bims-mibica Biomed News
on Mitochondrial bioenergetics in cancer
Issue of 2025–11–09
nineteen papers selected by
Kelsey Fisher-Wellman, Wake Forest University
  1. Metabolic environment-driven remodeling of mitochondrial ribosomes regulates translation and biogenesis.
  2. Functionally dominant hotspot mutations of mitochondrial ribosomal RNA genes in cancer.
  3. Proteolytic cleavage activates the mitochondrial isoform of TOP3A.
  4. Guanine nucleotides drive ribosome biogenesis and glycolytic reprogramming in acute myeloid leukemia stem cells.
  5. An orphan no more: SLC25A45 controls mitochondrial import of methylated amino acids.
  6. Mitochondrial metabolic alterations fuel bladder cancer initiation.
  7. Targeting cancer glutamine dependency with a first-in-class inhibitor of the mitochondrial glutamine transporter SLC1A5_var.
  8. Menin inhibitor DS-1594b drives differentiation and induces synergistic lethality in combination with venetoclax in acute myeloid leukemia cells with rearranged mixed-lineage leukemia and mutated nucleophosmin-1.
  9. A novel strategy to target metabolic dependencies in acute myeloid leukemia.
  10. Mitochondria-transliterated ALDH1L1 functions as a feedback regulator of redox homeostasis in cancer cells to enhance the resistance to pro-oxidative therapy.
  11. NUDT5 regulates purine metabolism and thiopurine sensitivity by interacting with PPAT.
  12. Regenerating liver uses ammonia to support de novo pyrimidine synthesis and cell proliferation.
  13. Silencing of mitochondrial gene expression using polymorpholino chimeras.
  14. Size control: Tune the mitochondrial volume to time your cell division!
  15. Cyclophilin D is a new non-canonical substrate of the mitochondrial intermembrane space assembly pathway.
  16. ANT1 suppression inhibits the progression of colorectal cancer by suppressing PINK1/Parkin-mediated mitophagy.
  17. Cysteine S-acetylation is a widespread post-translational modification on metabolic proteins.
  18. Phytochemicals in overcoming venetoclax resistance in acute myeloid leukemia: mechanistic insights and therapeutic potential.
  19. Potential Off-Target Effect of Gilteritinib With Venetoclax Decreases Tumor Burden for Patients With Relapsed/Refractory Wild-Type FLT3 Acute Myeloid Leukemia/Myelodysplastic Neoplasms.
  1. Mol Cell. 2025 Nov 06. pii: S1097-2765(25)00853-6. [Epub ahead of print]
    Metabolic environment-driven remodeling of mitochondrial ribosomes regulates translation and biogenesis.
    Fan Zheng, Zanlin Yu, Junming Zhuang, Lingraj Vannur, William Nickols, YongQiang Wang, Liying Li, Sho Joseph Ozaki Tan, Seungmin Yoo, Yifan Cheng, Chuankai Zhou.
      Cytosolic translation activity is fine-tuned by environmental conditions primarily through signaling pathways that target translation initiation factors. Although mitochondria possess their own translation machinery, they lack an autonomous signaling network analogous to their cytosolic counterpart for regulating translation activity. Consequently, our understanding of how mitochondrial translation activity is adjusted under different metabolic environments remains very limited. Here, we report a noncanonical mechanism for regulating mitochondrial translation activity via metabolism-dependent changes in the mitochondrial ribosome (mitoribosome) in S. cerevisiae. These changes arise from a metabolism-modulated mitoribosome assembly pathway that regulates the composition and conformation of the mitoribosome, thereby adjusting its translation activity to meet metabolic demands. Moreover, the translation activity of the mitoribosome feeds back to regulate the biogenesis of nuclear-encoded mitochondrial proteins, influencing mitochondrial functions and aging. Such a ribosomal remodeling-based "gear-switching" mechanism represents an orthogonal mode of translation regulation, compensating for the absence of a translation-modulating signaling network within mitochondria.
