bims-mibica Biomed News
on Mitochondrial bioenergetics in cancer
Issue of 2025–08–17
twenty-two papers selected by
Kelsey Fisher-Wellman, Wake Forest University
  1. Respiration defects limit serine synthesis required for lung cancer growth and survival.
  2. Restricting metabolic plasticity enhances stress adaptation through the modulation of PDH and HIF1A in TRAP1-depleted colon cancer.
  3. Co-Targeting Bcl-xL with Mcl-1 Induces Lethal Mitochondrial Dysfunction in Diffuse Mesothelioma.
  4. Resilience and vulnerabilities of tumor cells under purine shortage stress.
  5. Pharmacodynamic determinants of mitochondrial one-carbon flux and serine hydroxymethyltransferase inhibition in human tumors.
  6. Complex II assembly drives metabolic adaptation to OXPHOS dysfunction.
  7. MacroD1 sustains mitochondrial integrity and oxidative metabolism.
  8. Principles of cotranslational mitochondrial protein import.
  9. Mitochondrially Targeted p53-Bad* Fusion Gene Therapy Promotes Apoptosis in Hepatocellular Carcinoma by Pan-Bcl-2 Inhibition.
  10. SUCLG1 deficiency-induced histone succinylation impairs oncogene expression in acute myeloid leukemia.
  11. Venetoclax plus gilteritinib is effective in preclinical models of FLT3-mutant BCL11B-a lineage-ambiguous leukemia.
  12. The ALDH2/PolG2 axis enhances mitochondrial biogenesis via transcriptional regulation of Nrf2 and promotes chemotherapy resistance in acute myeloid leukaemia.
  13. Mitochondria protect against an intracellular pathogen by restricting access to folate.
  14. PP2A activation drives aberrant macropinocytosis and cell death in pancreatic ductal adenocarcinoma.
  15. Comprehensive view on chemotherapy-free management of acute myeloid leukemia by using venetoclax in combination with targeted and/or immune therapies.
  16. D-cysteine impairs tumour growth by inhibiting cysteine desulfurase NFS1.
  17. Overcoming venetoclax resistance through heme-mediated NOXA/cyclin D1/Mcl-1 axis with a novel artemisinin conjugate.
  18. The Loss of Complex I in Renal Oncocytoma Is Associated with Defective Mitophagy Due to Lysosomal Dysfunction.
  19. Mitochondrial Metabolism in T-Cell Exhaustion.
  20. Cathepsin D promotes acute myeloid leukemia progression through stabilization of the anti-apoptotic proteins.
  21. ROS-dependent localization of glycolytic enzymes to mitochondria.
  22. Succinate preserves CD8+ T cell fitness to augment antitumor immunity.
  1. Nat Commun. 2025 Aug 15. 16(1): 7621
    Respiration defects limit serine synthesis required for lung cancer growth and survival.
    Eduardo Cararo Lopes, Fuqian Shi, Akshada Sawant, Maria Ibrahim, Maria Gomez-Jenkins, Zhixian Hu, Pranav Manchiraju, Vrushank Bhatt, Wenping Wang, Christian S Hinrichs, Douglas C Wallace, Xiaoyang Su, Joshua D Rabinowitz, Chang S Chan, Jessie Yanxiang Guo, Shridar Ganesan, Edmund C Lattime, Eileen White.
      Mitochondrial function supports energy and anabolic metabolism. Pathogenic mitochondrial DNA (mtDNA) mutations impair these processes, causing mitochondrial diseases. Their role in human cancers is less clear; while some cancers harbor high mtDNA mutation burden, others do not. Here we show that a proofreading mutant of DNA polymerase gamma (PolGD256A) increases the mtDNA mutation burden in non-small-cell lung cancer (NSCLC). This mutation promotes the accumulation of defective mitochondria, reduces tumor cell proliferation and viability, and improves cancer survival. In NSCLC, pathogenic mtDNA mutations enhance glycolysis and create a glucose dependency to support mitochondrial energy, but at the expense of a lower NAD+/NADH ratio that hinders de novo serine synthesis. Thus, mitochondrial function in NSCLC is essential for maintaining adequate serine synthesis, which in turn supports the anabolic metabolism and redox homeostasis required for tumor growth, explaining why these cancers preserve functional mtDNA.
    DOI:  https://doi.org/10.1038/s41467-025-62911-7
  2. Cancer Lett. 2025 Aug 09. pii: S0304-3835(25)00547-6. [Epub ahead of print] 217977
    Restricting metabolic plasticity enhances stress adaptation through the modulation of PDH and HIF1A in TRAP1-depleted colon cancer.
    Hong-Yuan Tsai, Miao-Hsueh Chen, Jihye Yun, Lisa A Lai, John F Valentine, Mary P Bronner, Teresa A Brentnall, Sheng Pan, Ru Chen.
      Metabolic plasticity allows cancer cells to survive under adverse conditions. To investigate the role of mitochondrial chaperone tumor necrosis factor receptor-associated protein 1 (TRAP1) in this process, we used CRISPR/Cas9 mediated genetic deletion to knock out (KO) TRAP1 in colon cancer cells. Depletion of TRAP1 triggered a series of events: induced metabolic reprogramming, increased glycolytic flux, downregulation of mitochondrial complex I, and elevated ROS generation. TRAP1-deficient cells showed tolerance to Oxidative Phosphorylation (OXPHOS) inhibitors and exhibited a higher extracellular acidification rate (ECAR). Additionally, TRAP1 depletion activated hypoxia response elements (HREs) and upregulated HIF1A target genes such as GLUT1 and MCT1. Furthermore, pyruvate dehydrogenase kinases 1 (PDK1) was upregulated in KO cells, leading to the inactivation of the tricarboxylic acid (TCA) cycle enzyme, pyruvate dehydrogenase (PDH). This metabolic shift towards glycolytic metabolism resulted in increased glycolytic metabolism, elevated lactic acid production, and higher glucose consumption, making TRAP1-depleted cancer cells more dependent on this altered metabolism for survival. Treatment with DCA, a PDK inhibitor, restored PDH activity, exacerbated oxidative stress, and increased cell death in KO cells. Our study here sheds light on how TRAP1 depletion affects metabolic plasticity, driving colon cancer cells to adapt to metabolic and oxidative stress. These findings highlight TRAP1 as a promising therapeutic target for manipulating metabolic plasticity and overcoming drug resistance in cancer therapy.
