bims-celmim Biomed News
on Cellular and mitochondrial metabolism
Issue of 2025–12–21
twenty papers selected by
Marc Segarra Mondejar, AINA
  1. TMEM65-dependent Ca2+ extrusion safeguards mitochondrial homeostasis.
  2. RHOA regulates mitochondria-ER contact sites through modulation of the VAPB/PTPIP51 tether.
  3. The fate of pyruvate dictates cell growth by modulating cellular redox potential.
  4. Transporting the transporter: TIM22 translocates mitoferrins to enable mitochondrial iron-sulfur cluster synthesis.
  5. Lactate mitochondrial oxidation drives stemness potential in metastatic breast cancer.
  6. Vesicle-mediated mitochondrial clearance presents an actionable metabolic vulnerability in triple-negative breast cancer.
  7. Autophagy-regulated mitochondrial inheritance controls early CD8+ T cell fate commitment.
  8. Splicing factor SF3B4 promotes mitochondrial glutamine metabolism in hepatocellular carcinoma by regulating GLS1 isoform switching.
  9. Lactate and Lactylation in Immune Cell Function and Autoimmune Diseases: Mechanisms and Therapeutic Potential.
  10. The TIM22 carrier translocase supports cell proliferation by facilitating mitochondrial iron uptake for Fe-S biogenesis.
  11. A green lifetime biosensor for calcium that remains bright over its full dynamic range.
  12. Notch1 regulates Orai1 and Orai3 expression in breast cancer cells.
  13. Depletion of individual dietary amino acids induce distinct metabolic and chromatin states.
  14. AMP-activated protein kinase-driven lipid droplet dynamics govern melanoma sensitivity to polyunsaturated fatty acid and iron-induced ferroptosis.
  15. Metabolic profiling of therapy-induced senescent cancer cells via TPEF, MALDI-MS, and RNA-sequencing.
  16. MISO regulates mitochondrial dynamics and mtDNA homeostasis by establishing membrane subdomains.
  17. Serotonin-licensed macrophages potentiate chemoresistance via inositol metabolic crosstalk in ovarian cancer.
  18. Immunometabolic insights into the foreign body response.
  19. A seven-year longitudinal study of the Alzheimer's disease blood metabolome.
  20. Sodium disrupts mitochondrial energy metabolism to execute NECSO.
  1. Nat Commun. 2025 Dec 17.
    TMEM65-dependent Ca2+ extrusion safeguards mitochondrial homeostasis.
    Massimo Vetralla, Lena Wischhof, Asrat Kahsay, Vanessa Cadenelli, Enzo Scifo, Beijia Xie, Miriana Sbrissa, Maëlle Sandhira Habert, Dan Ehninger, Rosario Rizzuto, Daniele Bano, Diego De Stefani.
      The bidirectional transport of Ca2+ into and out of mitochondria regulates metabolism, signaling, and cell fate. While influx is mediated by the Mitochondrial Calcium Uniporter (MCU) complex, efflux mechanisms are more diversified, involving Na⁺ or H⁺ exchange pathways. We here demonstrate that TMEM65 is a fundamental component of the Ca2+ efflux machinery of mitochondria. Its overexpression specifically enhances Na⁺- and Li⁺-dependent mitochondrial Ca²⁺ extrusion. This effect is inhibited by CGP-37157 and does not depends on NCLX, currently considered the bona fide mitochondrial Na+/Ca2+ exchanger. Its downregulation chronically elevates basal [Ca²⁺]mt and impairs efflux upon stimulation. In Caenorhabditis elegans, deletion of TMEM65 homologs compromises embryonic development under mild thermal stress, causing necrotic lesions that are suppressed by genetic inhibition of MCU-1. These findings highlight a molecular component that may be relevant in pathological settings in which excessive mitochondrial Ca2+ accumulation critically contribute to degenerative pathways.
    DOI:  https://doi.org/10.1038/s41467-025-67647-y
  2. Nat Commun. 2025 Dec 14. 16(1): 11260
    RHOA regulates mitochondria-ER contact sites through modulation of the VAPB/PTPIP51 tether.
    Zheng Yang, Shintaro Nakajima, Hsiuchen Chen, Yogaditya Chakrabarty, Huibao Feng, David C Chan.