    Keywords:  aging; metabolism; mitochondria; mitoribosome; translation activity
    DOI:  https://doi.org/10.1016/j.molcel.2025.10.012
  2. Nat Genet. 2025 Nov 03.
    Functionally dominant hotspot mutations of mitochondrial ribosomal RNA genes in cancer.
    Sonia Boscenco, Jacqueline Tait-Mulder, Minsoo Kim, Cerise Tang, Tricia Park, Flora McNulty, Sergio Lilla, Sara Zanivan, Alejandro Huerta-Uribe, Benan Nalbant, Mark Zucker, David Sumpton, Geoffray Monteuuis, Christopher B Jackson, Wei Wei, Patrick F Chinnery, Ronan Chaligne, Caleb A Lareau, Ed Reznik, Payam A Gammage.
      The vast majority of recurrent somatic mutations arising in tumors affect protein-coding genes in the nuclear genome. Here, through population-scale analysis of 14,106 whole tumor genomes, we report the discovery of highly recurrent mutations affecting both the small (12S, MT-RNR1) and large (16S, MT-RNR2) mitochondrial RNA subunits of the mitochondrial ribosome encoded within mitochondrial DNA (mtDNA). Compared to non-hotspot positions, mitochondrial rRNA hotspots preferentially affected positions under purifying selection in the germline and demonstrated structural clustering within the mitoribosome at mRNA and tRNA interacting positions. Using precision mtDNA base editing, we engineered models of an exemplar MT-RNR1 hotspot mutation, m.1227G>A. Multimodal profiling revealed a heteroplasmy-dependent decrease in mitochondrial function and loss of respiratory chain subunits from a heteroplasmic dosage of ~10%. Mutation of conserved positions in ribosomal RNA that disrupt mitochondrial translation therefore represent a class of functionally dominant, pathogenic mtDNA mutations that are under positive selection in cancer genomes.
    DOI:  https://doi.org/10.1038/s41588-025-02374-0
  3. Nucleic Acids Res. 2025 Oct 28. pii: gkaf1140. [Epub ahead of print]53(20):
    Proteolytic cleavage activates the mitochondrial isoform of TOP3A.
    Direnis Erdinc, Christin A Albus, Alejandro Rodríguez-Luis, Katja E Menger, Annika Thorsell, Ilian Atanassov, Urška Rovšnik, Maria Falkenberg, Claes M Gustafsson, Thomas J J Nicholls.
      The TOP3A gene encodes two isoforms, one targeted to the nucleus and one to mitochondria. Nuclear TOP3A functions as part of the BTRR complex to resolve double Holliday junctions during homologous recombination, while the mitochondrial isoform separates hemicatenated daughter mitochondrial DNA (mtDNA) molecules following DNA replication. Here, we show that the mitochondrial isoform of TOP3A undergoes proteolytic cleavage by the mitochondrial processing peptidase, removing ~90 amino acids from the C-terminus. This cleavage enhances the enzyme's biochemical properties, increasing single-stranded DNA binding and decatenation activity. Notably, all BTRR complex subunits, except TOP3A, are absent from mitochondria, suggesting that proteolytic processing enables TOP3A to function autonomously in mtDNA maintenance. We propose that this cleavage represents a post-import maturation step that tailors TOP3A to its mitochondrial context by uncoupling it from nuclear protein interactions and enhancing its catalytic efficiency.
    DOI:  https://doi.org/10.1093/nar/gkaf1140
  4. Blood. 2025 Nov 05. pii: blood.2025030209. [Epub ahead of print]
    Guanine nucleotides drive ribosome biogenesis and glycolytic reprogramming in acute myeloid leukemia stem cells.
    Gentaro Kawano, Riichiro Ikeda, Daisuke Ishihara, Takahiro Shima, Teppei Sakoda, Shunsuke Yamamoto, Yu Kochi, Yuichiro Semba, Sanae Ashitani, Yasuo Mori, Koji Kato, Takahiro Maeda, Toshihiro Miyamoto, Tomoyoshi Soga, Koichi Akashi, Yoshikane Kikushige.
