel combustion, induces ferroptosis independently of ZBP1, while suppressing necroptosis in cancer cells by inhibiting the oligomerization of the necroptosis effector MLKL. Loss of the enzyme SAT1, which contributes to intracellular acrolein production, sensitizes cells to necroptosis. In mice, administration of an acrolein-trapping agent relieves necroptosis blockade and enhances the anti-tumor efficacy of the chemotherapeutic drug cyclophosphamide. Human patients with cancer coupled with a higher cell death activity but a lower expression of genes controlling polyamine metabolism exhibit improved survival. These findings highlight that the removal of metabolic byproducts improves the success of certain chemotherapies.
    DOI:  https://doi.org/10.1038/s41467-025-60226-1
  29. Proc Natl Acad Sci U S A. 2025 Jun 03. 122(22): e2505197122
    Cocrystal structure reveals the mechanism of FSP1 inhibition by FSEN1.
    Sitao Zhang, Amalia H Megarioti, Joseph M Hendricks, Junshu Zhou, Qingxiang Sun, Da Jia, James A Olzmann.
      FSP1 is an FAD-dependent oxidoreductase that uses NAD(P)H to regenerate the reduced forms of lipophilic quinone antioxidants, such as coenzyme Q10 and vitamin K. These quinone antioxidants function as radical scavenging agents that prevent the propagation of lipid peroxidation and the induction of ferroptosis. Although several small-molecule inhibitors of FSP1 have been developed and found to sensitize cancer cells to ferroptosis, our understanding of their molecular mechanisms remains limited and no structures of FSP1 in complex with its inhibitors have been solved. Here, we solve the cocrystal structure of FSP1 in complex with the FSP1 inhibitor FSEN1, revealing that FSEN1 binds within the FSP1 substrate-binding pocket. FSEN1 makes key interactions with a critical phenylalanine, which is absent in mouse FSP1, providing an explanation for the selectivity of FSEN1 for human FSP1. These conclusions are supported by mutagenesis of FSP1 and biochemical and cellular assays of FSP1 function. Our findings provide the first cocrystal structure of FSP1 in complex with an inhibitor, enhancing our understanding of the mechanism of FSP1 inhibition and enabling future rational medicinal chemistry efforts to advance FSP1 inhibitors as therapeutics.
    Keywords:  cancer; ferroptosis; inhibitor; small molecule; structure
    DOI:  https://doi.org/10.1073/pnas.2505197122
  30. Nat Aging. 2025 May 27.
    Mitochondrial clonal mosaicism encodes a biphasic molecular clock of aging.
    Zhenguo Wang, Zhe Li, Hongyu Liu, Chenghua Yang, Xin Li.
      Mitochondria rapidly accumulate mutations throughout a lifetime, potentially acting as a molecular clock for aging and disease. We profiled mitochondrial RNA across 47 human tissues from 838 individuals, revealing rapid development of clonal mosaicism with two distinct tissue-specific aging signatures. Tissues with constant cellular turnover such as the gastrointestinal tract or skin exhibit accelerated accumulation of sporadic mutations and clonal expansions, implicating increased susceptibility to age-related tumorigenesis and dysfunction. By contrast, post-mitotic tissues, such as the heart and brain, accumulate mutations at deterministic hotspots (tissue-specific, recurrently mutated sites), reflecting the cumulative burden of high energy demand and mitochondrial turnover independent of cell division. These findings support a biphasic model of the mitochondrial clock: stochastic clonal expansion of sporadic replication errors in proliferative tissues, versus age-dependent heteroplasmy increases at hotspots in high-metabolic tissues. This mutational landscape provides a map of tissue-specific vulnerabilities during aging and offers potential therapeutic targets.
    DOI:  https://doi.org/10.1038/s43587-025-00890-6
  31. Int J Mol Sci. 2025 May 13. pii: 4644. [Epub ahead of print]26(10):
    ARID1A and Its Impact Across the Hallmarks of Cancer.
