bims-mibica Biomed News
on Mitochondrial bioenergetics in cancer
Issue of 2025–08–31
fifteen papers selected by
Kelsey Fisher-Wellman, Wake Forest University
  1. RTN4IP1 is required for the final stages of mitochondrial complex I assembly and CoQ biosynthesis.
  2. ClpP-based MtPTAC technology enables targeted degradation of inner mitochondrial membrane proteins.
  3. Putative PINK1/Parkin activators lower the threshold for mitophagy by sensitizing cells to mitochondrial stress.
  4. A repurposed AMP binding domain reveals mitochondrial protein AMPylation as a regulator of cellular metabolism.
  5. C19orf12 inhibits mitochondrial function and enhances the antitumor effects of metformin in non-small cell lung cancer.
  6. MYC deregulation sensitizes cancer cells to N-myristoyltransferase inhibition.
  7. MRPL13 enhances mitochondrial function and promotes tumor progression in ovarian cancer by inhibiting mPTP opening via SLC25A6.
  8. From Warburg to Warnings: A Genomic Approach to Oral Cancer Surveillance.
  9. Isoliensinine inhibits mitophagy and sensitizes T cell malignancies for STING-mediated NK clearance.
  10. Inhibition of ELOVL6 activity impairs mitochondrial respiratory function and inhibits tumor progression in FGFR3-mutated bladder cancer cells.
  11. GPT2 mediates glutamine metabolism-driven metabolic alterations in platinum-resistant ovarian cancer cells.
  12. Fatty acid addiction in cancer: A high-fat diet directly promotes tumor growth through fatty acid oxidation.
  13. Highly specific intracellular ubiquitination of a small molecule.
  14. α-Ketoglutarate dictates AMPK protein synthesis for energy sensing in human cancers.
  15. Plasma lipid levels predict chemotherapy response and survival in acute myeloid leukemia.
  1. EMBO J. 2025 Aug 26.
    RTN4IP1 is required for the final stages of mitochondrial complex I assembly and CoQ biosynthesis.
    Monika Oláhová, Rachel M Guerra, Jack J Collier, Juliana Heidler, Kyle Thompson, Chelsea R White, Paulina Castañeda-Tamez, Alfredo Cabrera-Orefice, Robert N Lightowlers, Zofia M A Chrzanowska-Lightowlers, Alexander Galkin, Ilka Wittig, David J Pagliarini, Robert W Taylor.
      A biochemical deficiency of mitochondrial complex I (CI) underlies approximately 30% of cases of primary mitochondrial disease, yet the inventory of molecular machinery required for CI assembly remains incomplete. We previously characterised patients with isolated CI deficiency caused by segregating variants in RTN4IP1, a gene that encodes a mitochondrial NAD(P)H oxidoreductase. Here, we demonstrate that RTN4IP1 deficiency causes a CI assembly defect in both patient fibroblasts and knockout cells, and report that RTN4IP1 is a bona fide CI assembly factor. Complexome profiling revealed accumulation of unincorporated ND5-module and impaired N-module production. RTN4IP1 patient fibroblasts also exhibited defective coenzyme Q biosynthesis, substantiating a second function of RTN4IP1. Thus, our data reveal RTN4IP1 plays necessary and independent roles in both the terminal stages of CI assembly and in coenzyme Q metabolism, and that pathogenic RTN4IP1 variants impair both functions in patients with mitochondrial disease.
    Keywords:  Coenzyme Q; Complex I Assembly; Complexome Profiling; Mitochondria; RTN4IP1
    DOI:  https://doi.org/10.1038/s44318-025-00533-x
  2. Bioorg Med Chem. 2025 Aug 11. pii: S0968-0896(25)00291-3. [Epub ahead of print]130 118350
    ClpP-based MtPTAC technology enables targeted degradation of inner mitochondrial membrane proteins.
    Yuxin Yao, Dachi Wang, Haoyu Gong, Ruibin Jiang, Yang Liu, Yijun Liu, Xin Lai, Zhaoyang Xu, Wei Zhou, Haorong Li, Xiaohong Fang.
