bims-mibica Biomed News
on Mitochondrial bioenergetics in cancer
Issue of 2025–03–23
twenty-one papers selected by
Kelsey Fisher-Wellman, Wake Forest University
  1. Lactate dehydrogenase A-coupled NAD+ regeneration is critical for acute myeloid leukemia cell survival.
  2. Horizontal mitochondrial transfer in cancer biology: Potential clinical relevance.
  3. Developmental mitochondrial complex I activity determines lifespan.
  4. Mitochondrial reactive oxygen species regulate acetyl-CoA flux between cytokine production and fatty acid synthesis in effector T cells.
  5. Unspliced XBP1 enhences metabolic reprogramming in colorectal cancer cells by interfering with the mitochondrial localization of MGME1.
  6. In-cell architecture of the mitochondrial respiratory chain.
  7. A splendid molecular factory: De- and reconstruction of the mammalian respiratory chain.
  8. A metabolic shift to the serine pathway induced by lipids fosters epigenetic reprogramming in nontransformed breast cells.
  9. Advances in mitophagy initiation mechanisms.
  10. Selective and iron-independent ferroptosis in cancer cells induced by manipulation of mitochondrial fatty acid oxidation.
  11. Mitochondrial fission - changing perspectives for future progress.
  12. Pak1 dysregulates Pyruvate metabolism in PDAC cells by exerting a phosphorylation-mediated regulatory effect on PDHA1.
  13. Acute diacylglycerol production activates critical membrane-shaping proteins leading to mitochondrial tubulation and fission.
  14. Pyruvate metabolism enzyme DLAT promotes tumorigenesis by suppressing leucine catabolism.
  15. DNA damage response regulator ATR licenses PINK1-mediated mitophagy.
  16. Hierarchical Lineage Tracing Reveals Diverse Pathways of AML Treatment Resistance.
  17. VDAC2 loss elicits tumour destruction and inflammation for cancer therapy.
  18. Mitoxantrone-liposome Sensitizes FLT3-ITD Acute Myeloid Leukemia to Gilteritinib Treatment.
  19. β-hydroxybutyrate facilitates mitochondrial-derived vesicle biogenesis and improves mitochondrial functions.
  20. Mutations that accrue through life set the stage for stomach cancer.
  21. Ubiquinol-mediated suppression of mitochondria-associated ferroptosis is a targetable function of lactate dehydrogenase B in cancer.
  1. bioRxiv. 2025 Mar 07. pii: 2025.03.03.641255. [Epub ahead of print]
    Lactate dehydrogenase A-coupled NAD+ regeneration is critical for acute myeloid leukemia cell survival.
    Ayşegül Erdem, Séléna Kaye, Francesco Caligiore, Manuel Johanns, Fleur Leguay, Jan Jacob Schuringa, Keisuke Ito, Guido Bommer, Nick van Gastel.
      Enhanced glycolysis plays a pivotal role in fueling the aberrant proliferation, survival and therapy resistance of acute myeloid leukemia (AML) cells. Here, we aimed to elucidate the extent of glycolysis dependence in AML by focusing on the role of lactate dehydrogenase A (LDHA), a key glycolytic enzyme converting pyruvate to lactate coupled with the recycling of NAD+. We compared the glycolytic activity of primary AML patient samples to protein levels of metabolic enzymes involved in central carbon metabolism including glycolysis, glutaminolysis and the tricarboxylic acid cycle. To evaluate the therapeutic potential of targeting glycolysis in AML, we treated AML primary patient samples and cell lines with pharmacological inhibitors of LDHA and monitored cell viability. Glycolytic activity and mitochondrial oxygen consumption were analyzed in AML patient samples and cell lines post-LDHA inhibition. Perturbations in global metabolite levels and redox balance upon LDHA inhibition in AML cells were determined by mass spectrometry, and ROS levels were measured by flow cytometry. Among metabolic enzymes, we found that LDHA protein levels had the strongest positive correlation with glycolysis in AML patient cells. Blocking LDHA activity resulted in a strong growth inhibition and cell death induction in AML cell lines and primary patient samples, while healthy hematopoietic stem and progenitor cells remained unaffected. Investigation of the underlying mechanisms showed that LDHA inhibition reduces glycolytic activity, lowers levels of glycolytic intermediates, decreases the cellular NAD+ pool, boosts OXPHOS activity and increases ROS levels. This increase in ROS levels was however not linked to the observed AML cell death. Instead, we found that LDHA is essential to maintain a correct NAD+/NADH ratio in AML cells. Continuous intracellular NAD+ supplementation via overexpression of water-forming NADH oxidase from Lactobacillus brevis in AML cells effectively increased viable cell counts and prevented cell death upon LDHA inhibition. Collectively, our results demonstrate that AML cells critically depend on LDHA to maintain an adequate NAD+/NADH balance in support of their abnormal glycolytic activity and biosynthetic demands, which cannot be compensated for by other cellular NAD+ recycling systems. These findings also highlight LDHA inhibition as a promising metabolic strategy to eradicate leukemic cells.