    Keywords:  HIF1A; Metabolism; PDH; ROS; TRAP1; mitochondria
    DOI:  https://doi.org/10.1016/j.canlet.2025.217977
  3. Mol Cancer Ther. 2025 Aug 14.
    Co-Targeting Bcl-xL with Mcl-1 Induces Lethal Mitochondrial Dysfunction in Diffuse Mesothelioma.
    R Taylor Ripley, Yuan Xu, Cristian G Medina, Deborah R Surman, Lacey E Dobrolecki, Monica Vilchis, Maheshwari Ramineni, Susan G Hilsenbeck, Yanming Li, Naren Li, Siqi Wu, Jaylon C Aggison, Xi Chen, Yi Zhu, Ying H Shen.
      Diffuse mesothelioma (DM) is a rare but highly aggressive and treatment resistant neoplasm with low survival rates. Effective therapeutic strategies are limited, and resistance to treatment is a major obstacle. Myeloid Cell Leukemia (MCL)-1 and B-cell leukemia (BCL)-xL are anti-apoptotic B-cell lymphoma 2 (Bcl-2) family proteins that block cell-intrinsic apoptosis through interactions on the mitochondrial outer membrane which contribute to therapeutic resistance. We investigated whether B-cell homology domain (BH)-3 profiles were consistent between intra-patient fresh tumor sample, patient-derived cells (PDC), and patient-derived xenografts (PDX) by BH3 profiling; we observed striking consistency which enabled cross model comparisons. Next, we co-targeted BCL-xl and MCL-1 and noted that the combination synergistically reduced cell viability and increased apoptosis. Mechanistically, BCL-xL inhibition affected the cells through both the canonical and the emerging non-canonical apoptotic pathways. BCL-xL induced mitochondrial depolarization which resulted in MCL-1 cellular dependency rendering cells highly sensitive to MCL-1 inhibition. Next, we co-targeted BCL-xL and MCL-1 in vivo which induced synthetic lethality in PDX models within hours, implying that this approach is not a safe strategy for clinical development. However, targeting MCL-1, which exerts its anti-apoptotic activity without non-apoptotic on-target effects, decreased the mitochondrial threshold for apoptosis and enhanced chemosensitivity without toxicity in PDX models. Our findings suggest that targeting the mitochondria via MCL-1 enhances the efficacy of chemotherapy but co-targeting two proteins in the Bcl-2 pathways results in synergistic lethality. These results will help define a safe clinical strategy to utilize Bcl-2 targeted therapy to undermine therapeutic resistance in patients with DM.
    DOI:  https://doi.org/10.1158/1535-7163.MCT-24-0873
  4. Clin Cancer Res. 2025 Aug 11.
    Resilience and vulnerabilities of tumor cells under purine shortage stress.
    Jianpeng Yu, Chen Jin, Cheng Su, David Moon, Michael Sun, Hong Zhang, Xue Jiang, Fan Zhang, Nomi Tserentsoodol, Michelle L Bowie, Christopher J Pirozzi, Daniel George, Robert Wild, Xia Gao, David M Ashley, Yiping He, Jiaoti Huang.
       PURPOSE: Purine metabolism is a promising therapeutic target in cancer; however, how cancer cells respond to purine shortage, particularly their adaptation and vulnerabilities, remains unclear.
    EXPERIMENTAL DESIGN: Using the recently developed purine shortage-inducing prodrug DRP-104 and genetic approaches, we investigated the responses in prostate, lung, and glioma cancer models.
    RESULTS: We demonstrate that when de novo purine biosynthesis is compromised, cancer cells employ microtubules to assemble purinosomes, multi-protein complexes of de novo purine biosynthesis enzymes that enhance purine biosynthesis efficiency. While this process enables tumor cells to adapt to purine shortage stress, it also renders them more susceptible to the microtubule-stabilizing chemotherapeutic drug Docetaxel. Furthermore, we show that although cancer cells primarily rely on de novo purine biosynthesis, they also exploit Methylthioadenosine Phosphorylase (MTAP)-mediated purine salvage as a crucial alternative source of purine supply, especially under purine shortage stress. In support of this finding, combining DRP-104 with an MTAP inhibitor significantly enhances tumor suppression in prostate cancer (PCa) models in vivo. Finally, despite the resilience of the purine supply machinery, purine shortage-stressed tumor cells exhibit increased DNA damage and activation of the cGAS-STING pathway, which may contribute to impaired immunoevasion and provide a molecular basis of the previously observed DRP-104-induced anti-tumor immunity.
    CONCLUSIONS: Together, these findings reveal purinosome assembly and purine salvage as key mechanisms of cancer cell adaptation and resilience to purine shortage while identifying microtubules, MTAP, and immunoevasion deficits as therapeutic vulnerabilities.
    DOI:  https://doi.org/10.1158/1078-0432.CCR-25-1667
  5. Drug Metab Dispos. 2025 Jul 17. pii: S0090-9556(25)09129-9. [Epub ahead of print]53(8): 100120
    Pharmacodynamic determinants of mitochondrial one-carbon flux and serine hydroxymethyltransferase inhibition in human tumors.