      Mitochondrial proteostasis is essential for tumorigenesis, and mitochondrial inner membrane proteins have emerged as meaningful targets due to their crucial functions in regulating apoptosis, maintaining oxidative phosphorylation, and influencing tumor initiation and progression. Targeted protein degradation (TPD) has garnered significant attention as a promising therapeutic approach. However, conventional TPD platforms relying on the ubiquitin-proteasome system or lysosomal pathways encounter inherent obstacles in targeting proteins sequestered within the mitochondrial compartment and cannot degrade mitochondrial inner membrane proteins. Utilizing our previously established MtPTAC system, we selected dihydroorotate dehydrogenase (DHODH), the rate-limiting enzyme in de novo pyrimidine biosynthesis, as a model substrate. We designed and synthesized a series of degraders, with 3D-2 achieving over 50 % degradation efficiency of DHODH via the ClpP protease. This degrader can form a stable ternary complex with DHODH and ClpP, and it exhibits significant inhibitory effects across various tumor cell lines. This technological innovation is the first to successfully degrade endogenous mitochondrial inner membrane proteins. It provides a diverse toolkit for investigating mitochondrial protein functions and paving the way for novel anticancer therapies.
    Keywords:  DHODH degrader; Inner mitochondrial membrane; MtPTAC; Targeting protein degradation
    DOI:  https://doi.org/10.1016/j.bmc.2025.118350
  3. Sci Adv. 2025 Aug 29. 11(35): eady0240
    Putative PINK1/Parkin activators lower the threshold for mitophagy by sensitizing cells to mitochondrial stress.
    William M Rosencrans, Ryan W Lee, Logan McGraw, Ian Horsburgh, Ting-Yu Wang, Baiyi Quan, Diana Huynh, Jennifer A Johnston, David C Chan, Tsui-Fen Chou.
      The PINK1/Parkin pathway targets damaged mitochondria for degradation via mitophagy. Genetic evidence implicates impaired mitophagy in Parkinson's disease, making its pharmacological enhancement a promising therapeutic strategy. Here, we characterize two mitophagy activators: a novel Parkin activator, FB231, and the reported PINK1 activator MTK458. Both compounds lower the threshold for mitochondrial toxins to induce PINK1/Parkin-mediated mitophagy. However, global proteomics revealed that FB231 and MTK458 independently induce mild mitochondrial stress, resulting in impaired mitochondrial function and activation of the integrated stress response, effects that result from PINK1/Parkin-independent off-target activities. We find that these compounds impair mitochondria by distinct mechanisms and synergistically decrease mitochondrial function and cell viability in combination with classical mitochondrial toxins. Our findings support a model whereby weak or "silent" mitochondrial toxins potentiate other mitochondrial stressors, enhancing PINK1/Parkin-mediated mitophagy. These insights highlight important considerations for therapeutic strategies targeting mitophagy activation in Parkinson's disease.
    DOI:  https://doi.org/10.1126/sciadv.ady0240
  4. Nat Commun. 2025 Aug 23. 16(1): 7863
    A repurposed AMP binding domain reveals mitochondrial protein AMPylation as a regulator of cellular metabolism.
    Abner Gonzalez, Alex Pon, Kelly Servage, Krzysztof Pawłowski, Yan Han, Anju Sreelatha.
      Protein AMPylation, the covalent addition of adenosine monophosphate (AMP) to protein substrates, has been known as a post translational modification for over 50 years. Research in this field is largely underdeveloped due to the lack of tools that enable the systematic identification of AMPylated substrates. Here, we address this gap by developing an enrichment technique to isolate and study AMPylated proteins using a nucleotide-binding protein, hinT. Cryo-EM reconstruction of an AMPylated protein bound to hinT provides a structural basis for AMP selectivity. Using structure guided mutagenesis, we optimize enrichment to identify novel substrates of the evolutionarily conserved AMPylase, Selenoprotein O. We show that mammalian Selenoprotein O regulates metabolic flux through AMPylation of key mitochondrial proteins including glutamate dehydrogenase and pyruvate dehydrogenase. Our findings highlight the broader significance of AMPylation, an emerging post translational modification with critical roles in signal transduction and disease pathology. Furthermore, we establish a powerful enrichment platform for the discovery of novel AMPylated proteins to study the mechanisms and significance of protein AMPylation in cellular function.