    DOI:  https://doi.org/10.1101/2025.03.03.641255
  2. Cancer Cell. 2025 Mar 18. pii: S1535-6108(25)00081-9. [Epub ahead of print]
    Horizontal mitochondrial transfer in cancer biology: Potential clinical relevance.
    Michael V Berridge, Renata Zobalova, Stepana Boukalova, Andrés Caicedo, Stuart A Rushworth, Jiri Neuzil.
      Recent research highlights horizontal mitochondrial transfer as a key biological phenomenon linked to cancer onset and progression. The transfer of mitochondria and their genomes between cancer and non-cancer cells shifts our understanding of intercellular gene trafficking, increasing the metabolic fitness of cancer cells and modulating antitumor immune responses. This process not only facilitates tumor progression but also presents potential therapeutic opportunities.
    DOI:  https://doi.org/10.1016/j.ccell.2025.03.002
  3. EMBO Rep. 2025 Mar 17.
    Developmental mitochondrial complex I activity determines lifespan.
    Rhoda Stefanatos, Fiona Robertson, Beatriz Castejon-Vega, Yizhou Yu, Alejandro Huerta Uribe, Kevin Myers, Tetsushi Kataura, Viktor I Korolchuk, Oliver D K Maddocks, L Miguel Martins, Alberto Sanz.
      Aberrant mitochondrial function has been associated with an increasingly large number of human disease states. Observations from in vivo models where mitochondrial function is altered suggest that maladaptations to mitochondrial dysfunction may underpin disease pathology. We hypothesized that the severity of this maladaptation could be shaped by the plasticity of the system when mitochondrial dysfunction manifests. To investigate this, we have used inducible fly models of mitochondrial complex I (CI) dysfunction to reduce mitochondrial function at two stages of the fly lifecycle, from early development and adult eclosion. Here, we show that in early life (developmental) mitochondrial dysfunction results in severe reductions in survival and stress resistance in adulthood, while flies where mitochondrial function is perturbed from adulthood, are long-lived and stress resistant despite having up to a 75% reduction in CI activity. After excluding developmental defects as a cause, we went on to molecularly characterize these two populations of mitochondrially compromised flies, short- and long-lived. We find that our short-lived flies have unique transcriptomic, proteomic and metabolomic responses, which overlap significantly in discrete models of CI dysfunction. Our data demonstrate that early mitochondrial dysfunction via CI depletion elicits a maladaptive response, which severely reduces survival, while CI depletion from adulthood is insufficient to reduce survival and stress resistance.
    Keywords:  Ageing; Complex I; Drosophila; Mitochondria; Mitochondrial Disease
    DOI:  https://doi.org/10.1038/s44319-025-00416-6
  4. Cell Rep. 2025 Mar 13. pii: S2211-1247(25)00201-3. [Epub ahead of print]44(3): 115430
    Mitochondrial reactive oxygen species regulate acetyl-CoA flux between cytokine production and fatty acid synthesis in effector T cells.
    Beibei Wu, Jin Seok Woo, Spyridon Hasiakos, Calvin Pan, Shawn Cokus, Cristiane Benincá, Linsey Stiles, Zuoming Sun, Matteo Pellegrini, Orian S Shirihai, Aldon J Lusis, Sonal Srikanth, Yousang Gwack.
      Genetic and environmental factors shape an individual's susceptibility to autoimmunity. To identify genetic variations regulating effector T cell functions, we used a forward genetics screen of inbred mouse strains and uncovered genomic loci linked to cytokine expression. Among the candidate genes, we characterized a mitochondrial inner membrane protein, TMEM11, as an important determinant of Th1 responses. Loss of TMEM11 selectively impairs Th1 cell functions, reducing autoimmune symptoms in mice. Mechanistically, Tmem11-/- Th1 cells exhibit altered cristae architecture, impaired respiration, and increased mitochondrial reactive oxygen species (mtROS) production. Elevated mtROS hindered histone acetylation while promoting neutral lipid accumulation. Further experiments using genetic, biochemical, and pharmacological tools revealed that mtROS regulate acetyl-CoA flux between histone acetylation and fatty acid synthesis. Our findings highlight the role of mitochondrial cristae integrity in directing metabolic pathways that influence chromatin modifications and lipid biosynthesis in Th1 cells, providing new insights into immune cell metabolism.