    Mathew Schneider, Carrie O'Connor, Xun Bao, Md Junayed Nayeen, Tejashree Magdum, Abhishekh Sharma, Jing Li, Seongho Kim, Charles E Dann, Aleem Gangjee, Zhanjun Hou, Larry H Matherly.
      One-carbon (C1) metabolism includes cytosolic and mitochondrial pathways connected by interchange between serine, glycine, and formate. Mitochondrial C1 metabolism through serine hydroxymethyltransferase (SHMT) 2 generates glycine and C1 units for de novo nucleotide biosynthesis in the cytosol, whereas cytosolic SHMT1 consumes C1 units and glycine. Folates and classical antifolates are transported into tumors by facilitative folate transporters (reduced folate carrier [RFC] and proton-coupled folate transporter [PCFT]) and are metabolized to polyglutamates by folylpolyglutamate synthetase (FPGS). Folate transporter-null HeLa cells were engineered to express RFC under the control of a tetracycline-inducible promoter. Constitutive expression of PCFT and/or FPGS increased cytosolic and mitochondrial folates over that of RFC alone. By targeted metabolomics, the C1 flux in mitochondria through SHMT2 paralleled RFC transport and folate accumulation in mitochondria and cytosol, whereas the SHMT1 flux was constant. Expression of PCFT resulted in further increased C1 flux through SHMT2, in excess of SHMT1. In vitro inhibition of cell proliferation by targeting SHMT1/2 with pyrrolo[3,2-d]pyrimidine antifolates (eg, AGF347) decreased with increasing RFC and with PCFT. Inhibition by AGF347 (not SHIN1/2) was stimulated with ectopic FPGS, accompanying increased AGF347 polyglutamates; decreased sensitivities were seen for nonclassical SHMT1/2 inhibitors (SHIN1/2), which are neither substrates for facilitative transport nor polyglutamylation. Our results document the complex interrelationships among (anti)folate membrane transport, polyglutamylation, and C1 fluxes through SHMT1 and SHMT2. They also demonstrate the profound impact of physiologic folates on antitumor activities and the extraordinary promise of multitargeted pyrrolo[3,2-d]pyrimidine antifolates for cancer therapy. SIGNIFICANCE STATEMENT: Novel pyrrolo[3,2-d]pyrimidine antifolates typified by AGF347 target serine hydroxymethyltransferase (SHMT) 2 in the mitochondria and SHMT1 and de novo purine biosynthesis in the cytosol. This manuscript documents the complex interrelationships among (anti)folate membrane transport, polyglutamylation, and one-carbon fluxes through SHMT1 and SHMT2 in the context of physiologic folate levels. The results document the therapeutic promise of classical multitargeted pyrrolo[3,2-d]pyrimidine antifolates typified by AGF347. These novel compounds offer an exciting new platform for one-carbon-targeted drug development for cancer.
    Keywords:  Antifolate; Folylpolyglutamate synthetase; One-carbon metabolism; Proton-coupled folate transporter; Reduced folate carrier; Serine hydroxymethyltransferase 2
    DOI:  https://doi.org/10.1016/j.dmd.2025.100120
  6. Sci Adv. 2025 Aug 15. 11(33): eadr6012
    Complex II assembly drives metabolic adaptation to OXPHOS dysfunction.
    Roopasingam Kugapreethan, Sheik Nadeem Elahee Doomun, Joanna Sacharz, Ann E Frazier, Tanavi Sharma, Yau Chung Low, Shuai Nie, Michael G Leeming, Linden Muellner-Wong, Karena Last, Tegan Stait, David P De Souza, David R Thorburn, Malcolm J McConville, David A Stroud.
      During acute oxidative phosphorylation (OXPHOS) dysfunction, reversal of succinate dehydrogenase (complex II) maintains the redox state of the Coenzyme Q (Q)-pool by using fumarate as terminal electron acceptor in certain tissues and cell lines. We identified the action of SDHAF2 protein, a complex II assembly factor, as critical for metabolic adaptation during complex III dysfunction in HEK293T cells. SDHAF2 loss during complex III inhibition led to a net reductive TCA cycle from loss of succinate oxidation, loss of SDHA active site-derived reactive oxygen species (ROS) signaling, insufficient glycolytic adaptation, and a severe growth impairment. Glycolysis adapted cells, however, did not accumulate SDHAF2 upon Q-pool stress, exhibited a net reductive TCA cycle and mild growth phenotypes regardless of SDHAF2 presence. Thus, our study reveals how complex II assembly controls a balance between dynamics of TCA cycle directionality, protection from Q-pool stress, and an ability to use ROS-meditated signaling to overcome acute OXPHOS dysfunction in cells reliant on mitochondrial respiration.
    DOI:  https://doi.org/10.1126/sciadv.adr6012
  7. Nat Commun. 2025 Aug 15. 16(1): 7595
    MacroD1 sustains mitochondrial integrity and oxidative metabolism.
    Ann-Katrin Hopp, Lorenza P Ferretti, Lisa Schlicker, Amalia Ruiz-Serrano, Udo Hetzel, Francesco Prisco, Anja Kipar, Lukas Muskalla, Elena Ferrari, Carsten C Scholz, Karsten Hiller, Francisco Verdeguer, Deena M Leslie Pedrioli, Michael O Hottiger.