    DOI:  https://doi.org/10.1038/s41467-025-63014-z
  5. Cell Rep. 2025 Aug 19. pii: S2211-1247(25)00934-9. [Epub ahead of print]44(9): 116163
    C19orf12 inhibits mitochondrial function and enhances the antitumor effects of metformin in non-small cell lung cancer.
    Ran Liu, Meng Zhao, Xinrui Zhang, Hao Wu, Li Ren, Junqiang Lv, Zhe Liu, Quan Wang, Zhi Yao.
      Glucose metabolic reprogramming from oxidative phosphorylation to glycolysis is a hallmark of cancer, yet the mechanisms driving aerobic glycolysis are unclear. In this study, we identified chromosome 19 open reading frame 12 (C19orf12), a gene associated with neurodegeneration, as upregulated in non-small cell lung cancer (NSCLC). Elevated C19orf12 expression is associated with poor prognosis and enhanced metastatic potential in NSCLC cells. High C19orf12 levels repress mitochondrial respiration and decrease glucose flux through the tricarboxylic acid cycle. Mechanistically, C19orf12 interacts with and suppresses the biological function of leucine-rich pentatricopeptide repeat motif-containing protein (LRPPRC) and downregulates the expression of mitochondrial electron transport chain (ETC) genes. Moreover, C19orf12 increases NSCLC cell sensitivity to the tumoricidal effects of metformin by synergistically inhibiting mitochondrial respiration. These findings highlight C19orf12 as a regulator of mitochondrial metabolism in NSCLC and suggest that its elevated expression could serve as a biomarker to predict improved responses to metformin therapy.
    Keywords:  C19orf12; CP: Cancer; CP: Metabolism; LRPPRC; NSCLC; glycolysis; metastasis; metformin; mitochondrial function
    DOI:  https://doi.org/10.1016/j.celrep.2025.116163
  6. Cell Rep. 2025 Aug 22. pii: S2211-1247(25)00951-9. [Epub ahead of print]44(9): 116180
    MYC deregulation sensitizes cancer cells to N-myristoyltransferase inhibition.
    Gregor A Lueg, James Zhang, Monica Faronato, Andrii Gorelik, Wouter W Kallemeijn, Francesco Falciani, Josephine Walton, Jack W Houghton, Silvia Vannini, Evon Poon, Barbara M Costa, Roberto Solari, Robin Carr, Andrew S Bell, Edward J Bartlett, Bernadette Brzezicha, Martin Janz, Louis Chesler, Dinis P Calado, Edward W Tate.
      Human N-myristoyltransferases (NMTs) catalyze N-terminal protein N-myristoylation and are promising targets in cancer, with an emerging mechanistic rationale for targeted therapy. Here, we screened 245 cancer cell lines against IMP-1320, a potent NMT inhibitor (NMTi), and conducted pathway-level analyses to identify that deregulated MYC increases cancer cell sensitivity to NMTis. Proteomics on detergent-enriched membrane fractions in MYC or MYCN-deregulated cancer cell models revealed that cell death is associated at least in part with loss of membrane association of mitochondrial respiratory complex I. This is concurrent with loss of myristoylation and degradation of the complex I assembly factor NDUFAF4, and induction of mitochondrial dysfunction, driven by MYC or MYCN-deregulation. NMTis eliminated or suppressed MYC- and MYCN-driven tumors in vivo without overt toxicity, suggesting that this constitutive co-translational protein modification can be targeted in MYC-driven cancers.
    Keywords:  CP: Cancer; CP: Molecular biology; Complex I; MYC; MYCN; N-myristoylation; N-myristoyltransferase; NDUFAF4; NMT
    DOI:  https://doi.org/10.1016/j.celrep.2025.116180
  7. Cell Death Dis. 2025 Aug 21. 16(1): 634
    MRPL13 enhances mitochondrial function and promotes tumor progression in ovarian cancer by inhibiting mPTP opening via SLC25A6.
    Ouxuan Liu, Yuexin Hu, Shuang Wang, Xin Nie, Yuxuan Wang, Xiangcheng Fan, Kai Zeng, Xiao Li, Bingying Liu, Bei Lin.