    Bridger Kearns, Andralyn McKell, Isaac Steveson, Peyton Worley, Braeden Barton, Jordan Bennett, DeLaney Anderson, Jacob Harris, James Christensen, Jared J Barrott.
      ARID1A, a subunit of the SWI/SNF chromatin remodeling complex, has emerged as a pivotal tumor suppressor altered in a broad range of human malignancies. Its frequent inactivation across diverse cancer types has revealed pleiotropic roles that intersect multiple Hallmarks of Cancer. In this review, we integrate current knowledge on how ARID1A loss influences cellular processes including proliferative signaling, resistance to cell death, genomic instability, metabolic reprogramming, immune evasion, and more. We discuss the context-specific consequences of ARID1A deficiency, its cooperation with other oncogenic events, and its implications for therapeutic vulnerability-particularly in the realm of synthetic lethality and immune modulation. By mapping ARID1A's functional impact onto the established hallmarks framework, we highlight its centrality in cancer biology and underscore opportunities for biomarker-driven strategies and targeted interventions. Understanding ARID1A's multifaceted roles offers a compelling lens through which to explore chromatin dysregulation in cancer and guide translational advances.
    Keywords:  ARID1A; dedifferentiation; genomic instability; immune evasion; proliferation; synthetic lethality
    DOI:  https://doi.org/10.3390/ijms26104644
  32. Neuro Oncol. 2025 May 27. pii: noaf128. [Epub ahead of print]
    Polyamine acetylation mediates crosstalk between cancer cells and myeloid cells to promote mesenchymal/plurimetabolic states in glioblastoma.
    Ayush B Rana, Timothy M Horton, Vijay S Thakur, Dazhi Wang, Varsha Thakur, Molly Dalzell, Juliano T Freitas, Durga Prasad Gannamedi, Ifeanyichukwu Ogobuiro, Barbara Bedogni, Sakir H Gultekin, Timothy J Garrett, Alejandro V Villarino, Jun Lu, David B Lombard, Ashish H Shah, Scott M Welford.
       BACKGROUND: Metabolic reprogramming in glioblastoma (GBM) is a putative determinant of GBM subtype, malignant cell state and tumor-immune crosstalk. In the present study, we investigated how polyamine metabolic rewiring contributes to the malignant cell-intrinsic and microenvironment-dependent biological processes underpinning GBM subtype classification.
    METHODS: Liquid chromatography/tandem mass spectrometry (LC-MS/MS) was used for polyamine quantification in human and murine GBM tumors and cell lines. Through single-cell RNA sequencing, metabolic profiling and additional functional experiments, we dissect the malignant cell-intrinsic and paracrine signaling processes regulated by SAT1 (spermidine/spermine-N1-acetyltransferase1) and its product, N1-acetylspermidine.
    RESULTS: We find that polyamine acetylation is elevated in human and murine GBM tumors and contributes to the classification of mesenchymal/plurimetabolic GBM through both regulation of tumor-cell intrinsic glucose metabolism and by facilitating metabolic crosstalk with tumor-associated macrophages/myeloid cells (TAMs). The impact of SAT1 on tumor cell metabolism is mediated, at least in part, by N1-acetylspermdine, the sole polyamine elevated in human and murine tumors. Furthermore, the relatively high levels of N1-acetylspermidine released by GBM is taken up by myeloid cells to promote intracellular polyamine flux, cellular respiration and migration. In vivo, both genetic disruption of polyamine acetylation and pharmacological inhibition of polyamine transport reduced myeloid cell infiltration and sensitized tumors to chemoradiation.
    CONCLUSIONS: Collectively, the findings highlight a previously unidentified role for SAT1 and its product, N1-acetylspermidine, in bridging the metabolic activity of tumor cells and tumor-associated macrophages/myeloid cells (TAMs), together promoting mesenchymal/plurimetabolic states and therapeutic resistance in GBM.
