bims-cesemi Biomed News
on Cellular senescence and mitochondria
Issue of 2025–06–29
twenty-two papers selected by
Julio Cesar Cardenas, Universidad Mayor
  1. Cancer cells get power boost by stealing mitochondria from nerves.
  2. Can a pill replace exercise? Swigging this molecule gives mice benefits of working out.
  3. External strain on the plasma membrane is relayed to the endoplasmic reticulum by membrane contact sites and alters cellular energetics.
  4. Tumors may get energy boost from nerve cells' mitochondria.
  5. Cell-Surface LAMP1 is a Senescence Marker in Aging and Idiopathic Pulmonary Fibrosis.
  6. Good neighbours transfer nucleotides.
  7. Loss of STIM2, but not of STIM1, drives colorectal cancer metastasis through metabolic reprogramming and the ATF4 ER stress pathway.
  8. JMJD3-mediated senescence is required to overcome stress-induced hematopoietic defects.
  9. Key challenges and recommendations for defining organelle membrane contact sites.
  10. Neuronal transfer of mitochondria to tumour cells promotes cancer spread.
  11. Nerve-to-cancer transfer of mitochondria during cancer metastasis.
  12. The Identification of a Key Regulator of Mitochondrial Metabolism, the LRPPRC Protein, as a Novel Therapeutic Target in SDHA-Overexpressing Ovarian Tumors.
  13. MICOS.
  14. Identifying the target, mechanism, and agonist of α-ketoglutaric acid in delaying mesenchymal stem cell senescence.
  15. New Insights into the Role of Cellular Senescence and Its Therapeutic Implications in Ocular Diseases.
  16. Metabolic reprogramming of the neovascular niche promotes regenerative angiogenesis in proliferative retinopathy.
  17. An In Vivo Model of Recurrent Glioblastoma.
  18. Autophagy-targeted NBR1-p62/SQSTM1 complexes promote breast cancer metastasis by sequestering ITCH.
  19. Oxamate, an LDHA Inhibitor, Inhibits Stemness, Including EMT and High DNA Repair Ability, Induces Senescence, and Exhibits Radiosensitizing Effects in Glioblastoma Cells.
  20. Unlocking the Distinct Roles of the Three Mammalian VDAC Isoforms in Mitochondrial Respiration and Cancer Cell Metabolism.
  21. An NADH-controlled gatekeeper of ATP synthase.
  22. MitCOM-based prognostic model identifies GLUD1 as a key suppressor of glioblastoma growth and invasion through regulation of mitochondrial structure and metabolism.
  1. Nature. 2025 Jun 25.
    Cancer cells get power boost by stealing mitochondria from nerves.
    Traci Watson.
      
    Keywords:  Cancer; Cell biology; Metabolism; Neuroscience
    DOI:  https://doi.org/10.1038/d41586-025-01941-z
  2. Nature. 2025 Jun 25.
    Can a pill replace exercise? Swigging this molecule gives mice benefits of working out.
    Heidi Ledford.
      
    Keywords:  Ageing; Immunology; Metabolism
    DOI:  https://doi.org/10.1038/d41586-025-01994-0
  3. Sci Adv. 2025 Jun 27. 11(26): eads6132
    External strain on the plasma membrane is relayed to the endoplasmic reticulum by membrane contact sites and alters cellular energetics.
    Ziming Chen, Peilin Chen, Jiayue Li, Euphemie Landao-Bassonga, John Papadimitriou, Junjie Gao, Delin Liu, Andrew Tai, Jinjin Ma, David Lloyd, Brendan F Kennedy, Ming Hao Zheng.
      Mechanotransduction is essential for living cells to adapt to their extracellular environment. However, it is unclear how the biophysical adaptation of intracellular organelles responds to mechanical stress or how these adaptive changes affect cellular homeostasis. Here, using the tendon cell as a mechanosensitive cell type within a bioreactor, we show that the tension of the plasma membrane (PM) and the endoplasmic reticulum (ER) adaptively increases in response to repetitive external stimuli. Depletion of stromal interaction molecule 1 (STIM1), the highest expressed PM-ER tether protein, interfered with mechanotransduction from the PM to the ER, and affected the ER tension. We found that an optimized mechanical strain increased ER tension in a homeostatic manner, but excessive strain resulted in ER expansion, as well as activating ER stress. Last, we showed that changes in ER tension were linked with ER-mitochondria interactions and associated with cellular energetics and function. Together, these findings identify a PM-ER mechanotransduction mechanism that dose-dependently regulates cellular metabolism.