    Keywords:  CP: Immunology; CP: Metabolism; EAE; MICOS complex; Th1 cells; cytokine production; histone acetylation; mitochondria; mitochondrial cristae architecture; neutral lipids; reactive oxygen species
    DOI:  https://doi.org/10.1016/j.celrep.2025.115430
  5. Biochem Biophys Res Commun. 2025 Mar 11. pii: S0006-291X(25)00327-4. [Epub ahead of print]757 151613
    Unspliced XBP1 enhences metabolic reprogramming in colorectal cancer cells by interfering with the mitochondrial localization of MGME1.
    Jiandong Zhang, Suyang Zhang, Fei Yu, Yuting Wan, Mingyue Wu, Can Huang.
      Tumor cells undergo metabolic reprogramming, which makes them tend to utilize anaerobic glycolysis rather than oxidation to rapidly produce energy and intermediate products required for proliferation. In this process, mitochondria inevitably undergo corresponding alterations; however, the specific alterations in mitochondria across different cancer types and the mechanisms governing these changes remain poorly understood. This study demonstrated that unspliced X-box binding protein 1 (XBP1-u) inhibits the translocation of mitochondrial genome maintenance exonuclease 1 (MGME1) into mitochondria by binding to the mitochondrial targeting sequence (MTS) of MGME1. This interaction results in the accumulation of mitochondrial 7sDNA, a reduction in mitochondrial DNA copy number, and a decrease in mitochondrial abundance. Consequently, this shift enhances the production of glycolysis and pentose phosphate pathway intermediates, thereby promoting the proliferation of colorectal cancer (CRC) cells. Our findings elucidated the critical mechanism by which XBP1-u enhances metabolic reprogramming by modulating mitochondrial biogenesis, and uncovered a novel role of MGME1 in the progression of CRC.
    Keywords:  MGME1; Metabolic reprogramming; Mitochondrial number; Warburg effect; XBP1-u
    DOI:  https://doi.org/10.1016/j.bbrc.2025.151613
  6. Science. 2025 Mar 21. 387(6740): 1296-1301
    In-cell architecture of the mitochondrial respiratory chain.
    Florent Waltz, Ricardo D Righetto, Lorenz Lamm, Thalia Salinas-Giegé, Ron Kelley, Xianjun Zhang, Martin Obr, Sagar Khavnekar, Abhay Kotecha, Benjamin D Engel.
      Mitochondria regenerate adenosine triphosphate (ATP) through oxidative phosphorylation. This process is carried out by five membrane-bound complexes collectively known as the respiratory chain, working in concert to transfer electrons and pump protons. The precise organization of these complexes in native cells is debated. We used in situ cryo-electron tomography to visualize the native structures and organization of several major mitochondrial complexes in Chlamydomonas reinhardtii cells. ATP synthases and respiratory complexes segregate into curved and flat crista membrane domains, respectively. Respiratory complexes I, III, and IV assemble into a respirasome supercomplex, from which we determined a native 5-angstrom (Å) resolution structure showing binding of electron carrier cytochrome c. Combined with single-particle cryo-electron microscopy at 2.4-Å resolution, we model how the respiratory complexes organize inside native mitochondria.
    DOI:  https://doi.org/10.1126/science.ads8738
  7. Proc Natl Acad Sci U S A. 2025 Mar 25. 122(12): e2416162122
    A splendid molecular factory: De- and reconstruction of the mammalian respiratory chain.
    Lukas Rimle, Ben P Phillips, Isabela M Codo Costa Barra, Noëlle Arnold, Charlie Hennebert, Thomas Meier, Christoph von Ballmoos.
      Mitochondrial respiratory complexes I to IV and the F1Fo-ATP synthase (complex V) are large protein assemblies producing the universal cellular energy currency adenosine triphosphate (ATP). Individual complexes have been extensively studied in vitro, but functional co-reconstitution of several mammalian complexes into proteoliposomes, in particular, the combination of a primary pump with the ATP synthase, is less well understood. Here, we present a generic and scalable strategy to purify mammalian respiratory complexes I, III and the ATP synthase from enriched mitochondria in enzymatically fully active form, and procedures to reassemble the complexes into liposomes. A robust functionality can be shown by in situ monitoring of ATP synthesis rates and by using selected inhibitors of the respiratory chain complexes. By inclusion of cytochrome c oxidase, our procedures allowed us to reconstruct the entire mitochondrial respiratory chain (complexes I, III, IV, and V) in ubiquinone Q10 containing liposomes, demonstrating oxidative phosphorylation by nicotinamide adenine dinucleotide hydrogen driven ATP synthesis. The system was fully coupled at all levels and was used to probe cardiolipin as an essential component to activate the mammalian respiratory chain. Structural characterization using electron cryomicroscopy allowed us to resolve apo-state complex III and complex V at high and medium resolution, respectively, using in silico particle sorting, confirming the presence of all protein subunits and cofactors in native stoichiometry and conformation. The reported findings will facilitate future endeavors to characterize or modulate these key bioenergetic processes.