      The mitochondria-endoplasmic reticulum contact site (MERCS) is critical for calcium exchange, phospholipid transfer, and bioenergetics. Impairment of MERCS is implicated in numerous pathological conditions, including cancer and neurodegenerative diseases. Remodeling of MERCS can affect calcium signaling or metabolism, but the mechanisms involved in dynamic MERCS remodeling are unknown. Employing a genome-wide CRISPRi screen, we uncover the ability of the small GTPase RHOA to tune the cellular MERCS level. RHOA knockdown, or increasing its degradation by CUL3 overexpression, reduces the MERCS level; conversely, upregulation of RHOA increases the MERCS level. RHOA binds to the ER protein VAPB and regulates complex formation between VAPB and mitochondrial PTPIP51, which form a tethering complex at the interface between ER and mitochondria. Furthermore, this regulatory mechanism is perturbed by disease alleles of RHOA, CUL3, and VAPB involved in cancer, hyperkalemia, and neurodegeneration, suggesting that MERCS may be affected in a range of pathological conditions. This study identifies RHOA as a regulator of mitochondria-ER communication, providing mechanistic insights into the dynamic remodeling of MERCS and potential therapeutic strategies for diseases linked to MERCS dysfunction.
    DOI:  https://doi.org/10.1038/s41467-025-66138-4
  3. Elife. 2025 Dec 16. pii: RP103705. [Epub ahead of print]13
    The fate of pyruvate dictates cell growth by modulating cellular redox potential.
    Ashish G Toshniwal, Geanette Lam, Alex J Bott, Ahmad A Cluntun, Rachel Skabelund, Hyuck-Jin Nam, Dona R Wisidagama, Carl S Thummel, Jared Rutter.
      Pyruvate occupies a central node in carbohydrate metabolism such that how it is produced and consumed can optimize a cell for energy production or biosynthetic capacity. This has been primarily studied in proliferating cells, but observations from the post-mitotic Drosophila fat body led us to hypothesize that pyruvate fate might dictate the rapid cell growth observed in this organ during development. Indeed, we demonstrate that augmented mitochondrial pyruvate import prevented cell growth in fat body cells in vivo as well as in cultured mammalian hepatocytes and human hepatocyte-derived cells in vitro. We hypothesize that this effect on cell size was caused by an increase in the NADH/NAD+ ratio, which rewired metabolism toward gluconeogenesis and suppressed the biomass-supporting glycolytic pathway. Amino acid synthesis was decreased, and the resulting loss of protein synthesis prevented cell growth. Surprisingly, this all occurred in the face of activated pro-growth signaling pathways, including mTORC1, Myc, and PI3K/Akt. These observations highlight the evolutionarily conserved role of pyruvate metabolism in setting the balance between energy extraction and biomass production in specialized post-mitotic cells.
    Keywords:  D. melanogaster; cell biology; cell growth; genetics; hepatocytes; human; pyruvate metabolism; redox state; translation
    DOI:  https://doi.org/10.7554/eLife.103705
  4. Mol Cell. 2025 Dec 18. pii: S1097-2765(25)00943-8. [Epub ahead of print]85(24): 4483-4484
    Transporting the transporter: TIM22 translocates mitoferrins to enable mitochondrial iron-sulfur cluster synthesis.
    Erdem M Terzi, Richard Possemato.
      Iron is a critical nutrient, especially to power mitochondrial iron-sulfur cofactor synthesis. In this issue of Molecular Cell, Liu et al.1 engineer a fluorescent iron sensor, enabling them to define a critical function of the mitochondrial translocase, TIM22, in powering mitochondrial iron use by proper targeting of the mitochondrial iron importers, the mitoferrins.
    DOI:  https://doi.org/10.1016/j.molcel.2025.11.026
  5. Nat Commun. 2025 Dec 18.
    Lactate mitochondrial oxidation drives stemness potential in metastatic breast cancer.
    Jia-Jia Zhang, Ruo-Fei Tian, Chang-Geng Song, Rui Liu, Duo He, Gai-Qin Zhang, Xin-Yu Fan, Zi-Chuan Duan, Kun Zhang, Tian-Jiao Zhang, Ya-Tong Chen, Jian Zhang, Ke Wang, Ju-Mei Zhao, Xiang-Min Yang, Zhi-Nan Chen, Ling Li.