      Therapy resistance in acute myeloid leukemia (AML) remains a major clinical obstacle, particularly due to the persistence of leukemia stem cells (LSCs) capable of metabolic adaptation. While venetoclax (Ven) inhibits oxidative phosphorylation (OXPHOS), we found that Ven-resistant LSCs undergo glycolytic reprogramming to bypass OXPHOS inhibition. This metabolic shift is supported by enhanced ribosome biogenesis, sustained by upregulated de novo guanine nucleotide biosynthesis. Abundant guanine nucleotides suppress the impaired ribosome biogenesis checkpoint (IRBC), leading to TP53 destabilization and persistent MYC expression. Inhibition of inosine monophosphate dehydrogenases (IMPDH1/2) depletes guanine nucleotides, activates IRBC, stabilizes TP53, represses MYC, and impairs the metabolic shift to glycolysis. This metabolic rewiring disrupts LSC stemness and suppresses the reconstitution of human AML cells in xenotransplantation experiments. Notably, the suppression of LSC stemness was observed regardless of Ven resistance or the TP53 mutational status of AML cells. These findings reveal that mutation-independent TP53 inactivation is involved in resistant AML and suggest that targeting guanine nucleotide biosynthesis may offer a clinically actionable strategy to eradicate therapy-resistant LSCs.
    DOI:  https://doi.org/10.1182/blood.2025030209
  5. Mol Cell. 2025 Nov 06. pii: S1097-2765(25)00858-5. [Epub ahead of print]85(21): 3893-3894
    An orphan no more: SLC25A45 controls mitochondrial import of methylated amino acids.
    Zachary L Sebo, Navdeep S Chandel.
      Solute carrier (SLC) genes encode the largest membrane transporter superfamily, with many orphan members of unknown function. In recent Cell Metabolism and Molecular Cell articles, Khan et al. and Dias et al. identify SLC25A45 as essential for mitochondrial import of methylated amino acids and subsequent carnitine synthesis.
    DOI:  https://doi.org/10.1016/j.molcel.2025.10.017
  6. Nat Rev Urol. 2025 Nov 04.
    Mitochondrial metabolic alterations fuel bladder cancer initiation.
    Maria Chiara Masone.
      
    DOI:  https://doi.org/10.1038/s41585-025-01110-x
  7. Nat Commun. 2025 Nov 03. 16(1): 9690
    Targeting cancer glutamine dependency with a first-in-class inhibitor of the mitochondrial glutamine transporter SLC1A5_var.
    Yulseung Sung, Ya Chun Yu, Mirim Lee, Seonghun Lim, Yechan Lee, Mincheol Kang, Doru Kwon, Apeksha Parajulee, Junjeong Choi, Do Sik Min, Kuglae Kim, Wan Namkung, Yun-Hee Kim, Sang Myung Woo, Nam Doo Kim, Hee Chan Yoo, Jung Min Han.
      The mitochondrial glutamine transporter SLC1A5_var plays a central role in the metabolic reprogramming of cancer cells by facilitating glutamine import into mitochondria for energy production and redox homeostasis. Despite its critical function, the development of effective and selective inhibitors targeting SLC1A5_var has remained a significant challenge. Here, we introduce iMQT_020, a selective allosteric inhibitor identified through structure-based screening. iMQT_020 disrupts the trimeric assembly of SLC1A5_var, causing metabolic crisis in cancer cells and selectively suppressing their growth. Mechanistically, iMQT_020 reduces glutamine anaplerosis and oxidative phosphorylation, resulting in a broad disruption of cancer metabolism. Additionally, iMQT_020 treatment epigenetically upregulates PD-L1 expression, enhancing the efficacy of combination therapies with anti-PD-L1 immune checkpoint inhibitors. These findings highlight the therapeutic potential of targeting SLC1A5_var as a critical metabolic vulnerability in cancer and demonstrate that targeting allosteric interprotomer interactions is a novel and promising therapeutic strategy for cancer treatment.