    Keywords:  artificial ATP production; cryo-EM; mitochondria; oxidative phosphorylation; respiratory chain
    DOI:  https://doi.org/10.1073/pnas.2416162122
  8. Sci Adv. 2025 Mar 21. 11(12): eads9182
    A metabolic shift to the serine pathway induced by lipids fosters epigenetic reprogramming in nontransformed breast cells.
    Mariana Bustamante Eduardo, Gannon Cottone, Curtis W McCloskey, Shiyu Liu, Flavio R Palma, Maria Paula Zappia, Abul B M M K Islam, Peng Gao, Joel Setya, Saya Dennis, Hongyu Gao, Qian Zhang, Xiaoling Xuei, Yuan Luo, Jason Locasale, Marcelo G Bonini, Rama Khokha, Maxim V Frolov, Elizaveta V Benevolenskaya, Navdeep S Chandel, Seema A Khan, Susan E Clare.
      Lipid metabolism and the serine, one-carbon, glycine (SOG) and methionine pathways are independently and significantly correlated with estrogen receptor-negative breast cancer (ERneg BC). Here, we propose a link between lipid metabolism and ERneg BC through phosphoglycerate dehydrogenase (PHGDH), the rate-limiting enzyme in the de novo serine pathway. We demonstrate that the metabolism of the paradigmatic medium-chain fatty acid octanoic acid leads to a metabolic shift toward the SOG and methionine pathways. PHGDH plays a role in both the forward direction, contributing to the production of S-adenosylmethionine, and the reverse direction, generating the oncometabolite 2-hydroxyglutarate, leading to epigenomic reprogramming and phenotypic plasticity. The methionine cycle is closely linked to the transsulfuration pathway. Consequently, we observe that the shift increases the antioxidant glutathione, which mitigates reactive oxygen species (ROS), enabling survival of a subset of cells that have undergone DNA damage. These metabolic changes contribute to several hallmarks of cancer.
    DOI:  https://doi.org/10.1126/sciadv.ads9182
  9. Curr Opin Cell Biol. 2025 Mar 20. pii: S0955-0674(25)00031-6. [Epub ahead of print]94 102493
    Advances in mitophagy initiation mechanisms.
    Catharina Küng, Michael Lazarou, Thanh Ngoc Nguyen.
      Mitophagy is an important lysosomal degradative pathway that removes damaged or unwanted mitochondria to maintain cellular and organismal homeostasis. The mechanisms behind how mitophagy is initiated to form autophagosomes around mitochondria have gained a lot of interest since they can be potentially targeted by mitophagy-inducing therapeutics. Mitophagy initiation can be driven by various autophagy receptors or adaptors that respond to different cellular and mitochondrial stimuli, ranging from mitochondrial damage to metabolic rewiring. This review will cover recent advances in our understanding of how mitophagy is initiated, and by doing so reveal the mechanistic plasticity of how autophagosome formation can begin.
    DOI:  https://doi.org/10.1016/j.ceb.2025.102493
  10. Biomaterials. 2025 Mar 14. pii: S0142-9612(25)00178-4. [Epub ahead of print]320 123259
    Selective and iron-independent ferroptosis in cancer cells induced by manipulation of mitochondrial fatty acid oxidation.
    Yan Gao, Zilin Song, Wenxin Gan, Xue Zou, Yaning Bai, Xiuli Zhao, Dawei Chen, Mingxi Qiao.
      Despite the promise of ferroptosis in cancer therapy, selectively inducing robust ferroptosis in cancer cells remains a significant challenge. In this study, manipulation of fatty acids β-oxidation (FAO) by combination of mild photodynamic therapy (PDT) and inhibition of triglycerides (TGs) synthesis was found to induce robust and iron-independent ferroptosis in cancer cells with dysregulated lipid metabolism for the first time. To achieve that, TGs synthesis inhibitor of xanthohumol (Xan) and FAO initiator of tetrakis (4-carboxyphenyl) porphyrin (TCPP) were co-delivered by a nanoplexes composed of pH-responsive amphiphilic lipopeptide C18-pHis10 and DSPE-PEG2000. TCPP was found to rapidly increase the intracellular ROS under laser irradiation without inducing antioxidant response and apoptosis, activating the AMPK in cancer cells and accelerating mitochondrial FAO. Xan fueled the mitochondrial FAO with substrates by suppressing the conversion of fatty acids (FAs) to TGs. This also led to augmented intracellular polyunsaturated fatty acids (PUFAs) and PUFAs-phospholipids levels, increasing the intrinsic susceptibility of cancer cells to lipid peroxidization. As a result, the excessive ROS generated from the sustained mitochondrial FAO caused remarkably lipid peroxidation and ultimately ferroptosis. Collectively, our study provides a new approach to selectively induce iron-independent ferroptosis in cancer cells by taking advantage of dysregulated lipid metabolism.