    Keywords:  Glioblastoma; immune; mesenchymal phenotype; metabolism; polyamines
    DOI:  https://doi.org/10.1093/neuonc/noaf128
  33. Nature. 2025 May 28.
    Cross-tissue multicellular coordination and its rewiring in cancer.
    Qiang Shi, Yihan Chen, Yang Li, Shishang Qin, Yu Yang, Yang Gao, Linnan Zhu, Dongfang Wang, Zemin Zhang.
      The multicellular coordination that underlies tissue homeostasis and disease progression is of fundamental interest1-5. However, how diverse cell types are organized within tissue niches for cohesive functioning remains largely unknown. Here we systematically characterized cross-tissue coordinated cellular modules in healthy tissues, uncovering their spatiotemporal dynamics and phenotypic associations, and examined their rewiring in cancer. We first compiled a comprehensive single-cell transcriptomic atlas from 35 human tissues, revealing substantial inter-tissue variability in cellular composition. By leveraging covariance in cellular abundance, we identified 12 cellular modules with distinct cellular compositions, tissue prevalences and spatial organizations, and demonstrated coordinated intercellular communication within cellular modules using in situ spatial and in vivo perturbation data. Among them, two immune cellular modules in the spleen showed contrasting chronological dynamics with ageing. Analysis of multicellular changes in the breast revealed a menopausal trajectory associated with fibroblast dynamics. Furthermore, interrogation across cancer types uncovered simultaneous rewiring of two types of multicellular ecosystem during tumour progression, including the loss of tissue-specific healthy organization and the emergence of a convergent cancerous ecosystem. These findings reveal fundamental organizing principles of multicellular ecosystems in health and cancer, laying a foundation for further investigations into tissue-level functional coordination across diverse contexts.
    DOI:  https://doi.org/10.1038/s41586-025-09053-4
  34. Nat Chem Biol. 2025 Jun;21(6): 791-792
    Remodeling and retooling metabolism.
      
    DOI:  https://doi.org/10.1038/s41589-025-01941-0
  35. Protein Sci. 2025 Jun;34(6): e70179
    Lysine acetylation modulates s-OPA1 GTPase activity and oligomerization in mitochondrial membrane remodeling.
    Javaid Jabbar, Bakht Afroze, Naomi X Y Ling, Jonathan S Oakhill, Isabelle Rouiller.
      Mitochondrial dynamics are regulated by coordinated fission and fusion events that rely on key proteins and lipids organized spatially within the mitochondria. The dynamin-related GTPase Optic Atrophy 1 (OPA1) is essential for inner mitochondrial membrane fusion and cristae structure maintenance. While post-translational modifications, particularly lysine acetylation, are emerging as critical regulators of mitochondrial protein function, their impact on OPA1 remains poorly characterized. In this study, we explored the effects of lysine acetylation on the short form of OPA1 (s-OPA1) using acetylation and deacetylation mimetic mutations. Through a combination of in silico analyses and functional assays, we identified lysine residues in s-OPA1 that are conserved across species and significantly influence protein stability, GTPase activity, and oligomeric assembly upon acetylation or deacetylation. Our findings reveal that acetylation at K328 and deacetylation at K342 within the G domain enhance the GTPase activity of s-OPA1 upon lipid membrane binding, whereas deacetylation at K772 abolishes membrane binding-induced GTPase activity. Negative-stain transmission electron microscopy indicated that while lysine acetylation does not alter the ability of s-OPA1 to bind and tubulate liposomes, it significantly impacts higher-order filament formation. These findings provide novel insights into how acetylation modulates s-OPA1 function, highlighting a potential mechanism for post-translational regulation of mitochondrial dynamics. Our study contributes to the understanding of how molecular changes influence broader cellular processes, with implications for mitochondrial function and related disorders.