    DOI:  https://doi.org/10.1126/sciadv.ads6132
  4. Science. 2025 Jun 26. 388(6754): 1357-1358
    Tumors may get energy boost from nerve cells' mitochondria.
    Mitch Leslie.
      Study shows the organelles traveling through "bridges" into nearby cancer cells.
    DOI:  https://doi.org/10.1126/science.aea0605
  5. Aging Cell. 2025 Jun 22. e70141
    Cell-Surface LAMP1 is a Senescence Marker in Aging and Idiopathic Pulmonary Fibrosis.
    Gabriel Meca-Laguna, Michael Qiu, Yafei Hou, Anna Barkovskaya, Apoorva Shankar, Bhavna Dixit, Michael J Rae, Amutha Boominathan, Amit Sharma.
      The accumulation of senescent cells (SEN) with aging produces a chronic inflammatory state that accelerates age-related diseases. Eliminating SEN has been shown to delay, prevent, and in some cases reverse aging in animal disease models and extend lifespan. There is thus an unmet clinical need to identify and target SEN while sparing healthy cells. Here, we show that Lysosomal-Associated Membrane Protein 1 (LAMP1) is a membrane-specific biomarker of cellular senescence. We have validated selective LAMP1 upregulation in SEN in human and mouse cells. Lamp1+ cells express high levels of the prototypical senescence markers p16, p21, Glb1, and have low Lmnb1 expression as compared to Lamp1- cells. The percentage of Lamp1+ cells is increased with age and in mice with fibrotic lungs due to bleomycin (BLM) instillation. The RNA-Sequencing analysis of the Lamp1-enriched populations in sham and BLM mice lung tissue revealed enrichment of several senescence-related genes in both groups when compared to the SenMayo gene set derived from transcriptomic profiling of senescence markers in Mayo Clinic research datasets. Finally, we use a dual antibody-drug conjugate (ADC) strategy to eliminate SEN in cell culture assay.
    Keywords:   ADC ; LAMP1 ; aging; biomarker; senescence; surface
    DOI:  https://doi.org/10.1111/acel.70141
  6. Nat Rev Mol Cell Biol. 2025 Jun 24.
    Good neighbours transfer nucleotides.
    Lisa Heinke.
      
    DOI:  https://doi.org/10.1038/s41580-025-00872-x
  7. Sci Signal. 2025 Jun 24. 18(892): eads6550
    Loss of STIM2, but not of STIM1, drives colorectal cancer metastasis through metabolic reprogramming and the ATF4 ER stress pathway.
    Trayambak Pathak, J Cory Benson, Martin T Johnson, Ping Xin, Ahmed Emam Abdelnaby, Vonn Walter, Walter A Koltun, Gregory S Yochum, Nadine Hempel, Mohamed Trebak.
      The large amounts of calcium (Ca2+) stored in the endoplasmic reticulum (ER) and the controlled release of this Ca2+ store into the cytosol regulate many cellular functions, and altered ER Ca2+ homeostasis induces ER stress. Stromal-interacting molecules 1 and 2 (STIM1/2) are homologous ER-resident Ca2+ sensors that synergistically activate cytosolic Ca2+ influx through Orai channels to promote Ca2+-dependent changes in gene expression and ER Ca2+ refilling. Here, we demonstrated that reduced abundance of STIM2, but not that of STIM1, was associated with poor prognosis in colorectal cancer (CRC). STIM2-deficient CRC cells showed enhanced ER Ca2+ content in a manner dependent on the ER Ca2+ pump SERCA2, increased expression of genes associated with protein translation, and transcriptional and metabolic rewiring. STIM2 deficiency in CRC xenografts led to increased tumor size, invasion, and metastasis. STIM2 loss activated the expression of genes involved in ER stress responses in a manner dependent on the chaperone BiP and the transcription factor ATF4 and independent of Orai channels. These results suggest that loss of STIM2 may inform CRC prognosis.