      Tumor cells typically exhibit dysregulation of mitochondrial energy metabolism and cell death. The role of mitochondrial function in ovarian cancer (OC) progression has garnered substantial attention, yet its precise molecular mechanisms remain elusive. Mitochondrial ribosomal protein L13 (MRPL13), involved in the translation of oxidative phosphorylation (OXPHOS) complex subunits, plays a critical role in regulating mitochondrial function. Our study demonstrated that MRPL13 is highly expressed in OC tissues and correlated with poor prognosis. Both in vitro and in vivo experiments confirmed that MRPL13 overexpression significantly promotes the malignant biological behavior of OC, while MRPL13 knockdown induces the opposite phenotype. Moreover, MRPL13 knockdown impairs mitochondrial function in OC cells, leading to decreased OXPHOS and ATP levels, increased reactive oxygen species (ROS) generation, mitochondrial depolarization, aberrant opening of the mitochondrial permeability transition pore (mPTP), and mitochondrial structural damage. Mechanistically, MRPL13 specifically interacts with SLC25A6 and facilitates its degradation via lysine (K)48-linked ubiquitination. MRPL13 inhibits mPTP opening by accelerating the degradation of SLC25A6, thereby preventing cytochrome c release into the cytoplasm, inhibiting cell death, and enhancing mitochondrial function. In conclusion, our study elucidates the mechanism by which the MRPL13-SLC25A6 axis enhances mitochondrial function and promotes tumor progression in OC by inhibiting mPTP opening, suggesting that MRPL13 holds significant potential for prognostic evaluation and targeted therapy in OC.
    DOI:  https://doi.org/10.1038/s41419-025-07953-x
  8. DNA Cell Biol. 2025 Aug 25.
    From Warburg to Warnings: A Genomic Approach to Oral Cancer Surveillance.
    Denis C Baiju, Logeswaran V M, Rosy Mondal.
      Mitochondria, originating from symbiotic ancestors, are acknowledged as the powerhouses of the cell. Their relevance to various cancer types is underscored by altered glucose metabolism (Warburg effect). Mitochondrial DNA (mtDNA) plays a crucial role in oxidative damage and is a significant contributor to cancer onset and progression. Tobacco and alcohol consumption increases reactive oxygen species generation, inducing oxidative stress that disrupts respiratory activity and mtDNA, thereby promoting carcinogenesis. This review emphasizes the link between mitochondrial dysfunction and cancer, particularly in oral squamous cell carcinoma (OSCC), highlighting the role of mtDNA mutations. This review discusses environmental factors, such as tobacco use and human papillomavirus infection, that impact mitochondrial function, stresses the importance of mitochondrial-targeted therapies, and explores the influence of microRNAs (miRNAs) on mitochondrial metabolism in cancer cells. Mitocans and miRNAs have emerged as promising therapeutic agents for OSCC. The subsequent sections delve into recent pivotal research on mitochondria, identifying mtDNA alterations as potential cancer biomarkers. These insights promise new perspectives on noninvasive cancer detection, heralding advancements in cancer therapeutics.
    Keywords:  biomarkers; cancer metabolism; cell-free mitochondrial DNA; mitochondrial DNA; mitochondrial dysfunction; oral squamous cell carcinoma
    DOI:  https://doi.org/10.1177/10445498251371120
  9. Acta Pharmacol Sin. 2025 Aug 21.
    Isoliensinine inhibits mitophagy and sensitizes T cell malignancies for STING-mediated NK clearance.
    Xiao Ge, Guang-Ming Yang, Xiao-Long Zhang, Jing Cao, Ying-Jie Qing, San-Bing Shen, Yang Pan, Po Hu.