    Keywords:  GTPase activity; OPA1; acetylation; membrane remodeling; oligomeric assembly
    DOI:  https://doi.org/10.1002/pro.70179
  36. Mol Cell. 2025 May 22. pii: S1097-2765(25)00408-3. [Epub ahead of print]
    YTHDF1 differentiates the contributing roles of mTORC1 in aging.
    Chenzhong Xu, Cong Yu, Jie Zhang, Zhen Zhang, Jin Zhang, Yuan Meng, Ming Wang, Minting Wen, Junhao Chen, Yuping Ning, Xinchun Chen, Jinke Gu, Wen Su, Baohua Liu.
      The mechanistic target of rapamycin (mTOR) serves as an essential hub in sensing metabolic stress and regulating aging, although the differential contributions of mTOR-regulated protein and cholesterol synthesis are unclear. Post-transcriptional modifications of mRNAs, such as N6-methyladenosine (m6A), occur rapidly in response to acute environmental changes to maintain tissue homeostasis. Here, we showed that loss of YTH m6A RNA-binding protein 1 (YTHDF1) accelerated murine aging. Mechanistically, YTHDF1 is anchored to the lysosome surface by lysosome-associated membrane protein (LAMP2), whereby it recruits tuberous sclerosis complex (TSC2) to inhibit mTOR complex 1 (mTORC1). Ythdf1 loss activated mTORC1-sterol regulatory element-binding protein 2 (SREBP2)-axis-mediated cholesterol biosynthesis but not m6A-reader-regulated protein translation. Rapamycin restored murine healthspan in contrast to the maximum lifespan shortening caused by Ythdf1 depletion. Our data reveal an m6A-independent function of YTHDF1, which differentiates the contributing roles of mTORC1 in the regulation of aging.
    Keywords:  SREBP2; TSC2; YTHDF1; aging; m6A; mTORC1; rapamycin
    DOI:  https://doi.org/10.1016/j.molcel.2025.05.003
  37. Mol Cell Biochem. 2025 May 28.
    GPR55 senses lactate to sustain motility in prostate cancer cells.
    Giovanna Sgrignani, Marta Iozzo, Lara Di Leonardo, Elisa Pardella, Erica Pranzini, Giulia Gangarossa, Giuseppina Comito, Luigi Ippolito, Elisa Giannoni, Paola Chiarugi.
      The enrichment of specific metabolites within the tumor microenvironment is emerging as a driver of tumor progression. Specifically, in prostate cancer (PCa), increased abundance of lactate is associated with primary-to-metastasis tumor spreading by supporting cancer cell invasiveness. Here, we highlight that the endocannabinoid receptor GPR55 is able to sense lactate and consequently trigger PCa cell amoeboid-like invasiveness, through the activation of the pro-migratory RhoA/MLC2 signaling pathway. These findings uncover a new role for GPR55 in sustaining lactate-driven PCa cell motility.
    Keywords:  Amoeboid motility; GPR55; Lactate; Prostate cancer
    DOI:  https://doi.org/10.1007/s11010-025-05312-0
  38. Nat Commun. 2025 May 24. 16(1): 4838
    Enabling pan-repository reanalysis for big data science of public metabolomics data.
    Yasin El Abiead, Michael Strobel, Thomas Payne, Eoin Fahy, Claire O'Donovan, Shankar Subramamiam, Juan Antonio Vizcaíno, Ozgur Yurekten, Victoria Deleray, Simone Zuffa, Shipei Xing, Helena Mannochio-Russo, Ipsita Mohanty, Haoqi Nina Zhao, Andres M Caraballo-Rodriguez, Paulo Wender P Gomes, Nicole E Avalon, Trent R Northen, Benjamin P Bowen, Katherine B Louie, Pieter C Dorrestein, Mingxun Wang.