    DOI:  https://doi.org/10.1126/scisignal.ads6550
  8. EMBO Rep. 2025 Jun 25.
    JMJD3-mediated senescence is required to overcome stress-induced hematopoietic defects.
    Yuichiro Nakata, Takeshi Ueda, Yasuyuki Sera, Miho Koizumi, Katsutoshi Imamura, Akinori Kanai, Ken-Ichiro Ikeda, Norimasa Yamasaki, Akiko Nagamachi, Kohei Kobatake, Masataka Taguchi, Yusuke Sotomaru, Tatsuo Ichinohe, Zen-Ichiro Honda, Takuro Nakamura, Ichiro Manabe, Toshio Suda, Keiyo Takubo, Osamu Kaminuma, Hiroaki Honda.
      Cellular senescence in stem cells compromises regenerative capacity, promotes chronic inflammation, and is implicated in aging. Hematopoietic stem and progenitor cells (HSPCs) are responsible for producing mature blood cells, however, how cellular senescence influences their function is largely unknown. Here, we show that JMJD3, a histone demethylase, activates cellular senescence by upregulating p16Ink4a in competition with Polycomb group proteins, and reprograms HSPC integrity to overcome hematopoietic defects induced by replicative and oncogenic stresses. Jmjd3 deficiency does not alter global H3K27me3 levels, indicating that JMJD3 epigenetically regulates specific and limited JMJD3 targets under stress. JMJD3 deficiency also impairs stem cell potential, proper cell cycle regulation, and WNT pathway activation in HSPCs under stress. These impaired phenotypes are rescued through exogenous and retroviral introduction of p16Ink4a. This JMJD3-p16INK4a axis in hematopoiesis is age-dependent and is distinct from cellular senescence. Treatment with a selective JMJD3 inhibitor attenuates leukemic potential during cellular senescence. Taken together, these results demonstrate that JMJD3-p16INK4a mediates cellular senescence and plays critical roles in the functional integrity of HSPCs under stress.
    Keywords:  Cellular senescence; Hematopoietic stem cell; Histone demethylase; Stress hematopoiesis
    DOI:  https://doi.org/10.1038/s44319-025-00502-9
  9. Nat Rev Mol Cell Biol. 2025 Jun 23.
    Key challenges and recommendations for defining organelle membrane contact sites.
    Tito Calì, Emmanuelle M Bayer, Emily R Eden, György Hajnóczky, Benoit Kornmann, Laura Lackner, Jen Liou, Karin Reinisch, Hyun-Woo Rhee, Rosario Rizzuto, Luca Scorrano, Marisa Brini.
      Intracellular membrane contact sites (MCSs) between organelles have crucial roles in cellular signalling and homeostasis. These sites, which are often disrupted in pathological conditions, enable the exchange of ions, lipids and metabolites between membrane-bound compartments, helping cells adapt to varying physiological conditions. Specific tether proteins and complexes stabilize these interactions and mediate responses to different intracellular or extracellular stimuli. The study of MCSs has progressed in recent years, owing to the development of new methods such as genetically encoded reporter constructs, advanced imaging techniques, including super-resolution microscopy and electron tomography, and proteomic approaches based on mass spectrometry. These tools have enabled unprecedented visualization and quantification of organelle interactions, as well as identification of the molecular players involved. This Expert Recommendation aims to define and map the 'organelle contactome', describing key proteins involved in contact site formation and the roles of MCSs in cellular function. We also explore contact site dynamics and detail advantages and disadvantages of the methodologies for studying them. Importantly, we consolidate open questions in contact site research and discuss challenges and limitations of the current experimental approaches.
    DOI:  https://doi.org/10.1038/s41580-025-00864-x
  10. Nature. 2025 Jun 25.
    Neuronal transfer of mitochondria to tumour cells promotes cancer spread.
    Anand K Singh, Yuan Pan.