    Keywords:  Cancer cell selective; Dysregulated lipid metabolism; Fatty acids β-oxidation; Iron-independent ferroptosis; Positive-feedback
    DOI:  https://doi.org/10.1016/j.biomaterials.2025.123259
  11. J Cell Sci. 2025 May 01. pii: jcs263640. [Epub ahead of print]138(9):
    Mitochondrial fission - changing perspectives for future progress.
    Sukrut C Kamerkar, Ao Liu, Henry N Higgs.
      Mitochondrial fission is important for many aspects of cellular homeostasis, including mitochondrial distribution, stress response, mitophagy, mitochondrially derived vesicle production and metabolic regulation. Several decades of research has revealed much about fission, including identification of a key division protein - the dynamin Drp1 (also known as DNM1L) - receptors for Drp1 on the outer mitochondrial membrane (OMM), including Mff, MiD49 and MiD51 (also known as MIEF2 and MIEF1, respectively) and Fis1, and important Drp1 regulators, including post-translational modifications, actin filaments and the phospholipid cardiolipin. In addition, it is now appreciated that other organelles, including the endoplasmic reticulum, lysosomes and Golgi-derived vesicles, can participate in mitochondrial fission. However, a more holistic understanding of the process is lacking. In this Review, we address three questions that highlight knowledge gaps. First, how do we quantify mitochondrial fission? Second, how does the inner mitochondrial membrane (IMM) divide? Third, how many 'types' of fission exist? We also introduce a model that integrates multiple regulatory factors in mammalian mitochondrial fission. In this model, three possible pathways (cellular stimulation, metabolic switching or mitochondrial dysfunction) independently initiate Drp1 recruitment at the fission site, followed by a shared second step in which Mff mediates subsequent assembly of a contractile Drp1 ring. We conclude by discussing some perplexing issues in fission regulation, including the effects of Drp1 phosphorylation and the multiple Drp1 isoforms.
    Keywords:  Drp1 receptors; Dynamin related protein-1; Inner mitochondrial membrane division; Mitochondrial fission
    DOI:  https://doi.org/10.1242/jcs.263640
  12. J Biol Chem. 2025 Mar 14. pii: S0021-9258(25)00258-3. [Epub ahead of print] 108409
    Pak1 dysregulates Pyruvate metabolism in PDAC cells by exerting a phosphorylation-mediated regulatory effect on PDHA1.
    Sowmiya Murugan, Srikanth Swamy Swaroop B, Prarthana Gopinath, Roshni Saravanan, Sandhya Sundaram, Gouthaman Shanmugasundaram, Ganesh Venkatraman, Suresh Kumar Rayala.
      Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive form of pancreatic cancer with the worst prognosis. Treating PDAC poses significant challenges, as tumor cells adapt metabolic alterations to thrive in the hypoxic environment created by desmoplasia surrounding the tumor cells. p21-activated kinase (Pak1), a serine-threonine kinase is found to be upregulated in many solid tumors and promotes tumor progression via diverse signalling pathways. In this study, we focussed on exploring the role of Pak1 in mediating tumor cell metabolism. Deletion of the Pak1 gene reduced the tumorigenic potential of PDAC cells. Also, Pak1 regulated both glycolysis and mitochondrial respiration in PDAC cells, contributing to the Warburg phenomenon. Untargeted metabolomic analysis revealed that Pak1 was strongly associated with Pyruvate metabolism. Interestingly, we found that Pak1 interacted and phosphorylated Pyruvate dehydrogenase E1α (PDHA1) at Serine 152. This phosphorylation negatively regulates PDHA1 activity, implying the direct regulatory role of Pak1 in Pyruvate metabolism. Moreover, deleting the Pak1 gene altered the expression and activity of PDHA1 and LDHA, as both are involved in regulating the direction of pyruvate flux inside the cells. Our study demonstrated that Pak1 plays a significant role in PDAC metabolism and Warburg effect, partly by phosphorylating PDHA1.
    Keywords:  PDAC; Pak1; Pyruvate dehydrogenase; Warburg effect
    DOI:  https://doi.org/10.1016/j.jbc.2025.108409
  13. Nat Commun. 2025 Mar 19. 16(1): 2685
    Acute diacylglycerol production activates critical membrane-shaping proteins leading to mitochondrial tubulation and fission.
    Joshua G Pemberton, Krishnendu Roy, Yeun Ju Kim, Tara D Fischer, Vijay Joshi, Elizabeth Ferrer, Richard J Youle, Thomas J Pucadyil, Tamas Balla.