      Metastatic cancer cells, originating from cancer stem cells with metastatic capacity, utilize nutrient flexibility to navigate the challenges of the metastatic cascade. However, the nutrient required to maintain the stemness potentials of metastatic cancer cells remains unclear. Here, we reveal that metastatic breast cancer cells sustain stemness and initiate metastasis upon detachment by taking up and oxidizing lactate. In detached metastasizing breast cancer cells, lactate is incorporated into the tricarboxylic acid cycle, boosting oxidative phosphorylation, and promoting the stemness potentials via α-KG-DNMT3B-mediated SOX2 hypomethylation. Moreover, lactate is taken up and oxidized in mitochondria by the CD147/MCT1/LDHB complex, which correlates with stemness potentials and tumor metastasis in patients with breast cancer. An intracellularly expressed single-chain variable fragment targeting mitochondrial CD147 (mito-CD147 scFv) effectively disrupts the mitochondrial CD147/MCT1/LDHB complex, inhibits lactate-induced stemness potential, depletes circulating breast cancer cells, and reduces metastatic burden, suggesting promising clinical applications in reducing lactate-fueled metastasis.
    DOI:  https://doi.org/10.1038/s41467-025-67091-y
  6. Cell Rep Med. 2025 Dec 16. pii: S2666-3791(25)00551-8. [Epub ahead of print]6(12): 102478
    Vesicle-mediated mitochondrial clearance presents an actionable metabolic vulnerability in triple-negative breast cancer.
    Jody Vykoukal, Yihui Chen, Mingxin Zuo, Riccardo Ballarò, Monica J Hong, Hansini Krishna, Daniela B Rodriquez-Perera, Hiroyuki Katayama, Ehsan Irajizad, Ranran Wu, Ricardo A León-Letelier, Jennifer B Dennison, Angelica M Gutierrez, Adriana Paulucci-Holthauzen, Timothy C Thompson, Leona Rusling, Yining Cai, Fu Chung Hsiao, Soyoung Park, Banu Arun, Samir Hanash, Johannes F Fahrmann.
      Selective autophagy of mitochondria is known to promote cancer cell survival and progression, including in triple-negative breast cancer (TNBC). Here, we apply an integrated multi-omics approach together with functional experimental analyses to investigate metabolic adaptations that support mitochondrial quality control in TNBC. We detail a mitochondrial quality control mechanism, complementary to mitophagy, that is enabled by a program of heightened extracellular sphingomyelin salvaging in TNBC coupled with extracellular vesicle-mediated intracellular clearance of mitochondrial damage. Targeting of this onco-metabolic pathway via repurposing of eliglustat, a selective small molecule inhibitor of glucosylceramide synthase, results in ceramide-mediated compensatory mitophagy and cancer cell death in vitro and attenuates tumor growth and prolongs overall survival at clinically achievable doses in orthotopic syngeneic mouse models of TNBC as well as in human cell line-derived xenograft models. Our study defines an unexplored mechanism of aberrant sphingolipid metabolism that underlies an actionable metabolic vulnerability for anti-cancer treatment.
    Keywords:  autophagy; eliglustat; extracellular vesicles; glucosylceramide synthase; mitochondria; sphingolipids; triple-negative breast cancer
    DOI:  https://doi.org/10.1016/j.xcrm.2025.102478
  7. Nat Cell Biol. 2025 Dec 19.
    Autophagy-regulated mitochondrial inheritance controls early CD8+ T cell fate commitment.
    Mariana Borsa, Ana Victoria Lechuga-Vieco, Amir H Kayvanjoo, Edward Jenkins, Yavuz Yazicioglu, Ewoud B Compeer, Felix C Richter, Simon Rapp, Robert Mitchell, Tom Youdale, Hien Bui, Emilia Kuuluvainen, Michael L Dustin, Linda V Sinclair, Pekka Katajisto, Anna Katharina Simon.
      T cell immunity deteriorates with age, accompanied by a decline in autophagy and asymmetric cell division. Here we show that autophagy regulates mitochondrial inheritance in CD8+ T cells. Using a mouse model that enables sequential tagging of mitochondria in mother and daughter cells, we demonstrate that autophagy-deficient T cells fail to clear premitotic old mitochondria and inherit them symmetrically. By contrast, autophagy-competent cells that partition mitochondria asymmetrically produce daughter cells with distinct fates: those retaining old mitochondria exhibit reduced memory potential, whereas those that have not inherited old mitochondria and exhibit higher mitochondrial turnover are long-lived and expand upon cognate-antigen challenge. Multiomics analyses suggest that early fate divergence is driven by distinct metabolic programmes, with one-carbon metabolism activated in cells retaining premitotic mitochondria. These findings advance our understanding of how T cell diversity is imprinted early during division and support the development of strategies to modulate T cell function.
    DOI:  https://doi.org/10.1038/s41556-025-01835-2
  8. Biochem Biophys Res Commun. 2025 Dec 15. pii: S0006-291X(25)01850-9. [Epub ahead of print]796 153134
    Splicing factor SF3B4 promotes mitochondrial glutamine metabolism in hepatocellular carcinoma by regulating GLS1 isoform switching.