      
    Keywords:  Cancer; Medical research; Neuroscience
    DOI:  https://doi.org/10.1038/d41586-025-01718-4
  11. Nature. 2025 Jun 25.
    Nerve-to-cancer transfer of mitochondria during cancer metastasis.
    Gregory Hoover, Shila Gilbert, Olivia Curley, Clémence Obellianne, Mike T Lin, William Hixson, Terry W Pierce, Joel F Andrews, Mikhail F Alexeyev, Yi Ding, Ping Bu, Fariba Behbod, Daniel Medina, Jeffrey T Chang, Gustavo Ayala, Simon Grelet.
      The nervous system has a pivotal role in cancer biology, and pathological investigations have linked intratumoural nerve density to metastasis1. However, the precise impact of cancer-associated neurons and the communication channels at the nerve-cancer interface remain poorly understood. Previous cancer denervation models in rodents and humans have highlighted robust cancer dependency on nerves, but the underlying mechanisms that drive nerve-mediated cancer aggressivity remain unknown2,3. Here we show that cancer-associated neurons enhance cancer metabolic plasticity by transferring mitochondria to cancer cells. Breast cancer denervation and nerve-cancer coculture models confirmed that neurons significantly improve tumour energetics. Neurons cocultured with cancer cells undergo metabolic reprogramming, resulting in increased mitochondrial mass and subsequent transfer of mitochondria to adjacent cancer cells. To precisely track the fate of recipient cells, we developed MitoTRACER, a reporter of cell-to-cell mitochondrial transfer that permanently labels recipient cancer cells and their progeny. Lineage tracing and fate mapping of cancer cells acquiring neuronal mitochondria in primary tumours revealed their selective enrichment at metastatic sites following dissemination. Collectively, our data highlight the enhanced metastatic capabilities of cancer cells that receive mitochondria from neurons in primary tumours, shedding new light on how the nervous system supports cancer metabolism and metastatic dissemination.
    DOI:  https://doi.org/10.1038/s41586-025-09176-8
  12. Cancers (Basel). 2025 Jun 11. pii: 1942. [Epub ahead of print]17(12):
    The Identification of a Key Regulator of Mitochondrial Metabolism, the LRPPRC Protein, as a Novel Therapeutic Target in SDHA-Overexpressing Ovarian Tumors.
    Anna Szulta, Lin Wang, Ameera Hasan, Michael Kinter, Atul Pranay, Jie Zhu, Kenneth M Humphries, Brooke Loveland, Timothy M Griffin, Magdalena Bieniasz.
      Background: Ovarian cancer is the deadliest of all gynecologic malignancies due to limited therapeutic options. Our data show that the tumor-specific metabolism of ovarian cancer could be effectively targetable, which highlights a path for new anti-cancer therapies. Methods and Results: Our work shows that the upregulation of mitochondrial enzyme SDHA is particularly prevalent in ovarian carcinoma. SDHA overexpression significantly induced orthotopic ovarian tumor growth, reducing mouse survival. We showed that SDHA-overexpressing tumors depend on glutaminolysis and increased activity of the tricarboxylic acid (TCA) cycle coupled with mitochondrial oxidative phosphorylation (OXPHOS), which are essential for high-energy metabolism and cell survival. We identified a distinctive vulnerability of SDHA-overexpressing tumors to agents targeting regulators of the OXPHOS pathway, particularly the LRPPRC protein. LRPPRC is a key regulator of mitochondrial energy metabolism, promoting OXPHOS and ATP generation. However, when overexpressed, the LRPPRC acts as a tumor oncogene. Our analysis of SDHA and LRPPRC gene and protein expression patterns in precursor lesions and established ovarian cancer demonstrated that the upregulation of SDHA is accompanied by LRPPRC overexpression, notably in advanced tumors. Our novel findings highlight for the first time a potential functional interaction between SDHA and LRPPRC in the development and progression of ovarian malignancy. Importantly, our in vivo data showed that pharmacological inhibition of LRPPRC results in a lasting therapeutic benefit and can be an effective therapy in SDHA- and LRPPRC-overexpressing ovarian tumors. Conclusions: Overall, our study underlines an understudied role of concomitant overexpression of SDHA and LRPPRC in ovarian cancer pathogenesis, highlighting new paths for therapeutic development.