    DOI:  https://doi.org/10.1038/s41467-025-64730-2
  8. Haematologica. 2025 Nov 06.
    Menin inhibitor DS-1594b drives differentiation and induces synergistic lethality in combination with venetoclax in acute myeloid leukemia cells with rearranged mixed-lineage leukemia and mutated nucleophosmin-1.
    Valerio Ciaurro, Vassilena Sharlandjieva, Anna Skwarska, Catherine Chahrour, Natalia Baran, Zhihong Zeng, Cassandra Ramage, Naval Daver, Bing Z Carter, Sovira Chaundhry, Palaniraja Thandapani, Maria Paola Martelli, Thomas A Milne, Marina Konopleva.
      Mixed-lineage leukemia (MLL) rearrangements and Nucleophosmin-1 (NPM1) mutations are associated with acute leukemias whose pathogenesis is critically influenced by protein-protein interactions between menin and MLL. We hypothesized that targeting the menin-MLL interaction using DS-1594b and blocking the antiapoptotic BCL-2 protein using venetoclax may promote differentiation and enhance eradication of MLL-rearranged and NPM1-mutated leukemias models. We treated acute myeloid leukemia (AML) cell lines with MLL rearrangements, NPM1 mutations, other leukemias and primary samples from AML patients with venetoclax alone, DS- 1594b alone, and their combination. We measured proliferation, viability, apoptosis, and differentiation using a variety of cellular assays, Western blotting, and BH3 profiling. Treatment with DS-1594b and venetoclax exerted significant synergy, resulting in enhanced differentiation and inhibited proliferation across several cell lines. In the NPM1-mutated AML PDX model, DS- 1594b single-agent treatment significantly extended survival. Importantly, compared with DS- 1594b monotherapy, the combination of DS-1594b and venetoclax more profoundly reduced leukemic burden and prolonged mouse survival. Menin inhibition was the primary driver of transcription changes in this model and impacted the expression of antiapoptotic regulators, providing a mechanistic explanation for the synergy observed between these drugs. Overall, we observed synergistic effects on differentiation induction and proliferation inhibition, both in vitro and in vivo. Together, our studies underscore the promise of this combination strategy as a novel therapeutic approach for improving treatment outcomes in patients with these specific genomic alterations.
    DOI:  https://doi.org/10.3324/haematol.2024.286833
  9. Cell Death Dis. 2025 Nov 04. 16(1): 792
    A novel strategy to target metabolic dependencies in acute myeloid leukemia.
    Nithya Balasundaram, Hamenth Kumar Palani, Arvind Venkatraman, Yolanda Augustin, Shruthi Pichandi, Clement Regnault, Majeela Solomon, Abirami Rajasekaran, Mohammed Yasar, Swathy Palani Kumar, Reeshma Nair Radhakrishnan, Anu Korula, Uday Prakash Kulkarni, Eunice Sindhuvi Edison, Poonkuzhali Balasubramanian, Biju George, Aby Abraham, Sanjeev Krishna, Vikram Mathews.
      Acute myeloid leukemia (AML) remains difficult to cure despite recent advances. Off-target side effects of drugs currently used lead to significant morbidity and mortality. There is recognition that in AML, there is an increased dependence on OXPHOS metabolism, especially in the leukemia stem cell compartment (AML-LSC). It is also recognized that there is potential to exploit this vulnerability to treat AML. Drug re-purposing screens have suggested the potential use of artesunate (ART) to inhibit mitochondrial respiration. We have explored the potential role of ART as an additive agent in treating AML in combination with conventional therapy. Through in-vitro and in-vivo mouse model studies, we demonstrate the mechanism and efficacy of these combinations and their potential to overcome venetoclax resistance. We further demonstrate the specificity of these combinations with minimal off-target effects on normal hematopoietic stem cells (HSC). These observations warrant exploration of the additive role of ART in clinical trials.