    Seungyeon Yang, Minbeom Ko, Wei Zhang, Seung Min Jeong.
      Metabolic reprogramming is a hallmark of cancer, enabling tumor cells to adapt to nutrient stress and sustain uncontrolled proliferation. In hepatocellular carcinoma (HCC), glutamine metabolism is markedly upregulated and plays a pivotal role in supporting tumor growth and survival. However, the molecular mechanisms underlying this metabolic shift remain poorly understood. Here, we identify the splicing factor SF3B4 as a key regulator of glutamine metabolism in HCC through its control of glutaminase 1 (GLS1) alternative splicing. SF3B4 is highly expressed HCC and is essential for tumor cell proliferation, migration and colony formation. Mechanistically, SF3B4 preferentially promotes the production of the GAC isoform of GLS1, which exhibits higher catalytic activity, while repressing the KGA isoform. Genetic or pharmacological inhibition of SF3B4 leads to reduced GAC expression, decreased GLS enzymatic activity, impaired glutaminolysis, and suppression of glutamine-driven mitochondrial respiration. Moreover, SF3B4 is required for tumor cell survival under glucose-deprived conditions, highlighting its role in supporting metabolic flexibility under nutrient stress. Collectively, these findings uncover a previously unrecognized function of SF3B4 in promoting mitochondrial glutamine metabolism in HCC and suggest that the SF3B4-GAC axis may represent a potential therapeutic target for glutamine-addicted liver cancers.
    Keywords:  GLS1; Glutamine metabolism; HCC; SF3B4
    DOI:  https://doi.org/10.1016/j.bbrc.2025.153134
  9. Immunology. 2025 Dec 16.
    Lactate and Lactylation in Immune Cell Function and Autoimmune Diseases: Mechanisms and Therapeutic Potential.
    Yiying Yang, Ying Zhang, Ke Liu, Huali Zhang, Xiaoxia Zuo, Muyao Guo.
      Lactate metabolism plays a crucial role in immune cell function, particularly during inflammation or metabolic stress. Under these conditions, immune cells often undergo a metabolic shift towards glycolysis, resulting in increased lactate production. This reprogramming not only provides energy but also influences cellular signalling pathways that regulate gene expression and immune responses. A key outcome of elevated lactate levels is lactylation, a novel post-translational modification where lactate molecules are covalently attached to proteins, typically at lysine residues. Lactylation regulates protein activity and function, impacting transcription factors, enzymes and other proteins involved in immune cell activation, differentiation and inflammation. The process of lactylation is controlled by specific enzymes known as 'writers', 'erasers' and 'readers', which add, remove and recognise lactate modifications on proteins. Lactylation plays a significant role in immune cell function, influencing cytokine production, immune cell proliferation and the regulation of inflammation. Abnormal lactylation can contribute to the pathogenesis of autoimmune diseases, such as rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE), by enhancing immune cell activation and promoting chronic inflammation. Elevated lactate levels in these diseases exacerbate immune responses, leading to tissue damage and autoantibody production. Targeting lactate metabolism or modulating lactylation presents a promising therapeutic strategy for autoimmune diseases. By regulating the enzymes involved in lactylation or controlling lactate accumulation, it may be possible to modulate immune responses, reduce inflammation and alleviate disease symptoms. Although current evidence largely derives from pre-clinical models and cell-based studies, emerging findings suggest that targeting lactate metabolism or modulating lactylation represents a promising therapeutic approach for autoimmune diseases. Future clinical studies are warranted to validate the translational potential of lactylation-related pathways and to develop safe and effective therapeutic strategies.
    Keywords:  PTMs; autoimmune diseases; glycolysis; immune cells; lactate; lactylation
    DOI:  https://doi.org/10.1111/imm.70075
  10. Mol Cell. 2025 Dec 18. pii: S1097-2765(25)00939-6. [Epub ahead of print]85(24): 4587-4601.e7
    The TIM22 carrier translocase supports cell proliferation by facilitating mitochondrial iron uptake for Fe-S biogenesis.
    Shuai Liu, Qingyu Li, Mengye Cao, Zefang Bimo Zhao, Cong Liu, Zhuoran Zhen, Jiankun Ren, Chengyang Liu, Danyang Ruan, Luna Zhang, Wenjuan Zhang, Hao Gong, Xiaolong Liu, Xuejie Zhang, Deng Pan, Weijun Pan, Jiajun Zhu.