      The mono-ADP-ribosylhydrolase MacroD1 has been recently reported to localize to mitochondria exclusively. However, the extent and means by which MacroD1 regulates metabolic homeostasis remains unclear. Here we show that the absence of MacroD1 in mice decreased mitochondrial load and negatively impacted muscle function, reducing maximal exercise capacity. Knockdown of MacroD1 in C2C12 myoblast cells amplified the production of reactive oxygen species which ultimately resulted in increased mitochondrial fission. Proteomic and metabolomic profiling showed that loss of MacroD1 re-routed metabolite flux from glucose to the pentose-phosphate cycle instead of the tricarboxylic acid cycle to support the production of antioxidants, including glutathione and NADPH. This resulted in increased glucose uptake and dependency both in vitro and in vivo. Hence, our research establishes MacroD1 as a regulator of metabolic homeostasis, which ensures the coordination of cellular carbohydrate flux and optimal mitochondrial function.
    DOI:  https://doi.org/10.1038/s41467-025-62410-9
  8. Cell. 2025 Aug 07. pii: S0092-8674(25)00811-6. [Epub ahead of print]
    Principles of cotranslational mitochondrial protein import.
    Zikun Zhu, Saurav Mallik, Taylor A Stevens, Riming Huang, Emmanuel D Levy, Shu-Ou Shan.
      Nearly all mitochondrial proteins are translated on cytosolic ribosomes. How these proteins are subsequently delivered to mitochondria remains poorly understood. Using selective ribosome profiling, we show that nearly 20% of mitochondrial proteins can be imported cotranslationally in human cells. Cotranslational import requires an N-terminal presequence on the nascent protein and contributes to localized translation at the mitochondrial surface. This pathway does not favor membrane proteins but instead prioritizes large, multi-domain, topologically complex proteins, whose import efficiency is enhanced when targeted cotranslationally. In contrast to the early onset of cotranslational protein targeting to the endoplasmic reticulum (ER), the presequence on mitochondrial proteins is inhibited from initiating targeting early during translation until a large globular domain emerges from the ribosome. Our findings reveal a multi-layered protein sorting strategy that controls the timing and specificity of mitochondrial protein targeting.
    Keywords:  NAC; TOM complex; cotranslational protein import; localized translation; mitochondria; mitochondrial targeting sequence; nascent polypeptide-associated complex; protein folding; protein targeting; ribosome profiling
    DOI:  https://doi.org/10.1016/j.cell.2025.07.021
  9. Mol Pharm. 2025 Aug 15.
    Mitochondrially Targeted p53-Bad* Fusion Gene Therapy Promotes Apoptosis in Hepatocellular Carcinoma by Pan-Bcl-2 Inhibition.
    Braxten D Hornsby, Julius K K Tuekpe, Cassidy A Steele, Amber A Devereaux, Katherine E Redd Bowman, Carol S Lim.
      Presenting a considerable disease burden and global health threat, hepatocellular carcinoma (HCC) is in desperate need of potent and effective therapies. p53-Bad* is designed to provide mitochondrial targeting, enhance binding interactions with antiapoptotic Bcl-2 family members, and improve apoptotic activity in various cancers. While we have shown that fusion of p53 and Bad* improves mitochondrial localization and increases apoptosis in HCC, critically, the mechanism of action and nature of this heightened apoptotic function have not been delineated. Here, the functional activity and apoptotic mechanism of action of our p53-Bad* construct was explored, demonstrating that fusion of pro-apoptotic Bad* to p53 does indeed enhance interactions with antiapoptotic Bcl-2 family members Mcl-1, Bcl-2, and Bcl-xL relative to p53-WT. We confirm that p53-Bad* acts as a pro-apoptotic agent specifically at the mitochondria by inhibition and blockade of downstream Bak/Bax oligomerization events, rescuing cells from p53-Bad*-induced cytotoxicity and apoptosis. Using mutant p53-Bad* variants designed to disrupt binding interactions with antiapoptotic targets, a direct relationship between functional binding interactions and the apoptotic activity of p53-Bad* is established. These findings present strong evidence for the use of p53-Bad* as a pan-Bcl-2 inhibitor and synergistic pro-apoptotic agent in cancers with upregulation of multiple antiapoptotic and prognostic markers.
    Keywords:  Bcl-2 Antagonist of Cell Death; Liver Cancer; Mitochondrial Apoptosis; Tumor Suppressor p53; p53-Bad*
    DOI:  https://doi.org/10.1021/acs.molpharmaceut.5c00773
  10. Cell Rep. 2025 Aug 12. pii: S2211-1247(25)00918-0. [Epub ahead of print]44(8): 116147
    SUCLG1 deficiency-induced histone succinylation impairs oncogene expression in acute myeloid leukemia.
    Mengqing Gao, Minhui Shi, Hao Ding, Lei Xu, Na Zhao, Li Wang, Shujuan Huang, Hui Jiang, Ekaterina Bourova-Flin, Jianqing Mi, Saadi Khochbin, Domenico Iuso, Xiaoyu Zhu.
      Mitochondria-driven histone lysine succinylation is emerging as a critical signaling system that links cellular metabolism to the pathogenesis of diseases, including cancer. Here, we report that a global increase in protein/histone succinylation is associated with mitochondrial tricarboxylic acid cycle defects in acute myeloid leukemia (AML). Depletion of the succinyl-coenzyme A (CoA) synthetase alpha subunit SUCLG1 causes protein/histone hypersuccinylation in leukemia cells, which impairs cell proliferation and leukemia progression in xenograft models. Mechanistically, increased histone succinylation, which could compete with acetylation, attenuates the interaction of the bromodomain-containing protein 4 (BRD4) bromodomain with chromatin, hence disrupting BRD4-mediated leukemogenic gene transcription and restoring BRD4-dependent fine-tuned gene regulatory circuits. Our study uncovers the crucial role of metabolism-controlled histone succinylation in cancer development and highlights it as an innovative therapeutic approach.