    DOI:  https://doi.org/10.1038/s41419-025-08129-3
  10. Cell Death Differ. 2025 Nov 03.
    Mitochondria-transliterated ALDH1L1 functions as a feedback regulator of redox homeostasis in cancer cells to enhance the resistance to pro-oxidative therapy.
    Dan Wu, Xin Zhao, Caiyu Shi, Jing Zhao, Zeyu Yan, Runjiao Zhang, Xianchun Lan, Jiaze An, Qichao Huang, Xianli He, Tingting Ren, Jinliang Xing.
      To prevent cell death induced by elevated oxidative stress, cancer cells activate a series of antioxidant defense mechanisms to mitigate cytotoxicity, thereby enhancing the resistance to pro-oxidative therapy. However, the underlying antioxidant mechanisms in cancer cells remain inadequately understood. Through co-immunoprecipitation followed by quantitative mass spectrometry analysis, we for the first time identified that cytoplasmic ALDH1L1 translocates into mitochondria and co-localizes with mitochondrial transcription factor TFAM in cancer cells in a ROS-dependent feedback manner. Mitochondria-translocated ALDH1L1 maintains mitochondrial redox homeostasis by producing NADPH. Moreover, our findings revealed that the ROS-mediated oxidative modification of ALDH1L1 is necessary for its interaction with HSP90β and subsequent translocation into mitochondria via TOM70, where it binds to TFAM to prevent degradation by LONP1. Furthermore, we found that mitochondrial ALDH1L1 antagonized the double-edged role of ROS in cancer cell survival, indicating that disruption of ALDH1L1 expression promoted cancer cell proliferation and autophagy but concurrently diminished cellular capacity to counteract ROS-induced apoptosis. Consistently, ALDH1L1 knockout enhanced the anti-tumor effect of low-dose pro-oxidant Elesclomol, thereby achieving better efficacy and safety of pro-oxidant therapy. Furthermore, our results demonstrated that the combination of Elesclomol with HSP90 inhibitor Ganetespib exhibited synergistic anti-tumor effects. In conclusion, our findings that mitochondria-translocated ALDH1L1 functions as a feedback regulator of redox homeostasis in cancer cells to enhance the resistance to pro-oxidative therapy can provide critical insights into developing effective pro-oxidative therapies against tumors.
    DOI:  https://doi.org/10.1038/s41418-025-01604-6
  11. Science. 2025 Nov 06. eadx9717
    NUDT5 regulates purine metabolism and thiopurine sensitivity by interacting with PPAT.
    Zheng Wu, Phong T Nguyen, Varun Sondhi, Run-Wen Yao, Zhifang Lu, Tao Dai, Jui-Chung Chiang, Feng Cai, Imani M Williams, Eliot B Blatt, Zengfu Shang, Ling Cai, Jing Zhang, Mya D Moore, Islam Alshamleh, Xiangyi Li, Tamaratare Ogu, Lauren G Zacharias, Rainah Winston, Joao S Patricio, Xandria Johnson, Wei-Min Chen, Qian Cong, Thomas P Mathews, Yuanyuan Zhang, Limei Zhang, Ralph J DeBerardinis.
      Cells generate purine nucleotides through de novo purine biosynthesis (DNPB) and purine salvage. Purine salvage represses DNPB to prevent excessive purine nucleotide synthesis through mechanisms that are incompletely understood. We identified Nudix hydrolase 5 (NUDT5) as a DNPB regulator. During purine salvage, NUDT5 suppresses DNPB independently of its catalytic function but through interaction with phosphoribosyl pyrophosphate amidotransferase (PPAT), the rate-limiting enzyme in the DNPB pathway. The NUDT5-PPAT interaction promoted PPAT oligomerization, suppressed PPAT's enzymatic activity, and facilitated disassembly of the purinosome, a metabolon that functions in DNPB. Disrupting the NUDT5-PPAT interaction overcame DNPB suppression during purine salvage, permitting excessive DNPB and inducing thiopurine resistance. Therefore, NUDT5 governs the balance between DNPB and salvage to maintain appropriate cellular purine nucleotide concentrations.