      Mitochondrial DNA (mtDNA) damage and accumulation activate the cGAS-STING DNA-sensing pathway, which promotes immune clearance of tumor cells. Maintenance of the cytosolic level of mtDNA is key to sustain immune activation. T cell malignancies (T-CMs) are a general name of diseases with abnormal clonal proliferation of T lymphocytes at various stages. Immunotherapy of T-CMs is challenged by the lack of specific antigens to discriminate T-CMs from normal T cells. As intrinsic STING activation can promote the clearance of T-CMs by immune cells, we herein explored whether isoliensinine (IsoL), a natural compound from Nelumbinis Plumula could enhance NK clearance by mtDNA-mediated immune responses in tumor cells. To investigate whether IsoL modulated immune recognition and clearance of T-CMs, we pre-treated three T-CM cell lines (Jurkat, Molt4 and Hut102) with IsoL then co-cultured with NK-92MI cells. We showed that IsoL pre-treatment promoted cytosolic mtDNA accumulation by inducing ROS-dependent mitochondrial damage and inhibiting mitophagy via peroxiredoxin 1 (PRDX1), an antioxidant enzyme. Loss of PRDX1 in T-CMs also induced ROS-dependent mitochondrial DNA damage, and blocked mitophagy by preventing accumulation of mature PINK1, which was required to initiate mitophagy via recruiting Parkin to the damaged mitochondria. Remarkably, IsoL could induce expression of activating ligands in vitro, enhance NK cell infiltrations, and increase apoptosis of T-CMs. Moreover, we demonstrated that IsoL could sensitize T-CMs for NK clearance in vitro and in vivo. These results suggest that IsoL could be a potential therapeutic agent to enhance immune therapy of T-CMs.
    Keywords:  NK cells; T cell malignancies; immune clearance; isoliensinine; mitophagy; peroxiredoxin 1
    DOI:  https://doi.org/10.1038/s41401-025-01636-1
  10. Biochim Biophys Acta Mol Basis Dis. 2025 Aug 18. pii: S0925-4439(25)00371-0. [Epub ahead of print]1871(8): 168023
    Inhibition of ELOVL6 activity impairs mitochondrial respiratory function and inhibits tumor progression in FGFR3-mutated bladder cancer cells.
    Erika Matsuda, Shiho Hasebe, Takashi Matsuzaka, Akio Hayashi, Hiroshi Ohno, Kaori Motomura, Shotaro Sakka, Susumu Kohno, Hayato Muranaka, Minako Yamamura, Asuka Suzuki, Yoshinori Takeuchi, Yoshinori Osaki, Takafumi Miyamoto, Motohiro Sekiya, Hirohito Sone, Naoya Yahagi, Yoshimi Nakagawa, Satoshi Nitta, Shuya Kandori, Takahiro Kojima, Chiaki Takahashi, Hiroyuki Nishiyama, Hitoshi Shimano.
       OBJECTIVE: Increased de novo fatty acid (FA) synthesis is a hallmark of cancer. ELOVL FA elongase 6 (ELOVL6) catalyze chain elongation of C16 saturated and monounsaturated FAs into C18 species and has been implicated in several cancers. This study investigated the role of ELOVL6 in bladder cancer (BC).
    METHODS: ELOVL6 expression was compared between BC and nontumor tissues. Human BC cell lines with ELOVL6-knockdown were assessed for proliferation and tumor growth. Metabolic and molecular alterations induced by ELOVL6 inhibition were analyzed using lipidomics and transcriptomics.
    RESULTS: ELOVL6 expression was significantly higher in BC tissues than in controls. In fibroblast growth factor receptor 3 (FGFR3)-mutant BC cell lines, ELOVL6 knockdown suppressed cell growth in vitro and tumor progression in vivo. Lipidomic analysis showed a marked reduction in phosphatidylethanolamine following ELOVL6 knockdown, which was accompanied by lower mitochondrial complex I and II protein levels and impaired mitochondrial oxidative phosphorylation (OXPHOS). RNA sequencing revealed that mitochondrial dysfunction resulting from ELOVL6 knockdown triggered changes in extracellular matrix (ECM) remodeling gene expression and activation of the ECM-integrin-focal adhesion kinase (FAK) pathway, likely as a compensatory response to reduced cell proliferation.
    CONCLUSION: ELOVL6 regulates lipid composition to preserve mitochondrial function, supporting cell growth and tumorigenesis in FGFR3-mutated BC. Targeting ELOVL6 may represent a novel therapeutic strategy for treating BC, particularly in tumors driven by FGFR3 mutations.
    Keywords:  Bladder cancer (BC); ELOVL fatty acid elongase 6 (ELOVL6); Extracellular matrix (ECM); Fibroblast growth factor receptor 3 (FGFR3); Mitochondrial oxidative phosphorylation (OXPHOS)
    DOI:  https://doi.org/10.1016/j.bbadis.2025.168023
  11. Sci Rep. 2025 Aug 20. 15(1): 30528
    GPT2 mediates glutamine metabolism-driven metabolic alterations in platinum-resistant ovarian cancer cells.