    Keywords:  BRD4; CP: Cancer; CP: Metabolism; SUCLG1; acute myeloid leukemia; histone succinylation
    DOI:  https://doi.org/10.1016/j.celrep.2025.116147
  11. Blood. 2025 Aug 14. pii: blood.2025028985. [Epub ahead of print]
    Venetoclax plus gilteritinib is effective in preclinical models of FLT3-mutant BCL11B-a lineage-ambiguous leukemia.
    Lindsey E Montefiori, Ilaria Iacobucci, Qingsong Gao, Jamila Moore, William C Wright, Huimei Wei, Pradyumna Baviskar, Surbhi Sona, Hongjian Jin, Amit Budhraja, Josi Lott, Qi Zhang Tatarata, Zhongshan Cheng, Tanya M Khan, Emily A Backhaus, Melissa D Johnson, Cyrus M Mehr, Burgess B Freeman, Laura J Janke, Torsten Haferlach, Paul Geeleher, Paul E Mead, Marina Y Konopleva, Joseph T Opferman, Charles G Mullighan.
      Aberrant activation of BCL11B ("BCL11B-a") defines a subtype of lineage ambiguous leukemias with T-lymphoid and myeloid features, co-occurring activating FLT3 mutations, and a stem/progenitor immunophenotype and gene expression profile. As with other lineage ambiguous leukemias, optimal treatment is unclear and there are limited targeted therapeutic options. Here, we investigated the efficacy of BCL-2 and FLT3 inhibition with venetoclax and gilteritinib, respectively, in preclinical models of BCL11B-a leukemia. Despite variation in response to single agent therapies, the combination of venetoclax plus gilteritinib (VenGilt) was highly effective in all models evaluated. BH3 profiling suggested that resistance to venetoclax monotherapy was due to the tumor-intrinsic dependence on additional BCL-2 family proteins prior to drug treatment. Longitudinal single cell RNA-seq analysis identified mitochondrial pathways and a pro-lymphoid gene expression signature as potential drivers of rare cell survival on VenGilt therapy. These data support clinical evaluation of venetoclax in combination with gilteritinib in BCL11B-a lineage ambiguous leukemias.
    DOI:  https://doi.org/10.1182/blood.2025028985
  12. Cell Death Dis. 2025 Aug 13. 16(1): 616
    The ALDH2/PolG2 axis enhances mitochondrial biogenesis via transcriptional regulation of Nrf2 and promotes chemotherapy resistance in acute myeloid leukaemia.
    Xiuying Hu, Tianzhen Hu, Shuyun Cao, Li Jiang, Yan Zhou, Qin Fang, Jishi Wang.
      Although patients with acute myeloid leukaemia (AML) initially respond to conventional treatments, many patients die from AML progression and relapsed/refractory (RR) disease. Eradicating AML thus remains therapeutically challenging. In this study, we found a strong expression of aldehyde dehydrogenase 2 (ALDH2) and increased mitochondrial biosynthesis in samples from patients with drug-resistant AML, and these changes were strongly associated with poor prognosis and recurrence of AML. We examined the clonogenic capacity, growth and apoptosis of AML cells, as well as mitochondrial DNA expression and reactive oxygen species production. Our results revealed that chemotherapeutic agents triggered the activation of NF-E2-related factor 2 (Nrf2) and promoted high expression of ALDH2, mediating the compensatory activation of mitochondrial respiration and resistance to chemotherapeutic agents in RR AML cells. Nrf2 promoted mitochondrial respiration by activating ALDH2 expression and stabilising the expression of DNA polymerase-gamma2 (PolG2) in mitochondria. Inhibition of the Nrf2-ALDH2/PolG2 pathway reduced AML metabolic fitness and oxidative phosphorylation levels, highlighting the key role of this pathway in promoting cell survival. Nrf2 inhibition reduced the translation of ALDH2, induced a unique mitochondrial stress response and inhibited mitochondrial biosynthesis in AML cells. Importantly, tumours in an in vivo xenograft model were sensitive to combined Nrf2 and ALDH2 inhibition. Given the role of the Nrf2-ALDH2/PolG2 pathway in the progression of AML, inhibition of this pathway may prevent disease relapse/resistance and promote sensitisation to chemotherapy.
    DOI:  https://doi.org/10.1038/s41419-025-07927-z
  13. Science. 2025 Aug 14. 389(6761): eadr6326
    Mitochondria protect against an intracellular pathogen by restricting access to folate.
    Tânia Catarina Medeiros, Jana Ovciarikova, Xianhe Li, Patrick Krueger, Tim Bartsch, Silvia Reato, John C Crow, Michelle Tellez Sutterlin, Bruna Martins Garcia, Irina Rais, Kira Allmeroth, Matías D Hartman, Martin S Denzel, Martin Purrio, Andrea Mesaros, Kit-Yi Leung, Nicholas D E Greene, Lilach Sheiner, Patrick Giavalisco, Lena Pernas.
      As major consumers of cellular metabolites, mitochondria are poised to compete with invading microbes for the nutrients that they need to grow. Whether cells exploit mitochondrial metabolism to protect from infection is unclear. In this work, we found that the activating transcription factor 4 (ATF4) activates a mitochondrial defense based on the essential B vitamin folate. During infection of cultured mammalian cells with the intracellular pathogen Toxoplasma gondii, ATF4 increased mitochondrial DNA levels by driving the one-carbon metabolism processes that use folate in mitochondria. Triggered by host detection of mitochondrial stress induced by parasite effectors, ATF4 limited Toxoplasma access to folates required for deoxythymidine monophosphate synthesis, thereby restricting parasite growth. Thus, ATF4 rewires mitochondrial metabolism to mount a folate-based metabolic defense against Toxoplasma.
    DOI:  https://doi.org/10.1126/science.adr6326
  14. bioRxiv. 2025 Jul 18. pii: 2025.07.14.664742. [Epub ahead of print]
    PP2A activation drives aberrant macropinocytosis and cell death in pancreatic ductal adenocarcinoma.
