bims-mibica Biomed News
on Mitochondrial bioenergetics in cancer
Issue of 2025–04–27
23 papers selected by
Kelsey Fisher-Wellman, Wake Forest University
  1. Mitochondrial NADPH fuels mitochondrial fatty acid synthesis and lipoylation to power oxidative metabolism.
  2. Mitochondrial transfer drives immune evasion in tumor microenvironment.
  3. Glutaminase-1 Mediated Glutaminolysis to Glutathione Synthesis Maintains Redox Homeostasis and Modulates Ferroptosis Sensitivity in Cancer Cells.
  4. Cell biology: Mitochondrial protease degrades unoccupied translocases upon import stress.
  5. Phospholipase D6 activates Wnt/β-catenin signaling through mitochondrial metabolic reprogramming to promote tumorigenesis in colorectal cancer.
  6. OXPHOS inhibition overcomes chemoresistance in triple negative breast cancer.
  7. DHODH modulates immune evasion of cancer cells via CDP-Choline dependent regulation of phospholipid metabolism and ferroptosis.
  8. Mitochondrial protein OPA1 is required for the expansion of effector CD8 T cells.
  9. NADH:ubiquinone oxidoreductase core subunit S8 expression and functional significance in non-small cell lung cancer.
  10. Combined inhibition of de novo glutathione and nucleotide biosynthesis is synthetically lethal in glioblastoma.
  11. Metabolic Effects of the Cancer Metastasis Modulator MEMO1.
  12. Treatment of acute myeloid leukemia models by targeting a cell surface RNA-binding protein.
  13. Mechanisms of chemotherapy failure in refractory/relapsed acute myeloid leukemia: the role of cytarabine resistance and mitochondrial metabolism.
  14. TOM20-driven E3 ligase recruitment regulates mitochondrial dynamics through PLD6.
  15. Conformational plasticity of mitochondrial VDAC2 controls the kinetics of its interaction with cytosolic proteins.
  16. Human RCC1L is involved in the maintenance of mitochondrial nucleoids and mtDNA.
  17. A new method to measure cell metabolism of rare cells in vivo reveals a high oxidative phosphorylation dependence of lung T cells.
  18. Mitochondrial Dysfunction and Reduced TCA Cycle Metabolite Levels in Inflammatory Bowel Disease Patients.
  19. Origin and evolution of mitochondrial inner membrane composition.
  20. Blood cancer driven by 'one hit' mutation event undergoes rapid growth.
  21. SMAD3 and PINK1 constitute a new positive feedback loop in regulation of mitophagy.
  22. An orally administered gene editing nanoparticle boosts chemo-immunotherapy in colorectal cancer.
  23. Downregulation of rRNA synthesis by BCL-2 induces chemoresistance in diffuse large B cell lymphoma.
  1. Nat Cell Biol. 2025 Apr 21.
    Mitochondrial NADPH fuels mitochondrial fatty acid synthesis and lipoylation to power oxidative metabolism.
    Dohun Kim, Rushendhiran Kesavan, Kevin Ryu, Trishna Dey, Austin Marckx, Cameron Menezes, Prakash P Praharaj, Stewart Morley, Bookyong Ko, Mona H Soflaee, Harrison J Tom, Harrison Brown, Hieu S Vu, Shih-Chia Tso, Chad A Brautigam, Andrew Lemoff, Marcel Mettlen, Prashant Mishra, Feng Cai, Doug K Allen, Gerta Hoxhaj.
      Nicotinamide adenine dinucleotide phosphate (NADPH) is a vital electron donor essential for macromolecular biosynthesis and protection against oxidative stress. Although NADPH is compartmentalized within the cytosol and mitochondria, the specific functions of mitochondrial NADPH remain largely unexplored. Here we demonstrate that NAD+ kinase 2 (NADK2), the principal enzyme responsible for mitochondrial NADPH production, is critical for maintaining protein lipoylation, a conserved lipid modification necessary for the optimal activity of multiple mitochondrial enzyme complexes, including the pyruvate dehydrogenase complex. The mitochondrial fatty acid synthesis (mtFAS) pathway utilizes NADPH for generating protein-bound acyl groups, including lipoic acid. By developing a mass-spectrometry-based method to assess mammalian mtFAS, we reveal that NADK2 is crucial for mtFAS activity. NADK2 deficiency impairs mtFAS-associated processes, leading to reduced cellular respiration and mitochondrial translation. Our findings support a model in which mitochondrial NADPH fuels the mtFAS pathway, thereby sustaining protein lipoylation and mitochondrial oxidative metabolism.
    DOI:  https://doi.org/10.1038/s41556-025-01655-4
  2. Trends Cancer. 2025 Apr 22. pii: S2405-8033(25)00094-9. [Epub ahead of print]
    Mitochondrial transfer drives immune evasion in tumor microenvironment.
    Qiang Cai, Xiaojun Cai, Quazi T H Shubhra.