      Public untargeted metabolomics data is a growing resource for metabolite and phenotype discovery; however, accessing and utilizing these data across repositories pose significant challenges. Therefore, here we develop pan-repository universal identifiers and harmonized cross-repository metadata. This ecosystem facilitates discovery by integrating diverse data sources from public repositories including MetaboLights, Metabolomics Workbench, and GNPS/MassIVE. Our approach simplified data handling and unlocks previously inaccessible reanalysis workflows, fostering unmatched research opportunities.
    DOI:  https://doi.org/10.1038/s41467-025-60067-y
  39. Nat Aging. 2025 May 28.
    The geroprotectors trametinib and rapamycin combine additively to extend mouse healthspan and lifespan.
    Lisonia Gkioni, Tobias Nespital, Maarouf Baghdadi, Carolina Monzó, Jitin Bali, Taim Nassr, Anna Lena Cremer, Andreas Beyer, Joris Deelen, Heiko Backes, Sebastian Grönke, Linda Partridge.
      Suppression of the insulin-IGF-mTORC1-Ras network ameliorates aging in animals. Many drugs have targets in the network because of its roles in cancer and metabolic disease and are candidates for repurposing as geroprotectors. Rapamycin, an established geroprotective drug, blocks mTORC1 signaling, and trametinib inhibits the Ras-MEK-ERK pathway. In this study, we assessed survival and health of male and female mice treated with trametinib, rapamycin or their combination. We show here that trametinib treatment extended lifespan in both sexes and that its combination with rapamycin was additive. Combination treatment reduced liver tumors in both sexes and spleen tumors in male mice, blocked the age-related increase in brain glucose uptake and strongly reduced inflammation in brain, kidney, spleen and muscle and circulating levels of pro-inflammatory cytokines. We conclude that trametinib is a geroprotector in mice and that its combination with rapamycin is more effective than either drug alone, making the combination a candidate for repurposing as a gerotherapy in humans.
    DOI:  https://doi.org/10.1038/s43587-025-00876-4
  40. Curr Opin Immunol. 2025 May 26. pii: S0952-7915(25)00042-1. [Epub ahead of print]95 102566
    Tipping the balance: innate and adaptive immunity in mitochondrial disease.
    Andrew Phillip West, Peter J McGuire.
      Mitochondrial diseases (MtD) provide a unique window into the complex interplay between metabolism and immune function. These rare disorders, caused by defects in oxidative phosphorylation, result in bioenergetic deficiencies that disrupt multiple organ systems. While traditionally studied for their metabolic impact, MtD also profoundly affect the immune system, altering both innate and adaptive responses. This review explores how mitochondrial dysfunction shapes immune dysregulation, influencing thymocyte maturation, regulatory T cells, and B cell function while also driving innate immune activation through mitochondrial DNA instability and type I interferon signaling. Additionally, MtD highlight an emerging overlap between inborn errors of metabolism and inborn errors of immunity, revealing shared pathways that connect mitochondrial dysfunction to immune deficiencies and inflammatory disease. Studying MtD not only advances our understanding of immunometabolism but also provides critical insights into more common inflammatory and autoimmune conditions, offering potential therapeutic targets that extend beyond rare mitochondrial disorders.
    DOI:  https://doi.org/10.1016/j.coi.2025.102566
  41. Cell Death Discov. 2025 May 26. 11(1): 253
    MLN4924 suppresses tumor metabolism and growth of clear cell renal cell carcinoma by stabilizing nuclear FBP1.
    Yajing Yang, Yan Ma, Shiyin Fan, Jie Zhu, Bin Ye, Ruonan Zhang, Jiaxi Li, Hongchen Li, Zhencang Zheng, Yufeng Li, Lei Lv.