    Garima Baral, Claire M Pfeffer, Sara N Filippelli, Indiraa Doraivel, Brittany N Heil, Lauren E Gartenhaus, Kasi Hansen, Joy Wu, Goutham Narla, Emma H Doud, Amber L Mosley, Shalini T Low-Nam, Brittany L Allen-Petersen.
      Pancreatic cancer is highly aggressive with a five-year survival rate of just 13%. Metabolic rewiring in response to oncogenic signals plays a critical role in pancreatic ductal adenocarcinoma (PDAC) survival, tumor growth, and metastasis. These alterations make PDAC tumors dependent on anabolic metabolism for survival, highlighting a unique vulnerability that can be therapeutically exploited. However, during nutrient deprivation, PDAC cells can circumvent this vulnerability by engulfing extracellular fluids to replenish amino acids in a process called, macropinocytosis. This process can be induced downstream of oncogenic KRAS expression, a small GTPase that is almost universally mutated in PDAC patients. The inhibition of macropinocytosis in vivo reduces PDAC tumor growth, emphasizing the importance of this pathway to cancer cell survival. However, the signaling mechanisms that regulate this process remain poorly understood. Protein phosphatase 2A (PP2A) is a heterotrimeric complex that regulates a wide variety of cell signaling pathways, including KRAS, and is commonly dysregulated in human PDAC tumors. Here, we show that acute PP2A activation prevents macropinosome processing leading to cell death. Furthermore, we demonstrate that PP2A posttranslationally regulates the lipid kinase, PIKfyve, a key regulator of macropinosome-lysosome fusion. Finally, we determine that PP2A activating compounds can function synergistically with metabolic inhibitors, supporting a new therapeutic strategy in this aggressive and deadly cancer. Together, our results implicate PP2A as a critical suppressor of PDAC metabolic plasticity and highlight the use of PP2A activating compounds to prevent PDAC nutrient scavenging.
    DOI:  https://doi.org/10.1101/2025.07.14.664742
  15. Cell Death Discov. 2025 Aug 13. 11(1): 379
    Comprehensive view on chemotherapy-free management of acute myeloid leukemia by using venetoclax in combination with targeted and/or immune therapies.
    David Kegyes, Andrei Tat, Alin Stefan Vizitiu, Daiana Vazar-Tripon, Radu Ilie, Adrian Bogdan Tigu, Diana Cenariu, Anamaria Bancos, Sabina Iluta, Ciprian Jitaru, Madalina Nistor, Radu Tomai, Diana Gulei, Mihnea Zdrenghea, Hermann Einsele, Gabriel Ghiaur, Carlo M Croce, Ciprian Tomuleasa.
      A hallmark of cancer biology is resistance to apoptosis. BCL-2 is an anti-apoptotic molecule that is being overexpressed in several myeloid diseases, such as acute myeloid leukemia and myelodysplastic syndromes, but also in several lymphoid cancers, such as acute lymphoblastic leukemia, chronic lymphocytic leukemia, non-Hodgkin lymphomas and multiple myeloma. Venetoclax (VEN) is a BCL-2 small molecule inhibitor. Data about its structure, biochemical characteristics and in vitro efficacy against several blood cancer cell lines were first reported in 2013. Shortly after, the first clinical trials reported that single-agent VEN provides no long-term survival benefits. In contrast, when used in combination, VEN led to significantly improved outcomes and eventually to its first US FDA approvals in 2018. As the modern approach to treating hematological malignancies are the chemotherapy-free regimen, in the current manuscript, we provide a comprehensive view on all available therapies that are considered to be chemotherapy-free, with a special emphasis on acute myeloid leukemia (AML), where phase I-III clinical trials have provided the most data.
    DOI:  https://doi.org/10.1038/s41420-025-02678-4
  16. Nat Metab. 2025 Aug 12.
    D-cysteine impairs tumour growth by inhibiting cysteine desulfurase NFS1.
    Joséphine Zangari, Oliver Stehling, Sven A Freibert, Kaushik Bhattacharya, Florian Rouaud, Veronique Serre-Beinier, Kinsey Maundrell, Sylvie Montessuit, Sabrina Myriam Ferre, Evangelia Vartholomaiou, Vinzent Schulz, Karim Zuhra, Víctor González-Ruiz, Sahra Hanschke, Takashi Tsukamoto, Michaël Cerezo, Csaba Szabo, Serge Rudaz, Michal T Boniecki, Miroslaw Cygler, Roland Lill, Jean-Claude Martinou.
      Selective targeting of cancer cells is a major challenge for cancer therapy. Many cancer cells overexpress the cystine/glutamate antiporter xCT/CD98, an L-cystine transport system that strengthens antioxidant defences, thereby promoting tumour survival and progression. Here, we show that the D-enantiomer of cysteine (D-Cys) is selectively imported into xCT/CD98-overexpressing cancer cell lines and impairs their proliferation, particularly under high oxygen concentrations. Intracellular D-Cys specifically inhibits the mitochondrial cysteine desulfurase NFS1, a key enzyme of cellular iron-sulfur protein biogenesis, by blocking sulfur mobilization due to steric constraints. NFS1 inhibition by D-Cys affects all cellular iron-sulfur cluster-dependent functions, including mitochondrial respiration, nucleotide metabolism and maintenance of genome integrity, leading to decreased oxygen consumption, DNA damage and cell cycle arrest. D-Cys administration diminishes tumour growth of human triple-negative breast cancer cells implanted orthotopically into the mouse mammary gland. Hence, D-Cys could represent a simple therapy to selectively target those forms of cancer characterized by overexpression of xCT/CD98.