    Adriana Ponton-Almodovar, Mary P Udumula, Vrinda Khullar, Faraz Rashid, Ramandeep Rattan, Jamie J Bernard, Sachi Horibata.
      Metabolic reprogramming is recognized as a hallmark of cancer frequently associated with drug resistance in ovarian cancer. This is problematic as ovarian cancer is one of the deadliest gynecologic cancers with platinum resistance contributing to poor survival. However, the mechanism by which ovarian cancer cell metabolism contributes to platinum resistance is not well understood. Herein, metabolic signatures were determined in platinum-resistant ovarian cancer cell lines compared to the more platinum-sensitive parental lines. Chemoresistant ovarian cancer cells showed increased oxidative phosphorylation (OXPHOS) compared to chemosensitive cells. This was associated with elevated levels of glutaminolysis and tricarboxylic acid (TCA)-related metabolites supporting their dependence on OXPHOS. Key enzymes involved in glutaminolysis, specifically, glutamic-pyruvic transaminase 2 (GPT2), were upregulated in chemoresistant compared to chemosensitive cells. Interestingly, high GPT2 gene expression is associated with worse prognosis in ovarian cancer patients, adding translational relevance to the pre-clinical findings. GPT2 knockout in chemoresistant cells restored the metabolic phenotype to that of the sensitive cells and reversed drug resistance. These data suggest that GPT2 is a critical link between glutaminolysis, the TCA cycle, and OXPHOS and is a potential target to attenuate the increased metabolic activity associated with a chemoresistant phenotype.
    Keywords:  GPT2; Glutamine; Metabolism; Ovarian cancer
    DOI:  https://doi.org/10.1038/s41598-025-15707-0
  12. Biochim Biophys Acta Rev Cancer. 2025 Aug 20. pii: S0304-419X(25)00170-2. [Epub ahead of print]1880(5): 189428
    Fatty acid addiction in cancer: A high-fat diet directly promotes tumor growth through fatty acid oxidation.
    Soo-Youl Kim.
      Tumor growth promoted by a high-fat diet (HFD) was completely reversed by inhibiting fatty acid oxidation (FAO). The promotion of tumors by an HFD is known to result from the indirect effects of sex hormones, leptin, and adipokines such as insulin-like growth factor-1 (IGF-1) on cancer cells. However, even though HFD notably increased blood levels of IGF-1, knocking down the carnitine-acylcarnitine carrier (CAC) to inhibit FAO completely reversed the tumor-promoting effects in pancreatic cancer cells, accompanied by a significant decrease in ATP production. When ATP levels dropped due to FAO inhibition in cancer cells, mTOR - a key regulator of survival - became inactive, leading to reduced cell viability and increased cell death. This shows that HFD promotes cancer cell growth by supplying more calories through FAO, indicating that cancer is addicted to fatty acids. This review emphasizes the crucial role of cancer-specific FAO in tumor growth and proposes potential new therapeutic strategies targeting various FAO enzymes as innovative anti-cancer treatments.
    Keywords:  ATP production; Fatty acid oxidation; High-fat diet (HFD); Obesity; cancer
    DOI:  https://doi.org/10.1016/j.bbcan.2025.189428
  13. Nat Chem Biol. 2025 Aug 21.
    Highly specific intracellular ubiquitination of a small molecule.
    Weicheng Li, Enrique M Garcia-Rivera, Dylan C Mitchell, Joel M Chick, Micah Maetani, Rohit Bhadoria, John M Knapp, Ryosuke Misu, Geoffrey M Matthews, Ryosuke Shirasaki, Ricardo de Matos Simoes, Vasanthi Viswanathan, John L Pulice, Matthew G Rees, Jennifer A Roth, Steven P Gygi, Constantine S Mitsiades, Cigall Kadoch, Stuart L Schreiber, Jonathan M L Ostrem.