      Mitochondria host a number of reductive biosynthetic pathways and rely on extensive metabolite exchanges with the cytosol to support cellular anabolic metabolism. Mitochondrial iron-sulfur cluster (Fe-S) biogenesis is essential for multiple cellular functions, and its disruption causes various inborn genetic diseases. How mammalian cells regulate Fe-S biogenesis remains incompletely understood. Here, mitochondria-focused CRISPR screening and DepMap-based gene co-essentiality analysis consistently reveal that components of the carrier translocase of the inner mitochondrial membrane (TIM22) complex, including TIMM29, are selectively required for Fe-S biogenesis. Mechanistically, loss of TIM22 complex function reduced iron transporter presence on mitochondria, thereby impairing iron uptake from the cytosol. Reconstituting mitochondrial iron level was sufficient to restore Fe-S biogenesis and proliferation of TIMM29-deficient cells or rescue the embryonic development of timm29-deficient zebrafish. Thus, a primary function of the TIM22 carrier translocase is to facilitate transporter-mediated iron uptake required for Fe-S biogenesis, underscoring a biosynthetic role of mitochondria in cellular anabolism.
    Keywords:  TIM22 carrier translocase; cellular metabolism; iron-sulfur cluster; mitochondria
    DOI:  https://doi.org/10.1016/j.molcel.2025.11.022
  11. Elife. 2025 Dec 19. pii: RP105086. [Epub ahead of print]14
    A green lifetime biosensor for calcium that remains bright over its full dynamic range.
    Franka H van der Linden, Stephen C Thornquist, Rick M Ter Beek, Jelle Y Huijts, Mark A Hink, Theodorus W J Gadella, Gaby Maimon, Joachim Goedhart.
      Fluorescent biosensors toggle between two states, and for the vast majority of biosensors, one state is bright and the other state is dim. As a consequence, there is a substantial difference in the signal-to-noise ratio (SNR) for the two states. The dim state has a low SNR, which is problematic when precise, quantitative measurements are needed. During the engineering of a red-shifted variant of an mTurquoise-based calcium sensor, we serendipitously generated a green-emitting sensor that shows high brightness in both the calcium-bound and -unbound state, while still showing a calcium-dependent lifetime change of >1 ns. This sensor, named G-Ca-FLITS, is comparable in brightness to the bright state of GCaMP3 and jGCaMP7c in mammalian cells. The calcium-induced loss in fluorescence intensity is only around 30% and therefore we observe little variation in the SNR when calcium levels change. G-Ca-FLITS shows negligible sensitivity to pH in the physiological range, like its turquoise parent. Using fluorescence lifetime imaging (FLIM), we measured the calcium concentration with G-Ca-FLITS in various organelles and observed in HeLa cells transient and spatially heterogeneous calcium elevations in mitochondria. Finally, we evaluated the use of G-Ca-FLITS and its turquoise predecessor for two-photon FLIM in Drosophila brains.
    Keywords:  D. melanogaster; FLIM; GFP; biochemistry; biosensor; calcium; chemical biology; human; lifetime; mitochondria
    DOI:  https://doi.org/10.7554/eLife.105086
  12. Sci Rep. 2025 Dec 18.
    Notch1 regulates Orai1 and Orai3 expression in breast cancer cells.
    Joel Nieto-Felipe, Alvaro Macias-Diaz, Sandra Alvarado, Pedro C Redondo, Vanesa Jimenez-Velarde, Jose J Lopez, Astrid Gorischek, Isaac Jardin, Tarik Smani, Juan A Rosado.
      Store-operated Ca²⁺ entry (SOCE) is a major pathway for Ca²⁺ entry that regulates several cellular functions. SOCE remodeling mediated by changes in the expression and/or function of the Orai channels results in the reorganization of intracellular Ca2+ homeostasis leading to a variety of pathologies, including cancer. Notably, a significant alteration of Orai function has been reported in breast cancer cells, where the dysregulation of the Notch1 signaling pathway plays a role in the development and progression of cancer hallmarks. Here, we have investigated the possible role of Notch1 in the regulation of the expression of Orai1 and Orai3 in different breast cancer cell lines. Expression of the active form of Notch1, as well as cell stimulation with the Notch1 agonist Jagged-1 (Jag-1), demonstrates a differential role of Notch1 in the regulation of Orai expression in non-tumoral breast epithelial cells and triple negative or luminal breast cancer cells. The role of Notch1 was confirmed using DAPT, a γ-secretase inhibitor that prevents activation of the Notch pathway. Modulation of Orai1 and Orai3 expression by Notch1 was paralleled by changes in SOCE. The effect in Orai expression mediated by activation of Notch1 signaling pathway was mimicked by the expression of HEY1 or the non-phosphorylatable HEY1-S68A mutant; by contrast, expression of the phosphomimetic HEY1-S68D mutant was without effect on Orai expression. Understanding the Notch1-HEY1-Orai axis might provide insights into the development of subtype-specific therapeutic strategies targeting breast cancer.