    Keywords:  LRPPRC; OXPHOS; SDHA; high-grade serous ovarian cancer; metabolism; ovarian cancer; patient-derived xenograft; shikonin; succinate dehydrogenase
    DOI:  https://doi.org/10.3390/cancers17121942
  13. Curr Biol. 2025 Jun 23. pii: S0960-9822(25)00576-7. [Epub ahead of print]35(12): R595-R597
    MICOS.
    Karina von der Malsburg, Anastasiia Maitova, Martin van der Laan.
      von der Malsburg et al. introduce the mitochondrial contact site and cristae organizing system, a complex that localises to the inner mitochondrial membrane at crista junctions and stabilises these curved membrane domains.
    DOI:  https://doi.org/10.1016/j.cub.2025.05.001
  14. Cell Rep. 2025 Jun 25. pii: S2211-1247(25)00688-6. [Epub ahead of print]44(7): 115917
    Identifying the target, mechanism, and agonist of α-ketoglutaric acid in delaying mesenchymal stem cell senescence.
    Zhao Cui, Jiameng Li, Caifeng Li, Shiwen Deng, Wei Liu, Tong Lei, Junxian Cao, Ziyi Wang, Xiaoxu Wang, Shuhua Ma, Yinhua Zhu, Hongjun Yang, Peng Chen.
      α-ketoglutaric acid (AKG), a tricarboxylic acid cycle metabolite central to aerobic metabolism and longevity, retains unresolved anti-aging protein targets. Here, we demonstrate that reduced isocitrate dehydrogenase 1 (IDH1) expression during senescence lowers AKG production, accelerating the aging of mesenchymal stem cells (MSCs). Exogenous AKG or IDH1 overexpression restores AKG levels, enabling 2-oxoglutarate and Fe(II)-dependent oxygenase domain-containing protein 1 (OGFOD1)-catalyzed hydroxylation of ribosomal protein S23 (RPS23) at proline 62. Mechanistically, AKG stabilizes the OGFOD1-RPS23 complex, enhancing translation accuracy to limit misfolded protein accumulation while sustaining synthesis rates, thereby balancing proteostasis. The natural flavonoid scutellarin (Scu), identified as an IDH1 agonist, elevates AKG to delay MSC senescence. In aged mice, Scu improves cognitive function, reduces osteoporosis and skin aging, and suppresses senescence-associated secretory phenotype. Our findings identify the AKG-IDH1-RPS23 axis as a regulator of stem cell senescence and we propose metabolic reprogramming strategies for anti-aging therapies.
    Keywords:  CP: Metabolism; CP: Stem cell research; OGFOD1; RPS23; Scutellarin; isocitrate dehydrogenase; mesenchymal stem cells; protein homeostasis; senescence; α-ketoglutaric acid
    DOI:  https://doi.org/10.1016/j.celrep.2025.115917
  15. Bioengineering (Basel). 2025 May 23. pii: 563. [Epub ahead of print]12(6):
    New Insights into the Role of Cellular Senescence and Its Therapeutic Implications in Ocular Diseases.
    Junying Wu, Xiuxing Liu, Yidan Liu, Wenru Su, Yehong Zhuo.
      The process of aging exerts profound effects on various physiological systems, leading to the progression of chronic degenerative disorders and pathologies associated with advancing age. Cellular senescence plays a central role in the aging process and the onset of various eye conditions associated with advancing age, including age-related macular degeneration (AMD), diabetic retinopathy (DR), glaucoma, cataracts, and ocular surface disorders. The accumulation of senescent cells (SnCs) and their secretion of pro-inflammatory and tissue-remodeling factors, collectively known as the senescence-associated secretory phenotype (SASP), exacerbate chronic inflammation, oxidative stress, and tissue dysfunction, contributing to disease progression. This study is the first to systematically integrate the multifaceted mechanisms of cellular senescence in ocular diseases, revealing differential regulatory mechanisms of specific signaling pathways across different ocular pathologies, thereby providing novel insights into the pathogenesis of these disorders. SnC-targeted therapies such as senolytics, senomorphics, SASP modulators, mitochondrial-targeted antioxidants, and epigenetic reprogramming are emerging as regenerative therapies, demonstrating potent anti-inflammatory effects, restoration of normal tissue physiology, and successful regeneration of ocular defects in preclinical models and clinical trials, while slowing senescence-associated disease progression. This review not only summarizes the role of cellular senescence in ocular diseases but also delves into potential therapeutic strategies, particularly highlighting novel perspectives for root-cause-targeted therapies from the unique angle of senescence biology, which may pioneer new directions for the treatment of ocular pathologies.