    DOI:  https://doi.org/10.1038/s42255-025-01339-1
  17. Blood Adv. 2025 Aug 12. pii: bloodadvances.2025015806. [Epub ahead of print]
    Overcoming venetoclax resistance through heme-mediated NOXA/cyclin D1/Mcl-1 axis with a novel artemisinin conjugate.
    Jingyi Zhang, Zhenwei Zhang, Jinghua Liu, Shenglin Luan, Jiqiang Qu, Zi Wu, Yafei Kuang, Ping Gong, Yu Bao, Yuetong Wang, Xiaojing Yan, Samuel Waxman, Linxiang Zhao, Yongkui Jing.
      The Bcl-2 inhibitor venetoclax remains the sole apoptosis-inducing agent approved for combination therapy in elderly patients with acute myeloid leukemia (AML). However, its clinical efficacy is frequently constrained by the emergence of drug resistance, which involves the overexpression or induction of Mcl-1 and Bcl-xL proteins. To address this challenge, we developed a novel strategy to enhance venetoclax activity and overcome resistance by producing NOXA through the conjugation of dihydroartemisinin (DHA) to venetoclax using a chemical synthesis approach. The resulting conjugate, A1, retains potent Bcl-2 inhibitory activity and significantly enhances NOXA production by promoting interactions between the DHA-derived endoperoxide bridge and heme. Mechanistically, A1 effectively overcomes resistance caused by Mcl-1 and Bcl-xL protein through NOXA-mediated Mcl-1 and cyclin D1 protein degradation, respectively. Optimization of the linker design of A1 yielded PEG-linked conjugates with increased in vivo efficacy. This study introduces a new generation of venetoclax-based compounds with dual functionality: enhanced NOXA production and robust degradation of anti-apoptotic and cell-cycle-regulating proteins. Furthermore, we uncover a promising therapeutic strategy to overcome drug resistance in venetoclax-based AML treatments.
    DOI:  https://doi.org/10.1182/bloodadvances.2025015806
  18. Int J Mol Sci. 2025 Aug 07. pii: 7654. [Epub ahead of print]26(15):
    The Loss of Complex I in Renal Oncocytoma Is Associated with Defective Mitophagy Due to Lysosomal Dysfunction.
    Lin Lin, Neal Patel, Lucia Fernandez-Del-Rio, Cristiane Benica, Blake Wilde, Eirini Christodoulou, Shinji Ohtake, Anhyo Jeong, Aboubacar Kaba, Nedas Matulionis, Randy Caliliw, Xiaowu Gai, Heather Christofk, David Shackelford, Brian Shuch.
      Renal oncocytoma (RO) is a benign renal neoplasm characterized by dense accumulation of dysfunctional mitochondria possibly resulting from increased mitochondrial biogenesis and decreased mitophagy; however, the mechanisms controlling these mitochondrial changes are unclear. ROs harbor recurrent inactivating mutations in mitochondrial genes encoding the Electron Transport Chain (ETC) Complex I, and we hypothesize that Complex I loss in ROs directly impairs mitophagy. Our analysis of ROs and normal kidney (NK) tissues shows that a significant portion (8 out of 17) of ROs have mtDNA Complex I loss-of-function mutations with high variant allele frequency (>50%). ROs indeed exhibit reduced Complex I expression and activity. Analysis of the various steps of mitophagy pathway demonstrates that AMPK activation in ROs leads to induction of mitochondrial biogenesis, autophagy, and formation of autophagosomes. However, the subsequent steps involving lysosome biogenesis and function are defective, resulting in an overall inhibition of mitophagy. Inhibiting Complex I in a normal kidney cell line recapitulated the observed lysosomal and mitophagy defects. Our data suggest Complex I loss in RO results in defective mitophagy due to lysosomal loss and dysfunction.
    Keywords:  autophagy/mitophagy; complex I; lysosome; metabolism; mitochondrial dysfunction; renal oncocytoma
    DOI:  https://doi.org/10.3390/ijms26157654
  19. Int J Mol Sci. 2025 Jul 31. pii: 7400. [Epub ahead of print]26(15):
    Mitochondrial Metabolism in T-Cell Exhaustion.
    Fei Li, Yu Feng, Zesheng Yin, Yahong Wang.
      T cells play a vital role in resisting pathogen invasion and maintaining immune homeostasis. However, T cells gradually become exhausted under chronic antigenic stimulation, and this exhaustion is closely related to mitochondrial dysfunction in T cells. Mitochondria play a crucial role in the metabolic reprogramming of T cells to achieve the desired immune response. Here, we compiled the latest research on how mitochondrial metabolism determines T cell function and differentiation, with the mechanisms mainly including mitochondrial biogenesis, fission, fusion, mitophagy, and mitochondrial transfer. In addition, the alterations in mitochondrial metabolism in T-cell exhaustion were also reviewed. Furthermore, we discussed intervention strategies targeting mitochondrial metabolism to reverse T cell exhaustion in detail, including inducing PGC-1α expression, alleviating reactive oxygen species (ROS) production or hypoxia, enhancing ATP production, and utilizing mitochondrial transfer. Targeting mitochondrial metabolism in exhausted T cells may achieve the goal of reversing and preventing T cell exhaustion.
    Keywords:  T-cell exhaustion; metabolic reprogramming; metabolism; mitochondria; mitochondrial dynamics
    DOI:  https://doi.org/10.3390/ijms26157400
  20. Cell Death Dis. 2025 Aug 12. 16(1): 611
    Cathepsin D promotes acute myeloid leukemia progression through stabilization of the anti-apoptotic proteins.
    Huimin Jiang, Yongjian Wang, Churan Wang, Lu Yang, Shujuan Wang, Feng Wang, Situ Xue, Zhuan Zhang, Haigen Fu, Ting Dong, Jian Yuan, Zhuorong Li, Ke Li.