    Keywords:  Notch1; Orai1; Orai3; Store-operated Ca2+ entry
    DOI:  https://doi.org/10.1038/s41598-025-33071-x
  13. J Biol Chem. 2025 Dec 17. pii: S0021-9258(25)02926-6. [Epub ahead of print] 111074
    Depletion of individual dietary amino acids induce distinct metabolic and chromatin states.
    Spencer A Haws, Yang Liu, Cara L Green, Krittisak Chaiyakul, Pragyan Mishra, Reji Babygirija, Eric A Armstrong, Anusha T Mehendale, Irene M Ong, Dudley W Lamming, John M Denu.
      Reducing dietary levels of protein or specific essential amino acids (EAAs) promotes favorable metabolic reprogramming, including improved glucose tolerance, increased insulin sensitivity and reduced fat mass. However, the extent to which shared or EAA-specific mechanisms facilitate diet-associated phenotypes remains unclear. Here, we compared the physiological and molecular responses to dietary levels of methionine, leucine, and isoleucine by feeding C57BL/6J mice diets in which each of these specific AAs is depleted. Dietary depletion of Met, Leu, or Ile (Met-D, Leu-D, or Ile-D) elicited distinct, AA-specific physiological and hepatic molecular (transcriptome, metabolome, histone proteome) responses that were not phenocopied by mTORC1 inhibition via rapamycin treatment. Ile-D yielded the most distinct and dramatic responses, highlighted by expression of select chromatin modifying and metabolic enzymes that led to a prominent epigenetic state of histone H2A/H4 hypoacetylation and maintained hepatic acetyl-CoA levels despite downregulated β-oxidation. Multi-Omics Factor Analysis of 14,139 data points objectively affirmed Ile-D phenotypes are distinct from Met-D or Leu-D and identified metabolic and chromatin features as primary discriminators. We further demonstrated the metabolic and epigenetic responses to Ile-D can be recapitulated in vitro, suggesting that these responses are cell intrinsic. Together, these results demonstrate that dietary depletion of EAAs induce unique phenotypes and highlight distinct molecular mechanisms by which individual EAAs may control metabolic health.
    Keywords:  epigenetics; isoleucine; leucine; methionine; post-translational modification; protein depletion
    DOI:  https://doi.org/10.1016/j.jbc.2025.111074
  14. Nat Commun. 2025 Dec 17. 16(1): 11252
    AMP-activated protein kinase-driven lipid droplet dynamics govern melanoma sensitivity to polyunsaturated fatty acid and iron-induced ferroptosis.
    Sahar Motamedi, Nina Ravoet, Jonas Dehairs, Frank Vanderhoydonc, Abril Escamilla-Ayala, Malgorzata A Sliwinska, Shuncong Wang, Jakub Idkowiak, Stefaan Soenen, Patrizia Agostinis, Jean-Christophe Marine, Johannes V Swinnen.
      Ferroptosis, a regulated form of cell death driven by lipid peroxidation, holds promise for targeting treatment-resistant cancer cells. Using a panel of melanoma cell lines, we uncover variability in the timing of ferroptosis onset upon exposure to iron and polyunsaturated fatty acids (PUFAs). This heterogeneity is linked to differences in PUFA sequestration into lipid droplets (LDs) and their subcellular distribution, particularly near lipid-metabolizing organelles such as mitochondria. In late-onset models, ferroptosis is delayed by peripheral LD retention and triggered by nutrient deprivation and AMP-activated protein kinase (AMPK) activation, which promotes LD trafficking toward mitochondria. Early responders bypass this mechanism. Our findings identify nutrient status and LD dynamics as key modulators of PUFA- and iron-induced ferroptosis, offering insights for therapeutic exploitation in cancer.
    DOI:  https://doi.org/10.1038/s41467-025-66113-z
  15. Sci Rep. 2025 Dec 17.
    Metabolic profiling of therapy-induced senescent cancer cells via TPEF, MALDI-MS, and RNA-sequencing.