      Mitochondrial dynamics are orchestrated by protein assemblies that directly remodel membrane structure, however the influence of specific lipids on these processes remains poorly understood. Here, using an inducible heterodimerization system to selectively modulate the lipid composition of the outer mitochondrial membrane (OMM), we show that local production of diacylglycerol (DAG) directly leads to transient tubulation and rapid fragmentation of the mitochondrial network, which are mediated by isoforms of endophilin B (EndoB) and dynamin-related protein 1 (Drp1), respectively. Reconstitution experiments on cardiolipin-containing membrane templates mimicking the planar and constricted OMM topologies reveal that DAG facilitates the membrane binding and remodeling activities of both EndoB and Drp1, thereby independently potentiating membrane tubulation and fission events. EndoB and Drp1 do not directly interact with each other, suggesting that DAG production activates multiple pathways for membrane remodeling in parallel. Together, our data emphasizes the importance of OMM lipid composition in regulating mitochondrial dynamics.
    DOI:  https://doi.org/10.1038/s41467-025-57439-9
  14. Cell Metab. 2025 Mar 13. pii: S1550-4131(25)00066-X. [Epub ahead of print]
    Pyruvate metabolism enzyme DLAT promotes tumorigenesis by suppressing leucine catabolism.
    Ning Wang, Sijia Lu, Ziyi Cao, Huimin Li, Junting Xu, Qian Zhou, Hanrui Yin, Qiqi Qian, Xianjing Zhang, Mijia Tao, Quanxin Jiang, Peihui Zhou, Liaoyuan Zheng, Liu Han, Hongtao Li, Limin Yin, Yunqing Gu, Xuefeng Dou, Haipeng Sun, Wei Wang, Hai-Long Piao, Fuming Li, Yingjie Xu, Weiwei Yang, Suzhen Chen, Junli Liu.
      Pyruvate and branched-chain amino acid (BCAA) metabolism are pivotal pathways in tumor progression, yet the intricate interplay between them and its implications for tumor progression remain elusive. Our research reveals that dihydrolipoamide S-acetyltransferase (DLAT), a pyruvate metabolism enzyme, promotes leucine accumulation and sustains mammalian target of rapamycin (mTOR) complex activation in hepatocellular carcinoma (HCC). Mechanistically, DLAT directly acetylates the K109 residue of AU RNA-binding methylglutaconyl-coenzyme A (CoA) hydratase (AUH), a critical enzyme in leucine catabolism, inhibiting its activity and leading to leucine accumulation. Notably, DLAT upregulation correlates with poor prognosis in patients with HCC. Therefore, we developed an AUHK109R-mRNA lipid nanoparticles (LNPs) therapeutic strategy, which effectively inhibits tumor growth by restoring leucine catabolism and inhibiting mTOR activation in vivo. In summary, our findings uncover DLAT's unexpected role as an acetyltransferase for AUH, suppressing leucine catabolism. Restoring leucine catabolism with AUHK109R-mRNA LNP effectively inhibits HCC development, highlighting a novel direction for cancer research.
    Keywords:  DLAT; LNP-mRNA; acetylation; hepatocellular carcinoma; leucine catabolism
    DOI:  https://doi.org/10.1016/j.cmet.2025.02.008
  15. Nucleic Acids Res. 2025 Feb 27. pii: gkaf178. [Epub ahead of print]53(5):
    DNA damage response regulator ATR licenses PINK1-mediated mitophagy.
    Christian Marx, Xiaobing Qing, Yamin Gong, Joanna Kirkpatrick, Kanstantsin Siniuk, Galina V Beznoussenko, Gururaj Rao Kidiyoor, Murat Kirtay, Katrin Buder, Philipp Koch, Martin Westermann, Christopher Bruhn, Eric J Brown, Xingzhi Xu, Marco Foiani, Zhao-Qi Wang.
      Defective DNA damage response (DDR) and mitochondrial dysfunction are a major etiology of tissue impairment and aging. Mitochondrial autophagy (mitophagy) is a mitochondrial quality control (MQC) mechanism to selectively eliminate dysfunctional mitochondria. ATR (ataxia-telangiectasia and Rad3-related) is a key DDR regulator playing a pivotal role in DNA replication stress response and genomic stability. Paradoxically, the human Seckel syndrome caused by ATR mutations exhibits premature aging and neuropathies, suggesting a role of ATR in nonreplicating tissues. Here, we report a previously unknown yet direct role of ATR at mitochondria. We find that ATR and PINK1 (PTEN-induced kinase 1) dock at the mitochondrial translocase TOM/TIM complex, where ATR interacts directly with and thereby stabilizes PINK1. ATR deletion silences mitophagy initiation thereby altering oxidative phosphorylation functionality resulting in reactive oxygen species overproduction that attack cytosolic macromolecules, in both cells and brain tissues, prior to nuclear DNA. This study discloses ATR as an integrated component of the PINK1-mediated MQC program to ensure mitochondrial fitness. Together with its DDR function, ATR safeguards mitochondrial and genomic integrity under physiological and genotoxic conditions.