      Ubiquitin is a small, highly conserved protein that acts as a posttranslational modification in eukaryotes. Ubiquitination of proteins frequently serves as a degradation signal, marking them for disposal by the proteasome. Here we report a novel small molecule from a diversity-oriented synthesis library, BRD1732, that is directly ubiquitinated in cells, resulting in dramatic accumulation of inactive ubiquitin monomers and polyubiquitin chains, which causes broad inhibition of the ubiquitin-proteasome system. Ubiquitination of BRD1732 and its associated cytotoxicity are stereospecific and dependent on two homologous E3 ubiquitin ligases, RNF19A and RNF19B, and their shared E2 conjugating enzyme, UBE2L3. Our finding opens the possibility for indirect ubiquitination of a target through a ubiquitinated bifunctional small molecule and more broadly raises the potential for posttranslational modification in trans.
    DOI:  https://doi.org/10.1038/s41589-025-02011-1
  14. Nat Chem Biol. 2025 Aug 22.
    α-Ketoglutarate dictates AMPK protein synthesis for energy sensing in human cancers.
    Wen Mi, Yun Xue, Haohang Yan, Yurou Zhang, Xinlei Cai, Shuyuan Zhang, Ruiping He, Liucheng Li, Lingzhi Zhu, Xinyi Xia, Yifan Liang, Chongwen Cao, Yi Xu, Junfeng Bi, Guanlin Wang, Li Chen, Dan Ye, Fei Li, Ruobing Ren, Pingyu Liu, Hongbin Ji, Fuming Li.
      The energy sensor AMP-activated protein kinase (AMPK) promotes tumor cell survival under stress but how to prevent AMPK activation to blunt tumor progression remains unclear. Here we show that the metabolite α-ketoglutarate (α-KG) dictates AMPK translation through a TET-YBX1 axis, which can be exploited to sensitize human cancer cells to energy stress. α-KG-deficient cells fail to activate AMPK under glucose starvation, which elicits cytosolic NADPH depletion and disulfidptosis. Mechanistically, α-KG insufficiency inhibits TET-dependent transcription of YBX1, an RNA-binding protein required for human-specific AMPK protein synthesis. Similarly, α-KG competitors including succinate and itaconate inhibit the YBX1-AMPK axis and sensitize cancer cells to glucose deprivation. Lastly, cotargeting oncogenic YBX1 and GLUT1 creates synthetic lethality and blunts tumor growth in vivo. Together, our findings link α-KG to energy sensing through AMPK translation and propose that targeting α-KG-YBX1-dependent AMPK translation can sensitize human cancer cells to energy stress for treatment.
    DOI:  https://doi.org/10.1038/s41589-025-02013-z
  15. Blood. 2025 Aug 26. pii: blood.2025029132. [Epub ahead of print]
    Plasma lipid levels predict chemotherapy response and survival in acute myeloid leukemia.
    Cristiana O'Brien, Nirvana Nursimulu, Anit Tyagi, Rachel Culp-Hill, Andrea Arruda, Tracy Murphy, Mark D Minden, Andrew Kent, Brett M Stevens, Daniel A Pollyea, Kristin Hope, Sushant Kumar, Julie A Reisz, Angelo D'Alessandro, Courtney L Jones.
      Acute myeloid leukemia (AML) is characterized by a low five-year survival rate. Despite having many clinical metrics to assess patient prognosis, there remain opportunities to improve risk stratification. We hypothesized that an underexplored resource to examine AML patient prognosis is the plasma metabolome. Circulating metabolites are influenced by patients' clinical status and can serve as accessible cancer biomarkers. To establish a resource of circulating metabolites in genetically diverse AML patients, we performed an unbiased metabolomic and lipidomic analysis of 231 diagnostic AML plasma samples prior to treatment with intensive chemotherapy. Intriguingly, circulating metabolites were highly associated with the mutation status within the AML cells. Further, lipids were associated with refractory status. We established a machine learning algorithm trained on chemo-refractory associated lipids to predict patient survival. Cox regression and Kaplan-Meier analysis demonstrated that the high-risk lipid signature predicted overall survival in this patient cohort. Impressively, the top lipid in the high-risk lipid signature, sphingomyelin (d44:1), was sufficient to predict overall survival in the original and an independent validation dataset. Overall, this research underscores the potential of circulating metabolites to capture AML heterogeneity and lipids to be used as potential AML biomarkers.
    DOI:  https://doi.org/10.1182/blood.2025029132
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