    DOI:  https://doi.org/10.1126/science.adx9717
  12. Nat Commun. 2025 Nov 04. 16(1): 9664
    Regenerating liver uses ammonia to support de novo pyrimidine synthesis and cell proliferation.
    Berwini B Endaya, Lukáš Kučera, Dan-Diem Thi Le, Jessica B Spinelli, Andrea Brožková, Dominika Luptáková, Kryštof Klíma, Gabriela L Oliveira, Petra Brisudová, Klára Boháčová, Štěpána Boukalová, Renata Zobalová, František Kolář, Karel Chalupsky, Klára Dohnalová, Arash Yarmohammadi-Barzegar, Šárka Dvořáková, Evgeniya Biryukova, Marta Kaliaeva, Vladimír Havlíček, Radislav Sedláček, Jan Procházka, Libor Vítek, Sunghyouk Park, Pavel Martásek, Zdeněk Krška, Paulo J Oliveira, Michael V Berridge, Jiří Neužil.
      Liver is endowed with high regenerative activity, so that the tissue regrows in mouse after partial hepatectomy within days. We reason that this requires de novo pyrimidine synthesis to support rapid progression via the cell cycle. We find that suppression of de novo pyrimidine synthesis prevents proliferation in regenerating liver, suppressing liver regrowth. Tracing studies and spatial metabolomics reveal a metabolic shift such that ammonia, normally detoxified to urea in the periportal region under homeostasis, is redirected for generating aspartate and carbamoyl phosphate periportally, and glutamine pericentrally, and these products are utilized as precursors by the de novo pyrimidine synthesis pathway. Our research uncovers a metabolic reprogramming leading to utilization of a toxic byproduct for anabolic pathways that are essential for liver regeneration.
    DOI:  https://doi.org/10.1038/s41467-025-65451-2
  13. Nat Rev Mol Cell Biol. 2025 Nov 03.
    Silencing of mitochondrial gene expression using polymorpholino chimeras.
    Drishan Dahal.
      
    DOI:  https://doi.org/10.1038/s41580-025-00923-3
  14. Curr Biol. 2025 Nov 03. pii: S0960-9822(25)01254-0. [Epub ahead of print]35(21): R1053-R1055
    Size control: Tune the mitochondrial volume to time your cell division!
    Mikael Björklund.
      A new study links mitochondrial volume control with growth and cell division, suggesting that cells not only sense their mitochondrial content but also use this information to decide when to divide.
    DOI:  https://doi.org/10.1016/j.cub.2025.09.054
  15. J Biol Chem. 2025 Nov 04. pii: S0021-9258(25)02735-8. [Epub ahead of print] 110883
    Cyclophilin D is a new non-canonical substrate of the mitochondrial intermembrane space assembly pathway.
    Mara Equisoain Redin, Veronica Bazzani, Eve Harding, Joshua McHale, Carlo Vascotto.
      Mitochondrial protein import is essential for organelle function and cellular homeostasis. While Cyclophilin D (CypD) is a well-characterized regulator of the mitochondrial permeability transition pore (MPTP) and resides in the matrix, the mechanisms underlying its import remain poorly defined. In this study, we identify CypD as a novel non-canonical substrate of the mitochondrial intermembrane space assembly (MIA) pathway mediated by the oxidoreductase Mia40. Structural analysis revealed conserved cysteine pairs in CypD that are compatible with disulfide bond formation. Using in vitro pull-down assays, we demonstrate a redox-sensitive interaction between CypD and Mia40, which was further confirmed by co-immunoprecipitation and proximity ligation assays. Expression of CypD cysteine mutants in cells revealed that residues Cys82 and Cys203 are critical for Mia40-dependent interaction and protein stability. Notably, expression of the Cys203Ala mutant significantly reduced cell viability, suggesting a key functional role for this residue. Functional experiments showed that depletion of Mia40 leads to a significant reduction in mitochondrial CypD levels, a result that was confirmed in a series of leukemia cell lines with variable Mia40 expression. Our results shed light on a previously unrecognized import mechanism for CypD and expand the known substrate repertoire of Mia40, demonstrating that the MIA pathway also contributes to the import of mitochondrial matrix proteins. This work highlights the functional versatility of the MIA pathway beyond the intermembrane space and reveals an additional regulatory level in mitochondrial proteostasis with implications for cell death signalling and mitochondrial pathophysiology.