    DOI:  https://doi.org/10.1093/nar/gkaf178
  16. bioRxiv. 2025 Mar 03. pii: 2025.02.27.640600. [Epub ahead of print]
    Hierarchical Lineage Tracing Reveals Diverse Pathways of AML Treatment Resistance.
    Rachel Saxe, Hannah Stuart, Abigail Marshall, Fahiima Abdullahi, Zoë Chen, Francesco Emiliani, Aaron McKenna.
      Cancer cells adapt to treatment, leading to the emergence of clones that are more aggressive and resistant to anti-cancer therapies. We have a limited understanding of the development of treatment resistance as we lack technologies to map the evolution of cancer under the selective pressure of treatment. To address this, we developed a hierarchical, dynamic lineage tracing method called FLARE (Following Lineage Adaptation and Resistance Evolution). We use this technique to track the progression of acute myeloid leukemia (AML) cell lines through exposure to Cytarabine (AraC), a front-line treatment in AML, in vitro and in vivo. We map distinct cellular lineages in murine and human AML cell lines predisposed to AraC persistence and/or resistance via the upregulation of cell adhesion and motility pathways. Additionally, we highlight the heritable expression of immunoproteasome 11S regulatory cap subunits as a potential mechanism aiding AML cell survival, proliferation, and immune escape in vivo. Finally, we validate the clinical relevance of these signatures in the TARGET-AML cohort, with a bisected response in blood and bone marrow. Our findings reveal a broad spectrum of resistance signatures attributed to significant cell transcriptional changes. To our knowledge, this is the first application of dynamic lineage tracing to unravel treatment response and resistance in cancer, and we expect FLARE to be a valuable tool in dissecting the evolution of resistance in a wide range of tumor types.
    DOI:  https://doi.org/10.1101/2025.02.27.640600
  17. Nature. 2025 Mar 19.
    VDAC2 loss elicits tumour destruction and inflammation for cancer therapy.
    Sujing Yuan, Renqiang Sun, Hao Shi, Nicole M Chapman, Haoran Hu, Cliff Guy, Sherri Rankin, Anil Kc, Gustavo Palacios, Xiaoxi Meng, Xiang Sun, Peipei Zhou, Xiaoyang Yang, Stephen Gottschalk, Hongbo Chi.
      Tumour cells often evade immune pressure exerted by CD8+ T cells or immunotherapies through mechanisms that are largely unclear1,2. Here, using complementary in vivo and in vitro CRISPR-Cas9 genetic screens to target metabolic factors, we established voltage-dependent anion channel 2 (VDAC2) as an immune signal-dependent checkpoint that curtails interferon-γ (IFNγ)-mediated tumour destruction and inflammatory reprogramming of the tumour microenvironment. Targeting VDAC2 in tumour cells enabled IFNγ-induced cell death and cGAS-STING activation, and markedly improved anti-tumour effects and immunotherapeutic responses. Using a genome-scale genetic interaction screen, we identified BAK as the mediator of VDAC2-deficiency-induced effects. Mechanistically, IFNγ stimulation increased BIM, BID and BAK expression, with VDAC2 deficiency eliciting uncontrolled IFNγ-induced BAK activation and mitochondrial damage. Consequently, mitochondrial DNA was aberrantly released into the cytosol and triggered robust activation of cGAS-STING signalling and type I IFN response. Importantly, co-deletion of STING signalling components dampened the therapeutic effects of VDAC2 depletion in tumour cells, suggesting that targeting VDAC2 integrates CD8+ T cell- and IFNγ-mediated adaptive immunity with a tumour-intrinsic innate immune-like response. Together, our findings reveal VDAC2 as a dual-action target to overcome tumour immune evasion and establish the importance of coordinately destructing and inflaming tumours to enable efficacious cancer immunotherapy.
    DOI:  https://doi.org/10.1038/s41586-025-08732-6
  18. J Cancer. 2025 ;16(6): 1905-1917
    Mitoxantrone-liposome Sensitizes FLT3-ITD Acute Myeloid Leukemia to Gilteritinib Treatment.
    Shiyi Yuan, Ying Zhou, Yifei Li, Zhe Chen, Wenrui Xiao, Danqing Jiang, Ping Zhang, Ying Zhang, Fengxia Bai, Jianchuan Deng, Shifeng Lou.
      FMS-like tyrosine kinase 3 (FLT3) is the most frequently mutated gene in acute myeloid leukemia (AML), and is associated with poor prognosis and a high relapse rate. Gilteritinib, a second-generation FLT3 inhibitor, is an important target drug for treating patients with FLT3-internal tandem duplication (ITD) AML, is approved for the treatment of relapsed/refractory FLT3-mutant acute myeloid leukemia, although challenges such as drug resistance and reduced potency remain. Herein, mitoxantrone-liposomes sensitized FLT3-ITD AML cells to gitretinib both in vivo and in vitro. RNA-sequencing revealed that combination treatment resulted in specific changes in gene expression as well as predicted the mechanism. Primary AML cells harvested from patients with FLT3-ITD AML showed a significant response to combination treatment in vitro. Our data suggests a novel and promising therapeutic strategy for patients with FLT3-ITD AML and relapsed/refractory FTL3-ITD AML.