    Keywords:  epigenetic reprogramming; ocular disease; oxidative stress; senescence-associated secretory phenotypes; senescent cells; senolytics
    DOI:  https://doi.org/10.3390/bioengineering12060563
  16. Nat Commun. 2025 Jun 25. 16(1): 5377
    Metabolic reprogramming of the neovascular niche promotes regenerative angiogenesis in proliferative retinopathy.
    Gael Cagnone, Sheetal Pundir, Charlotte Betus, Tapan Agnihotri, Anli Ren, Jin Sung -Kim, Noémie-Rose Harvey, Emilie Heckel, Mei Xi Chen, Anu Situ, Perrine Gaub, Nicholas Kim, Ashim Das, Severine Leclerc, Florian Wünnemann, Louis Berillon, Gregor Andelfinger, Sergio Crespo-Garcia, Alexandre Dubrac, Flavio A Rezende, Clary B Clish, Bruno Maranda, José Carlos Rivera, Lois E H Smith, Przemyslaw Sapieha, Jean-Sébastien Joyal.
      Healthy blood vessels supply neurons to preserve metabolic function. In blinding proliferative retinopathies (PRs), pathological neovascular tufts often emerge in lieu of needed physiological revascularization. Here we show that metabolic shifts in the neovascular niche define angiogenic fate. Fatty acid oxidation (FAO) metabolites accumulated in human and murine retinopathy samples. Neovascular tufts with a distinct single-cell transcriptional signature highly expressed FAO enzymes. The deletion of Sirt3, an FAO regulator, shifted the neovascular niche metabolism from FAO to glycolysis and suppressed tuft formation. This metabolic transition increased Vegf expression in astrocytes and reprogrammed pathological neovessels to a physiological phenotype, hastening vascular regeneration of the ischemic retina and improving vision. Hence, strategies to change the metabolic environment of vessels could promote a regenerative phenotype in vascular diseases.
    DOI:  https://doi.org/10.1038/s41467-025-60061-4
  17. Methods Mol Biol. 2025 ;2944 279-286
    An In Vivo Model of Recurrent Glioblastoma.
    Muhammad Vaseem Shaikh, Benjamin Brakel, Alisha Anand, Chitra Venugopal, Sheila K Singh.
      Glioblastoma (GBM) is a highly aggressive and prevalent adult brain tumor. Despite an intensive standard of care consisting of surgical resection followed by radiation therapy and chemotherapy with temozolomide, patients invariably succumb to the recurrent tumor and face an overall survival of less than 15 months. Recurrent GBM often differs greatly from the primary counterparts and show greater resistance to genotoxic therapies. Despite these differences and implications this treatment resistance has, recurrent GBM remains relatively understudied due to the paucity of samples and a previous lack of interest in the field. In this chapter, we describe an in vivo xenograft model recapitulating the standard of care with radiation therapy and temozolomide, and the subsequent development of recurrent GBM.
    Keywords:   Immunocompromised mice; Radiation; TMZ; Glioblastoma recurrence
    DOI:  https://doi.org/10.1007/978-1-0716-4654-0_21
  18. Nat Cell Biol. 2025 Jun 27.
    Autophagy-targeted NBR1-p62/SQSTM1 complexes promote breast cancer metastasis by sequestering ITCH.