    Keywords:  Cyclophilin D; Mia40; mitochondria; protein import; redox
    DOI:  https://doi.org/10.1016/j.jbc.2025.110883
  16. Acta Biochim Biophys Sin (Shanghai). 2025 Nov 03.
    ANT1 suppression inhibits the progression of colorectal cancer by suppressing PINK1/Parkin-mediated mitophagy.
    Jin Ji, Mingrui Jiang, Shantanu Baral, Qiannan Sun, Dong Tang, Wei Wang, Jun Ren, Daorong Wang.
      Mitochondrial dysfunction is closely related to tumor development. Adenine nucleotide translocator 1 (ANT1), which promotes ADP/ATP translocation across the inner mitochondrial membrane, is an important protein involved in mitochondrial function and plays a role in a variety of diseases, including cancers. However, its role in colorectal cancer (CRC) progression remains poorly understood. This study aims to explore the potential role of ANT1 in CRC and its relationship with mitophagy. Through immunohistochemical analysis, we find that ANT1 expression is significantly higher in the tumor tissues of CRC patients than in adjacent normal tissues and that its overexpression is associated with poor prognosis. Further experiments demonstrate that ANT1 knockdown significantly inhibits CRC cell proliferation, migration, and invasion and leads to mitochondrial dysfunction, increased ROS production, and apoptosis by suppressing mitophagy. Mechanistically, ANT1 knockdown downregulates the PINK1/Parkin pathway, thereby inhibiting mitophagy activity. Notably, PINK1 overexpression partially rescues the cellular dysfunction induced by ANT1 knockdown, suggesting a potential role for PINK1 in reversing the suppression of mitophagy. In vivo xenograft models also show that ANT1 knockdown markedly inhibits tumor growth. In conclusion, ANT1 may play a critical role in CRC progression by regulating mitophagy, providing a basis for its potential as a therapeutic target.
    Keywords:  PINK1; Parkin; adenine nucleotide translocator 1; colorectal cancer; mitophagy
    DOI:  https://doi.org/10.3724/abbs.2025154
  17. NPJ Metab Health Dis. 2025 Nov 07. 3(1): 43
    Cysteine S-acetylation is a widespread post-translational modification on metabolic proteins.
    E Keith Keenan, Akshay Bareja, Yannie Lam, Paul A Grimsrud, Matthew D Hirschey.
      Protein acetylation is a fundamental regulatory mechanism occurring primarily on lysine amino acids. Here we report systematic in vivo characterization of cysteine S-acetylation as a widespread post-translational modification in mammalian tissues. By developing specialized sample preparation methods that preserve the labile thioester bond, we identified over 400 sites of cysteine acetylation in mouse liver, mirroring the abundance of lysine acetylation. Proteomic surveys across nine murine tissues revealed tissue-specific acetylation patterns that are enriched on metabolic enzymes in the cytoplasm. Cold exposure in mice triggers coordinated remodeling of the brown adipose tissue cysteine acetylome. Functional studies demonstrate that the acetylation of GAPDH Cys150 abolishes catalytic activity and correlates with nuclear enrichment, paralleling the known effects of S-nitrosylation on this enzyme. These findings establish cysteine acetylation as a widespread modification of metabolic proteins that responds to changes in cellular acetyl-CoA availability, fundamentally expanding the landscape of protein acetylation beyond lysine.