    Silvia Ghislanzoni, Federica Padelli, Matteo Niero, Alessia Bertolotti, Antonino Belfiore, Simone Torelli, Arianna Bresci, Andrea Masella, Silvia Betti, Dario Polli, Luca Agnelli, Italia Bongarzone.
      Despite advances in cancer therapies, treatment failure from resistance and recurrence remains a major clinical challenge. Therapy-induced senescence (TIS), a state of stable cell cycle arrest with sustained metabolic activity, has emerged as a driver of inflammation, tumor persistence, and relapse. However, the heterogeneity of TIS complicates its detection and targeting. Here, we applied a multi-modal strategy to characterize metabolic alterations in senescent cancer cells induced by doxorubicin or γ-irradiation across three tumor cell lines: MCF7, HeLa, and TPC-1. Mitochondrial dysfunction was assessed using MitoTracker and JC-1 staining, while two-photon excitation fluorescence (TPEF) microscopy enabled label-free visualization of intracellular NAD(P)H and FAD distribution. Lipid remodeling was evaluated by MALDI mass spectrometry imaging, and RNA sequencing was performed on control, senescent, and engulfing-senescent MCF7 cells to identify differentially expressed genes and enriched pathways. Senescent cells displayed mitochondrial dysfunction, with altered NAD(P)H/FAD distribution and decreased membrane potential. TPEF confirmed redistribution of coenzymes, reflecting redox changes. Lipidomics revealed consistent remodeling, notably involving cardiolipin precursors. Transcriptomic profiling showed engulfing-senescent MCF7 cells possess a distinct signature marked by increased lipid metabolism, endocrine signaling, and cell-cell communication. Overall, our findings reveal conserved and cell type-specific metabolic traits of TIS, highlighting metabolic vulnerabilities for senolytic intervention.
    Keywords:  Breast cancer; Engulfing; Senescence
    DOI:  https://doi.org/10.1038/s41598-025-32573-y
  16. Nat Cell Biol. 2025 Dec 15.
    MISO regulates mitochondrial dynamics and mtDNA homeostasis by establishing membrane subdomains.
    Yue Zhang, Yuchen Xia, Xinhui Wang, Yueqin Xia, Shang Wu, Jianshuang Li, Xuan Guo, Qinghua Zhou, Li He.
      Mitochondrial dynamics and mtDNA homeostasis have been linked to specialized mitochondrial subdomains known as small MTFP1-enriched mitochondria (SMEM), though the underlying molecular mechanisms remain unclear. Here we identified MISO (mitochondrial inner membrane subdomain organizer), a conserved protein that regulates both mitochondrial dynamics and SMEM formation in Drosophila and mammalian cells. MISO inhibits fusion by recruiting MTFP1 and promotes fission through FIS1-DRP1. Furthermore, MISO drives SMEM biogenesis and facilitates their peripheral fission that promotes lysosomal degradation of mtDNA. Genetic ablation of MISO abolishes SMEM generation, confirming that MISO is both necessary and sufficient for SMEM formation. Inner mitochondrial membrane stresses, including mtDNA damages, OXPHOS dysfunction and cristae disruption, stabilize the otherwise short-lived MISO protein, thereby triggering SMEM assembly. This process depends on the C-terminal domain of MISO, likely mediated by oligomerization. Together, our findings reveal a molecular pathway through which inner mitochondrial membrane stresses modulate mitochondrial dynamics and mtDNA homeostasis via MISO-orchestrated SMEM organization.
    DOI:  https://doi.org/10.1038/s41556-025-01829-0
  17. Cell Metab. 2025 Dec 17. pii: S1550-4131(25)00495-4. [Epub ahead of print]
    Serotonin-licensed macrophages potentiate chemoresistance via inositol metabolic crosstalk in ovarian cancer.
    Jie Li, Jingyi Lu, Cuimiao Zheng, Xi Huang, Haoyuan Li, Qiuwen Mai, Siqi Chen, Zhou Zhou, Jiayu Zhu, Tiantian Yu, Manman Xu, Hao Tan, Chun-Min Zhang, Qinglei Gao, Junxiu Liu, Chaoyun Pan.