      Fructose-1, 6-bisphosphatase (FBP1) is a tumor suppressor and frequently deficient in various cancers, including clear cell renal cell carcinoma (ccRCC). VHL inactivation mutations are usually observed in ccRCC, which can lead to abnormal activation of the HIF signaling pathway. FBP1 could enter the nucleus and restrain HIF function in a non-enzymatic manner. However, its regulatory mechanism in ccRCC tumorigenesis remains poorly understood. Here, we report that nuclear FBP1 is degraded through the ubiquitin-proteasome pathway, and CUL4B acts as Cullin-RING E3 ubiquitin ligase (CRL) to promote the degradation of FBP1 in nucleus, while the neddylation inhibitor MLN4924 could inactivate CUL4B E3 ligase, block proteasomal degradation of FBP1 and suppress HIF target gene expression, including GLUT1, LDHA, PDK1 and VEGF, leading to decreased glucose uptake and lactate and NADPH production, thereby repressing tumor growth of ccRCC. Furthermore, MLN4924 sensitizes ccRCC to γ-glutamylcysteine synthetase inhibitor Buthionine sulfoximine (BSO) treatment in vivo. Collectively, these findings proposed that MLN4924 could inhibit the tumor growth of VHL deficiency-driven ccRCC by stabilizing FBP1, providing new target and strategy for clinic treatment of ccRCC.
    DOI:  https://doi.org/10.1038/s41420-025-02426-8
  42. Sci Adv. 2025 May 30. 11(22): eads7269
    Kinetic modules are sources of concentration robustness in biochemical networks.
    Damoun Langary, Anika Küken, Zoran Nikoloski.
      Modules represent fundamental building blocks of cellular networks and are thought to facilitate robustness of phenotypes against perturbations. While reaction kinetic shapes the concentration of components and reaction rates, its use in identification of modules entails knowledge of parameter values. Here, we demonstrate that kinetic modules can be efficiently identified on the basis of steady-state reaction rate couplings in large-scale biochemical networks endowed with mass action kinetics without knowledge of parameter values. We then link the kinetic modules of metabolic networks with robustness of metabolite concentrations to perturbations. Analyzing 34 metabolic network models of 26 organisms, we demonstrate that the ordered binding enzyme mechanism leads to increased concentration robustness compared to random binding. Our findings pave the way for usage of modules in synthetic biology and biotechnological applications.
    DOI:  https://doi.org/10.1126/sciadv.ads7269
  43. Discov Oncol. 2025 May 26. 16(1): 929
    Post-translational modifications and the reprogramming of tumor metabolism.
    Yuqing Hu, Wenxia Xu, Lin Chen.
      Metabolic reprogramming occurs alongside tumor development. As cancers advance from precancerous lesions to locally invasive tumors and then to metastatic tumors, metabolic patterns exhibit distinct changes, including mutations in metabolic enzymes and modifications in the activity of metabolic regulatory proteins. Alterations in metabolic patterns can influence tumor evolution, either establishing or alleviating metabolic burdens and facilitating cancer growth. To fully understand how metabolic reprogramming helps tumors grow and find the metabolic activities that are most useful for treating tumors, we need to have a deeper understanding of how metabolic patterns are controlled as tumors grow. Post-translational modifications (PTMs), a critical mechanism in the regulation of protein function, can influence protein activity, stability, and interactions in several ways. In tumor cells, PTMs-mediated metabolic reprogramming is a crucial mechanism for adapting to the challenging microenvironment and sustaining fast growth. This article will deeply explore the intricate regulatory mechanism of PTMs on metabolic reprogramming and its role in tumor progression, with the expectation of providing new theoretical basis and potential targets for tumor treatment.
    Keywords:  Cancer metabolic; Post-translational modifications; Tumor metabolic reprogramming
    DOI:  https://doi.org/10.1007/s12672-025-02674-1
  44. Cancers (Basel). 2025 May 16. pii: 1681. [Epub ahead of print]17(10):
    High KYNU Expression Is Associated with Poor Prognosis, KEAP1/STK11 Mutations, and Immunosuppressive Metabolism in Patient-Derived but Not Murine Lung Adenocarcinomas.