    DOI:  https://doi.org/10.1038/s44324-025-00081-2
  18. Ann Hematol. 2025 Nov 07.
    Phytochemicals in overcoming venetoclax resistance in acute myeloid leukemia: mechanistic insights and therapeutic potential.
    Suresh Prajapati, Mansi Patel, Charmi Jyotishi, Reeshu Gupta.
      This review critically examines the complex mechanisms underlying venetoclax resistance in acute myeloid leukemia (AML) and explores the therapeutic potential of phytochemicals in overcoming this resistance. Emerging evidence suggests that resistance to venetoclax arises through multiple pathways, including the overexpression of anti-apoptotic proteins, such as MCL1 and BCL2L1, mitochondrial adaptations, metabolic rewiring, and genetic mutations in key regulators, such as TP53 and KMT2A. Phytochemicals, including curcumin, quercetin, triptolide, and parthenolide, have demonstrated anti-leukemic and chemosensitizing activities by modulating BCL2 family proteins and associated apoptotic pathways. Furthermore, in silico docking analyses indicated that several terpenoids possess strong binding affinities to BCL2 protein, in some cases outperforming venetoclax, highlighting their potential as alternative or complementary agents. Preclinical studies underscore the ability of phytochemicals to synergize with venetoclax, enhancing apoptosis and reducing leukemic burden while exhibiting minimal toxicity to normal hematopoietic cells. These bioactive compounds exert pleiotropic effects by modulating redox homeostasis, microRNA expression, epigenetic remodelling, and mitochondrial function, offering a multi-targeted approach to overcoming drug resistance. Despite their promise, translational challenges persist, notably poor solubility, limited bioavailability, and insufficient clinical validation of these compounds. Future research should prioritize the development of advanced delivery systems, such as nanoparticle formulations, and initiate well-designed clinical trials to evaluate the safety, pharmacokinetics, and efficacy of phytochemical-venetoclax combinations in AML.
    Keywords:  Acute Myeloid Leukemia; Chemoresistance; Phytochemicals; Venetoclax
    DOI:  https://doi.org/10.1007/s00277-025-06710-6
  19. Case Rep Hematol. 2025 ;2025 4335095
    Potential Off-Target Effect of Gilteritinib With Venetoclax Decreases Tumor Burden for Patients With Relapsed/Refractory Wild-Type FLT3 Acute Myeloid Leukemia/Myelodysplastic Neoplasms.
    Shuting Chang, Zhijuan Pan, Yiqun Zhang, Ying Zhang, Jiajia Sun, Yanru Guo, Xinlei Guo, Zhiping Guo.
      Many tyrosine kinase inhibitors show nonspecific activity against multiple kinases, causing off-target effects when used in a broad patient population. This study evaluated the effectiveness of gilteritinib combined with venetoclax in patients with relapsed/refractory (R/R) acute myeloid leukemia (AML) or myelodysplastic neoplasms (MDS) with wild-type FLT3, who currently lack targeted therapy. After a 28-day cycle of venetoclax-gilteritinib therapy, one patient with R/R AML and other genetic alterations achieved minimal residual disease (MRD)-positive complete remission (CR) with incomplete hematologic recovery (CRi). Another patient with R/R ASXL1-mutated MDS/AML achieved morphologic leukemia-free state (MLFS) after one cycle, but cytopenias persisted across two cycles. A patient with R/R TP53-mutated AML related to myelodysplasia did not respond (NR) after two cycles, although the blast percentage in bone marrow (BM) and peripheral blood (PB) decreased by 50%. In a patient with R/R AML carrying an in-frame bZIP-mutated CEBPA, NR and disease progression occurred after one cycle, but elevated white blood cell (WBC) counts declined after treatment initiation and lasted for 2 weeks. These findings suggest that combining gilteritinib with venetoclax may reduce tumor burden in R/R AML/MDS patients with wild-type FLT3.
    Keywords:  acute myeloid leukemia; gilteritinib; myelodysplastic neoplasms; refractory; relapsed; venetoclax; wild-type FLT3
    DOI:  https://doi.org/10.1155/crh/4335095
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