      Cathepsin D (CTSD) is a lysosomal aspartic protease that plays vital roles in regulating the properties of solid tumors, including proliferation, apoptosis, migration, metastasis, and angiogenesis. However, the function of CTSD in haematological malignancies remains largely elusive. Here we show that CTSD is highly expressed in acute myeloid leukemia (AML) and that high CTSD expression is associated with unfavourable prognosis. Knockdown of CTSD in AML cells inhibits cell proliferation and anti-apoptotic activity. Mechanistically, CTSD decreased the expression of the E3 ubiquitin ligase TRIM21, which mediates the ubiquitination and degradation of anti-apoptotic proteins BCL2, BCL-XL, and MCL1. Inhibition of CTSD expression via genetics or the small-molecule inhibitor N-8 decreases the protein levels of BCL2, BCL-XL, and MCL1 through accelerating their degradation. N-8 shows significant efficacy in eradicating AML in both venetoclax-sensitive and -resistant models. Collectively, our study reveals the role of CTSD in leukemia progression and highlights targeting CTSD as a potential therapeutic strategy in AML.
    DOI:  https://doi.org/10.1038/s41419-025-07949-7
  21. Redox Biol. 2025 Aug 12. pii: S2213-2317(25)00325-8. [Epub ahead of print]86 103812
    ROS-dependent localization of glycolytic enzymes to mitochondria.
    Pau B Esparza-Moltó, Arvind V Goswami, Süleyman Bozkurt, Christian Münch, Laura E Newman, Alexandra G Moyzis, Gladys R Rojas, Deann Guan, Jeffrey R Jones, Fred H Gage, Gerald S Shadel.
      Mitochondrial reactive oxygen species (mtROS) regulate cellular signaling pathways, but also cause oxidative stress when de-regulated during aging and pathological conditions such as neurodegenerative diseases. The dynamic redistribution of proteins between cellular compartments is a common mechanism to control their stability and biological activities. By targeting the BirA∗ biotin ligase to the outer mitochondrial membrane in HEK293 cells, we identified proteins whose labeling increased or decreased in response to treatment with menadione, consistent with a dynamic change in their mitochondrial localization in response to increased mtROS production. These proteins represent potential candidates for future studies of mitochondrial oxidative stress signaling. A subset of glycolytic enzymes was found in this screen and confirmed, by mitochondrial fractionation and imaging, to increase localization to mitochondria in response to menadione, despite no change in their overall abundance. Submitochondrial fractionation studies are consistent with import of a pool of these enzymes to the mitochondrial intermembrane space. Localization of glycolytic enzymes to mitochondria was also increased in cells grown under hypoxia or that express a mitochondria-targeted d-amino-acid oxidase (conditions that induce increased mtROS production), and inhibited basally under normal growth conditions by the mitochondrial antioxidant MnTBAP. Finally, primary Alzheimer's disease fibroblasts also had glycolytic enzymes associated with mitochondria that was reduced by antioxidants, consistent with increased mtROS altering their relative distribution between the cytoplasm and mitochondria. We speculate that the increased mitochondrial localization of glycolytic enzymes is an adaptive response to mtROS that alters glucose flux toward the antioxidant pentose phosphate pathway, creates distinct regulatory pools of mitochondrial metabolites or new metabolic circuits, and/or provides cytoprotection or other adaptive responses via moonlighting functions unrelated to their enzymatic activity.
    Keywords:  Alzheimer's disease; Glycolytic enzymes; Mitochondria; Proximity labeling; Reactive oxygen species; Stress signaling
    DOI:  https://doi.org/10.1016/j.redox.2025.103812
  22. Immunity. 2025 Aug 09. pii: S1074-7613(25)00326-7. [Epub ahead of print]
    Succinate preserves CD8+ T cell fitness to augment antitumor immunity.
    Kaili Ma, Hongcheng Cheng, Lin Wang, Han Xiao, Fenghua Liu, Yu Yang, Zhen Xiao, Kun Tang, Shicheng Li, Gang Wang, Minmin Ge, Jiajia Wang, Xiaowei Liu, Hai-Xi Sun, Ziyi Luo, Zhimin Gu, Ping-Chih Ho, Guideng Li, Lianjun Zhang.
      Succinate, a tricarboxylic acid cycle intermediate, accumulates in tumors with succinate dehydrogenase (SDH) mutations. Although succinate is recognized for modulating CD8+ T cell cytotoxicity, its impact on T cell differentiation remains poorly understood. Here, we reveal that succinate accumulation in tumors lacking the SDH subunit B (SDHB) enhanced tumor-reactive CD8+ T cell-mediated immune responses. Sustained succinate exposure promoted CD8+ T cell survival and facilitated the generation and maintenance of stem-like subpopulations. Mechanistically, succinate enhanced mitochondrial fitness through Bcl-2/adenovirus E1B 19 kDa-interacting protein 3 (BNIP3)-mediated mitophagy and also promoted stemness-associated gene expression via epigenetic modulation. Succinate-conditioned CD8+ T cells displayed superior long-term persistence and tumor control capacity. Moreover, succinate enrichment signature correlates with favorable clinical outcomes in certain melanoma and gastric cancer patients receiving immune checkpoint blockade therapy. These findings reveal how succinate preserves T cell stemness and highlight the therapeutic potential of succinate supplementation for enhancing T cell immunotherapy efficacy.
    Keywords:  SDHB-deficient tumor; T cell stemness; TCF-1; antitumor immune response; epigenetic reprogramming; exhaustion; immune checkpoint blockade; mitochondrial fitness; mitophagy; succinate
    DOI:  https://doi.org/10.1016/j.immuni.2025.07.017
This page is being maintained by Thomas Krichel. It was last updated on 2025‒08‒17 at 3:18.