    Ling Cai, Thomas J Rogers, Reza Mousavi Jafarabad, Hieu Vu, Chendong Yang, Nicole Novaresi, Ana Galán-Cobo, Luc Girard, Edwin J Ostrin, Johannes F Fahrmann, Jiyeon Kim, John V Heymach, Kathryn A O'Donnell, Guanghua Xiao, Yang Xie, Ralph J DeBerardinis, John D Minna.
      Background/Objectives: We aimed to discover genes with bimodal expression linked to patient outcomes, to reveal underlying oncogenotypes and identify new therapeutic insights in lung adenocarcinoma (LUAD). Methods: We performed meta-analysis to screen LUAD datasets for prognostic genes with bimodal expression patterns. Kynureninase (KYNU), a key enzyme in tryptophan catabolism, emerged as a top candidate. We then examined its relationship with LUAD mutations, metabolic alterations, immune microenvironment states, and expression patterns in human and mouse models using bulk and single-cell transcriptomics, metabolomics, and preclinical model datasets. Pan-cancer prognostic associations were also assessed. Results: Model-based clustering of KYNU expression outperformed median-based dichotomization in prognostic accuracy. KYNU was elevated in tumors with KEAP1 and STK11 co-mutations but remained a strong independent prognostic marker. Metabolomic analysis showed that KYNU-high tumors had increased anthranilic acid, a catalytic product, while maintaining stable kynurenine levels, suggesting a compensatory mechanism sustaining immunosuppressive signaling. Single-cell and bulk data showed KYNU expression was cancer cell-intrinsic in immune-cold tumors and myeloid-derived in immune-infiltrated tumors. In murine LUAD models, Kynu expression was predominantly immune-derived and uncoupled from Nrf2/Lkb1 signaling, indicating poor model fidelity. KYNU's prognostic associations extended across cancer types, with poor outcomes in pancreatic and kidney cancers but favorable outcomes in melanoma, underscoring the need for lineage-specific considerations in therapy development. Conclusions:KYNU is a robust prognostic biomarker and potential immunometabolic target in LUAD, especially in STK11 and KEAP1 co-mutated tumors. Its cancer cell-intrinsic expression and immunosuppressive metabolic phenotype offer translational potential, though species-specific expression patterns pose challenges for preclinical modeling.
    Keywords:  KEAP1; KYNU; NAD metabolism; STK11; immune suppression; kynureninase; kynurenine pathway; lung adenocarcinoma; mouse model limitations; prognostic biomarker; tryptophan catabolism
    DOI:  https://doi.org/10.3390/cancers17101681
  45. Nat Chem Biol. 2025 May 28.
    Reactivity-based metabolomics reveal cysteine has glyoxalase 1-like and glyoxalase 2-like activities.
    Marc Daniel Opfermann, Maria Bøgelund Søndergård, Louise Vase Bech, Camilla B Nielsen, Alejandro Mahía, Charlotte Brinck Holt, Tingting Wang, Sarah Bisgaard Olesen, Kim Frisch, Jakob Appel Østergaard, Dieter Britz, Kirstine Lykke Nielsen, James J Galligan, Thomas B Poulsen, Jakob Hansen, Mogens Johannsen.
      Methylglyoxal (MG) is a reactive metabolite involved in diabetes and aging through the formation of protein adducts. Less is known about the extent that MG and its metabolic product S-D-lactoylglutathione (LGSH) form adducts with cell metabolites. Using a 'symmetric' isotope-labeled and reactivity-based metabolomics approach in living cells, we found over 200 adducts and, surprisingly, discovered that 10 of the most abundant are lactoylated amino acids mainly derived from LGSH. The most abundant adduct D-Lac-Cys is formed rapidly between LGSH and cysteine, whereas the diastereoisomer L-Lac-Cys is formed directly from MG and cysteine, assigning cysteine with both glyoxalase 1-like and glyoxalase 2-like activity. Cellular cysteine and MG dynamically regulate D-Lac-Cys and L-Lac-Cys levels and the adducts are increased in diabetes, suggesting their use as novel biomarkers. Lastly, cysteine amides, as proxies for protein cysteines, also undergo lactoylation by MG and LGSH, suggesting the existence of two additional pathways for nonenzymatic lactoylation of proteins.