    Gourish Mondal, Hugo Gonzalez, Timothy Marsh, Andrew M Leidal, Ariadne Vlahakis, Pravin R Phadatare, Sofı́a Bustamante Eguiguren, Michael Bruck, Akul Naik, Mark Jesus M Magbanua, Laura A Huppert, Arun P Wiita, Jeroen P Roose, Jennifer M Rosenbluth, Jayanta Debnath.
      Autophagy deficiency in breast cancer promotes metastasis through the accumulation of the autophagy cargo receptor NBR1. Here we show that autophagy normally suppresses breast cancer metastasis by enabling the clearance of NBR1-p62/SQSTM1 complexes that instruct p63-mediated pro-metastatic basal differentiation programmes. When autophagy is inhibited, the autophagy cargo receptors NBR1 and p62/SQSTM1 accumulate within biomolecular condensates in cells, which drives basal differentiation in both mouse and human breast cancer models. Mechanistically, these NBR1-p62/SQSTM1 complexes sequester ITCH, a ubiquitin ligase that degrades and negatively regulates p63 in breast cancer cells, thereby stabilizing and activating p63. Accordingly, mutant forms of NBR1 unable to sequester ITCH into NBR1-p62/SQSTM1 complexes do not promote basal differentiation and metastasis in vivo. Overall, our findings illuminate how proteostatic defects arising in the setting of therapeutic autophagy inhibition modulate epithelial lineage fidelity and metastatic progression.
    DOI:  https://doi.org/10.1038/s41556-025-01689-8
  19. Int J Mol Sci. 2025 Jun 14. pii: 5710. [Epub ahead of print]26(12):
    Oxamate, an LDHA Inhibitor, Inhibits Stemness, Including EMT and High DNA Repair Ability, Induces Senescence, and Exhibits Radiosensitizing Effects in Glioblastoma Cells.
    Takuma Hashimoto, Go Ushikubo, Naoya Arao, Khaled Hatabi, Kazuki Tsubota, Yoshio Hosoi.
      Enhancement of glycolysis has been reported in tumor cells, and it is believed that this enhancement is important for maintaining the stemness of tumor cells and contributes to malignant phenotypes. Here, we investigated the effects of Oxamate, which inhibits glycolysis by blocking the conversion of pyruvate to lactate, on radiosensitivity and its molecular mechanisms in T98G glioblastoma cells. Oxamate significantly enhanced radiosensitivity by delaying DNA repair, as indicated by the persistence of γ-H2AX foci up to four days post-irradiation. Mechanistically, Oxamate suppressed the expression and phosphorylation of key DNA repair factors. Furthermore, Oxamate induced apoptosis and promoted cellular senescence, as evidenced by the accumulation of SA-β-gal and the upregulation of pS15-p53 and p21. In addition, Oxamate downregulated EGFR expression, reduced the levels of stem cell markers, and modulated epithelial-mesenchymal transition (EMT) markers, suggesting a potential suppression of EMT-related pathways. Together, these results demonstrate that Oxamate enhances radiosensitivity in glioblastoma cells through multiple mechanisms, including the inhibition of DNA repair, induction of apoptosis and senescence, and suppression of cancer stem cell properties and EMT. Our findings provide new insights into the potential use of Oxamate as a radiosensitizer and warrant further investigation of its clinical application in glioblastoma therapy.
    Keywords:  DNA repair; LDH inhibitor; Oxamate; apoptosis; glycolysis; radiation sensitivity; senescence
    DOI:  https://doi.org/10.3390/ijms26125710
  20. bioRxiv. 2025 Apr 07. pii: 2025.02.20.639106. [Epub ahead of print]
    Unlocking the Distinct Roles of the Three Mammalian VDAC Isoforms in Mitochondrial Respiration and Cancer Cell Metabolism.
    Megha Rajendran, William M Rosencrans, Wendy Fitzgerald, Diana Huynh, Bethel G Beyene, Baiyi Quan, Julie Hwang, Nina A Bautista, Tsui-Fen Chou, Sergey M Bezrukov, Tatiana K Rostovtseva.