      Therapeutic resistance in solid tumors frequently stems from enhanced homologous recombination (HR) repair capacity, yet systemic regulators of this pathway remain poorly defined. Here, we identify a serotonin-sensitive tumor-associated macrophage (TAM) subpopulation that orchestrates inositol metabolic crosstalk to potentiate HR repair in cancer cells. This TAM subset exhibited marked enrichment in ovarian tumors with low response to chemotherapy. Mechanistically, peripheral serotonin activates these TAMs via serotonin receptor HTR7, triggering extracellular vesicle (EV) secretion enriched with inositol metabolic enzymes PI4K2A and ITPKC. EV-mediated transfer of these metabolic enzymes elevates nuclear inositol-1,3,4,5-tetraphosphate (IP4) in cancer cells, where IP4 directly binds MRE11 and facilitates MRE11-DNA binding and HR repair. Attenuating peripheral serotonin using fluoxetine-a selective serotonin reuptake inhibitor (SSRI) antidepressant-ablates TAM-derived EV delivering of inositol metabolic enzymes and sensitizes tumors to cisplatin/PARP inhibitor (PARPi). Our study unveils a systemic serotonin-primed metabolic crosstalk within the tumor microenvironment that potentiates chemoresistance, revealing targetable HR repair regulation beyond cancer-cell-autonomous mechanisms.
    Keywords:  HR repair; cancer metabolism; chemotherapy; macrophage; ovarian cancer; serotonin
    DOI:  https://doi.org/10.1016/j.cmet.2025.11.011
  18. Sci Adv. 2025 Dec 19. 11(51): eaed8370
    Immunometabolic insights into the foreign body response.
    Srinidhi Venkatesan, Dauda L Mshelia, Chima V Maduka.
      Differences in energy use by immune cells cause long-lasting inflammation, with higher glucose uptake strongly linked to the formation of scar tissue around implanted materials.
    DOI:  https://doi.org/10.1126/sciadv.aed8370
  19. medRxiv. 2025 Dec 08. pii: 2025.12.05.25341709. [Epub ahead of print]
    A seven-year longitudinal study of the Alzheimer's disease blood metabolome.
    Alzheimer’s Disease Neuroimaging Initiative
      Metabolic dysregulation is a hallmark of Alzheimer's disease (AD), yet the temporal nature of metabolite-phenotype associations remains poorly understood. We systematically evaluated 506 serum metabolites across 4,063 longitudinal samples from 1,430 participants in the Alzheimer's Disease Neuroimaging Initiative (ADNI), applying cross-sectional single-timepoint analyses, multi-timepoint meta-analysis, and time-interaction analysis. Across 15 AD-related phenotypes, we identified 311 metabolites to be significantly associated with disease. Of those, 281 emerged from the multi-timepoint meta-analysis, 243 (216 overlapping/27 additional) from cross-sectional analyses, and 19 (16 overlapping/3 additional) metabolites that showed a significant evolution of their association with AD over time. In total, 128 metabolites (41%) showed persistent associations over time, providing evidence for chronic and systemic metabolic dysregulation in the disease. This, together with the comparably small number of metabolites showing evolving changes, suggests that many metabolic alterations in AD do not change substantially anymore once they manifested. Our findings confirm impaired fatty acid and energy metabolism, disrupted neurotransmitter systems, and oxidative stress as key metabolic features of AD. We demonstrate broad replication of the reported metabolite associations in prior studies and an independent lipidomics dataset in ADNI. In summary, this work expands previous metabolomics studies in AD and provides novel leads regarding timing and persistence of metabolic alterations across the disease trajectory.
    DOI:  https://doi.org/10.64898/2025.12.05.25341709
  20. Nat Commun. 2025 Dec 13.
    Sodium disrupts mitochondrial energy metabolism to execute NECSO.
    Yuhui Qiao, Jianghuang Wang, Bohong Wang, Hong Zhou, Qianlin Ni, Wan Fu, Zeping Hu, Qing Zhong.
      Na+ influx is a critical pathological event in various conditions such as ischemia, hyperosmotic stress, and organ failure. Although persistent activation of the transient receptor potential cation channel subfamily M member 4 (TRPM4) by chemical agonist Necrocide 1 (NC1) triggers necrosis by sodium overload (NECSO), the underlying mechanism remains to be elucidated. Here, we demonstrate that Na+ influx promotes necrosis by suppressing mitochondrial energy production. TRPM4-mediated Na⁺ entry elevates mitochondrial Na⁺ and reduces mitochondrial Ca²⁺ via NCLX, inhibiting oxidative phosphorylation and the Trichloroacetic acid (TCA) cycle, leading to severe energy depletion. This results in Na/K-ATPase inactivation, loss of ion gradients, cellular swelling and lysis. Our study reveals how sodium overload in NECSO disrupts mitochondrial metabolism to cause energy failure, potentially underlying diseases with elevated Na⁺.
    DOI:  https://doi.org/10.1038/s41467-025-67181-x
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