    DOI:  https://doi.org/10.1038/s41589-025-01909-0
  46. Nat Genet. 2025 May 26.
    Base editing of trinucleotide repeats that cause Huntington's disease and Friedreich's ataxia reduces somatic repeat expansions in patient cells and in mice.
    Zaneta Matuszek, Mandana Arbab, Maheswaran Kesavan, Alvin Hsu, Jennie C L Roy, Jing Zhao, Tian Yu, Ben Weisburd, Gregory A Newby, Neil J Doherty, Muzhou Wu, Shota Shibata, Ana Cristian, Y Allen Tao, Liam G Fearnley, Melanie Bahlo, Heidi L Rehm, Jun Xie, Guangping Gao, Ricardo Mouro Pinto, David R Liu.
      Trinucleotide repeat (TNR) diseases are neurological disorders caused by expanded genomic TNRs that become unstable in a length-dependent manner. The CAG•CTG sequence is found in approximately one-third of pathogenic TNR loci, including the HTT gene that causes Huntington's disease. Friedreich's ataxia, the most prevalent hereditary ataxia, results from GAA repeat expansion at the FXN gene. Here we used cytosine and adenine base editing to reduce the repetitiveness of TNRs in patient cells and in mice. Base editors introduced G•C>A•T and A•T>G•C interruptions at CAG and GAA repeats, mimicking stable, nonpathogenic alleles that naturally occur in people. AAV9 delivery of optimized base editors in Htt.Q111 Huntington's disease and YG8s Friedreich's ataxia mice resulted in efficient editing in transduced tissues, and significantly reduced repeat expansion in the central nervous system. These findings demonstrate that introducing interruptions in pathogenic TNRs can mitigate a key neurological feature of TNR diseases in vivo.
    DOI:  https://doi.org/10.1038/s41588-025-02172-8
  47. J Mol Biol. 2025 May 23. pii: S0022-2836(25)00295-5. [Epub ahead of print] 169229
    Immunoproteasome-specific subunit alterations as a potential therapeutic target for mitochondriopathies.
    Agata Kodroń, Konrad Kowalski, Ben Hur Marins Mussulini, Cem Hazir, Mayra A Borrero-Landazabal, Sonia Ngati, Michal Wasilewski, Agnieszka Chacinska.
      Mitochondria are double-membrane organelles crucial for eukaryotic cells due to their role in ATP production by oxidative phosphorylation (OXPHOS). Most of the ∼1500 proteins of the mitochondrial proteome are encoded in the nuclear genome, synthesized in the cytosol, and actively transported into mitochondria. The proteasome, a major cellular proteolytic machinery, plays an important role in the quality control of their transport by degradation of inefficiently imported mitochondrial proteins in the cytosol. Proteasome inhibition by bortezomib was described as a strategy to alleviate deficiencies stemming from an inefficient import of proteins into the mitochondria. Notably, an impairment of the respiratory complexes was shown to induce a rearrangement of the proteasome composition to incorporate some of the immunoproteasome catalytic subunits, such as PSMB9. In this study, we demonstrated that targeting immunoproteasome inhibited degradation, and thus restored the abundance of inefficiently imported respiratory complex IV proteins in the patient derived fibroblasts. Furthermore, we demonstrated that the immunoproteasome-specific inhibitors displayed a decreased toxicity compared to bortezomib. Our results indicate that immunoproteasome subunits present a novel molecular target for future therapies of mitochondriopathies.
    Keywords:  PSMB9; immunoproteasome inhibitors; immunoproteasome subunits; mitochondria; mitochondrial diseases
    DOI:  https://doi.org/10.1016/j.jmb.2025.169229
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