      The Voltage Dependent Anion Channel (VDAC) is the most ubiquitous protein in the mitochondrial outer membrane. This channel facilitates the flux of water-soluble metabolites and ions like calcium across the mitochondrial outer membrane. Beyond this canonical role, VDAC has been implicated, through interactions with protein partners, in several cellular processes such as apoptosis, calcium signaling, and lipid metabolism. There are three VDAC isoforms in mammalian cells, VDAC 1, 2, and 3, with varying tissue-specific expression profiles. From a biophysical standpoint, all three isoforms can conduct metabolites and ions with similar efficiency. However, isoform knockouts (KOs) in mice lead to distinct phenotypes, which may be due to differences in VDAC isoform interactions with partner proteins. To understand the functional role of each VDAC isoform within a single cell type, we created functional KOs of each isoform in HeLa cells and performed a comparative study of their metabolic activity and proteomics. We found that each isoform KO alters the proteome differently, with VDAC3 KO dramatically downregulating key members of the electron transport chain (ETC) while shifting the mitochondria into a glutamine-dependent state. Importantly, this unexpected dependence of mitochondrial function on the VDAC3 isoform is not compensated by the more ubiquitously expressed VDAC1 and VDAC2 isoforms. In contrast, VDAC2 KO did not affect respiration but upregulated ETC components and decreased key enzymes in the glutamine metabolic pathway. VDAC1 KO specifically reduced glycolytic activity linked to decreased hexokinase localization to mitochondria. These results reveal non-redundant roles of VDAC isoforms in cancer cell metabolic adaptability.
    DOI:  https://doi.org/10.1101/2025.02.20.639106
  21. Mol Cell. 2025 Jun 24. pii: S1097-2765(25)00507-6. [Epub ahead of print]
    An NADH-controlled gatekeeper of ATP synthase.
    Fabian Schildhauer, Petra S J Ryl, Simon M Lauer, Swantje Lenz, Ayşe Berçin Barlas, Vasileios R Ouzounidis, Kate Jeffrey, Daniel-Cosmin Marcu, Francis J O'Reilly, Andrea Graziadei, Marchel Stuiver, Kita Schmidt, Helge Ewers, Christian M T Spahn, Ezgi Karaca, Karl Emanuel Busch, Dhanya Cheerambathur, David Schwefel, Juri Rappsilber.
      ATP fuels crucial cellular processes and is obtained mostly by oxidative phosphorylation (OXPHOS) at the inner mitochondrial membrane. While significant progress has been made in mechanistic understanding of ATP production, critical aspects surrounding its substrate supply logistics are poorly understood. We identify an interaction between mitochondrial apoptosis-inducing factor 1 (AIFM1) and adenylate kinase 2 (AK2) as gatekeeper of ATP synthase. This interaction is NADH dependent and influenced by glycolysis, linking it to the cell's metabolic state. Genetic interference with AIFM1/AK2 association impedes the ability of Caenorhabditis elegans animals to handle altered metabolic rates and nutrient availability. Together, the results imply AIFM1 as a cellular NADH sensor, placing AK2 next to the OXPHOS complexes for local ADP regeneration as the substrate for ATP synthesis. This metabolic signal relay balances ATP synthase substrate supply against ATP conservation, enabling cells to adapt to fluctuating energy availability, with possible implications for AIFM1-related mitochondrial diseases.
    Keywords:  AIFM1; AK2; ATP synthesis; OXPHOS; adenylate kinase 2; apoptosis-inducing factor 1; cell signaling; crosslinking mass spectrometry; energy metabolism; mitochondria; mitochondrial; oxidative phosphorylation; protein structure; protein-protein interaction
    DOI:  https://doi.org/10.1016/j.molcel.2025.06.007
  22. Cancer Cell Int. 2025 Jun 21. 25(1): 222
    MitCOM-based prognostic model identifies GLUD1 as a key suppressor of glioblastoma growth and invasion through regulation of mitochondrial structure and metabolism.
    Yang Li, Chaoying Qin, Liangqi Jiang, Jun Su, Zhen Li, Qing Liu, Yuanbing Yao.
      
    Keywords:  GLUD1; Glioblastoma; MitCOM
    DOI:  https://doi.org/10.1186/s12935-025-03875-y
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