    Keywords:  FLT3-ITD; acute myloid leukemia (AML); cell cycle; combination therapy; gilteritinib; mitoxantrone-liposome
    DOI:  https://doi.org/10.7150/jca.105557
  19. Mol Cell. 2025 Mar 14. pii: S1097-2765(25)00183-2. [Epub ahead of print]
    β-hydroxybutyrate facilitates mitochondrial-derived vesicle biogenesis and improves mitochondrial functions.
    Min Tang, Yingfeng Tu, Yanqiu Gong, Qin Yang, Jinrui Wang, Zhenzhen Zhang, Junhong Qin, Shenghui Niu, Jiamin Yi, Zehua Shang, Hongyu Chen, Yingying Tang, Qian Huang, Yanmei Liu, Daniel D Billadeau, Xingguo Liu, Lunzhi Dai, Da Jia.
      Mitochondrial dynamics and metabolites reciprocally influence each other. Mitochondrial-derived vesicles (MDVs) transport damaged mitochondrial components to lysosomes or the extracellular space. While many metabolites are known to modulate mitochondrial dynamics, it is largely unclear whether they are involved in MDV generation. Here, we discovered that the major component of ketone body, β-hydroxybutyrate (BHB), improved mitochondrial functions by facilitating the biogenesis of MDVs. Mechanistically, BHB drove specific lysine β-hydroxybutyrylation (Kbhb) of sorting nexin-9 (SNX9), a key regulator of MDV biogenesis. Kbhb increased SNX9 interaction with inner mitochondrial membrane (IMM)/matrix proteins and promoted the formation of IMM/matrix MDVs. SNX9 Kbhb was not only critical for maintaining mitochondrial homeostasis in cells but also protected mice from alcohol-induced liver injury. Altogether, our research uncovers the fact that metabolites influence the formation of MDVs by directly engaging in post-translational modifications of key protein machineries and establishes a framework for understanding how metabolites regulate mitochondrial functions.
    Keywords:  MDV; PTMs; metabolite; mitochondrial functions
    DOI:  https://doi.org/10.1016/j.molcel.2025.02.022
  20. Nature. 2025 Mar 19.
    Mutations that accrue through life set the stage for stomach cancer.
    Callum Oddy, Marnix Jansen.
      
    Keywords:  Cancer; DNA sequencing; Genetics; Genomics
    DOI:  https://doi.org/10.1038/d41586-025-00803-y
  21. Nat Commun. 2025 Mar 16. 16(1): 2597
    Ubiquinol-mediated suppression of mitochondria-associated ferroptosis is a targetable function of lactate dehydrogenase B in cancer.
    Haibin Deng, Liang Zhao, Huixiang Ge, Yanyun Gao, Yan Fu, Yantang Lin, Mojgan Masoodi, Tereza Losmanova, Michaela Medová, Julien Ott, Min Su, Wenxiang Wang, Ren-Wang Peng, Patrick Dorn, Thomas Michael Marti.
      Lactate dehydrogenase B (LDHB) fuels oxidative cancer cell metabolism by converting lactate to pyruvate. This study uncovers LDHB's role in countering mitochondria-associated ferroptosis independently of lactate's function as a carbon source. LDHB silencing alters mitochondrial morphology, causes lipid peroxidation, and reduces cancer cell viability, which is potentiated by the ferroptosis inducer RSL3. Unlike LDHA, LDHB acts in parallel with glutathione peroxidase 4 (GPX4) and dihydroorotate dehydrogenase (DHODH) to suppress mitochondria-associated ferroptosis by decreasing the ubiquinone (coenzyme Q, CoQ) to ubiquinol (CoQH2) ratio. Indeed, supplementation with mitoCoQH2 (mitochondria-targeted analogue of CoQH2) suppresses mitochondrial lipid peroxidation and cell death after combined LDHB silencing and RSL3 treatment, consistent with the presence of LDHB in the cell fraction containing the mitochondrial inner membrane. Addressing the underlying molecular mechanism, an in vitro NADH consumption assay with purified human LDHB reveals that LDHB catalyzes the transfer of reducing equivalents from NADH to CoQ and that the efficiency of this reaction increases by the addition of lactate. Finally, radiation therapy induces mitochondrial lipid peroxidation and reduces tumor growth, which is further enhanced when combined with LDHB silencing. Thus, LDHB-mediated lactate oxidation drives the CoQ-dependent suppression of mitochondria-associated ferroptosis, a promising target for combination therapies.
    DOI:  https://doi.org/10.1038/s41467-025-57906-3
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