      Tumors subvert T cell metabolism through diverse mechanisms. Ikeda et al. reveal mitochondrial transfer as a tumor-driven immune evasion strategy, where cancer cells deliver dysfunctional mitochondria to T cells, impairing metabolism and inducing exhaustion. These findings highlight mitochondrial dynamics as a promising therapeutic target to improve immunotherapy outcomes.
    Keywords:  T cell exhaustion; cancer immunotherapy; mitochondrial transfer; tumor microenvironment
    DOI:  https://doi.org/10.1016/j.trecan.2025.04.002
  3. Cell Prolif. 2025 Apr 21. e70036
    Glutaminase-1 Mediated Glutaminolysis to Glutathione Synthesis Maintains Redox Homeostasis and Modulates Ferroptosis Sensitivity in Cancer Cells.
    Changsen Bai, Jialei Hua, Donghua Meng, Yue Xu, Benfu Zhong, Miao Liu, Zhaosong Wang, Wei Zhou, Liming Liu, Hailong Wang, Yang Liu, Lifang Li, Xiuju Chen, Yueguo Li.
      Glutaminase-1 (GLS1) has garnered considerable interest as a metabolic target in cancer due to its heightened involvement and activity. However, the precise fate of glutaminolysis catalysed by GLS1 in cancer cells remains elusive. We found that GLS1 knockout led to significant suppression of cancer cell proliferation, which can be reversed or partially restored by supplementation of glutamate or non-essential amino acids that can be converted into glutamate. The addition of spliceosomal KGA or GAC ameliorates cancer cell growth in vitro and in vivo, providing both simultaneously completely reverse the effect. The primary metabolic fate of glutamate produced through glutaminolysis in cancer cells is mainly used to produce glutathione (GSH) for redox homeostasis, not entering the tricarboxylic acid cycle or synthesising nucleotides. GSH monoethyl ester (GSH-MEE) effectively rescues the inhibition of cancer cell proliferation caused by GLS1 knockout. Deletion of GLS1 results in an elevation of reactive oxygen species (ROS) and malondialdehyde (MDA), a reduction of NADPH/NADP+ ratio, and an augmented susceptibility of cells to ferroptosis. Glutathione Peroxidase 4 (GPX4) and GPX1 exhibit complementary roles in redox regulation, with GLS1 knockout promoting GPX4 degradation. Pharmacological inhibition of GLS1 synergises with GPX4 inhibitor to suppress tumour growth. Dual targeting of GPX4 and GPX1 presents a potent anti-cancer strategy. This metabolic mechanism facilitates a deeper comprehension of the abnormal glutamine metabolism in cancer cells, establishing a theoretical basis for the potential clinical utilisation of GLS1 inhibitors and presenting novel perspectives for advancing combinatorial therapeutic approaches.
    Keywords:  GLS1; GPX4; GSH; cancer cell; ferroptosis; glutamate
    DOI:  https://doi.org/10.1111/cpr.70036
  4. Curr Biol. 2025 Apr 21. pii: S0960-9822(25)00296-9. [Epub ahead of print]35(8): R287-R290
    Cell biology: Mitochondrial protease degrades unoccupied translocases upon import stress.
    Mohamed A Eldeeb, Michael Shahid, Edward A Fon.
      Dysregulation of mitochondrial protein import induces significant cellular stress. Yet, our understanding of the dialogue between mitochondrial import, the stress it can trigger, and counteracting mechanisms remains incomplete. A recent study unveils how the mitochondrial protease YME1L1 degrades unoccupied mitochondrial translocases during mitochondrial import stress.
    DOI:  https://doi.org/10.1016/j.cub.2025.03.011
  5. Exp Mol Med. 2025 Apr 21.
    Phospholipase D6 activates Wnt/β-catenin signaling through mitochondrial metabolic reprogramming to promote tumorigenesis in colorectal cancer.
    Hyun Ji Lee, Seong Hun Lim, Hyesung Lee, Jung Min Han, Do Sik Min.
      Phospholipase D6 (PLD6) is a critical enzyme involved in mitochondrial fusion with a key role in spermatogenesis. However, the role of PLD6 in cancer remains unknown. Notably, Wnt signaling, energy metabolism and mitochondrial function show complex interactions in colorectal cancer (CRC) progression. Here we found that PLD6 is highly expressed in CRC and positively correlated with poor prognosis. We present a novel function of PLD6 in activating Wnt/β-catenin signaling by enhancing mitochondrial metabolism. PLD6 depletion suppresses the oncogenic properties of CRC cells and impairs mitochondrial respiration, leading to reduced mitochondrial length, membrane potential, calcium levels and reactive oxygen species. PLD6 depletion also disrupts mitochondrial metabolic reprogramming by inhibiting the tricarboxylic acid cycle and mitochondrial oxidative phosphorylation, resulting in altered intracellular levels of citrate and acetyl-CoA-both key modulators of Wnt/β-catenin activation. PLD6-mediated acetyl-CoA production enhances β-catenin stability by promoting its acetylation via the acetyltransferases CREB-binding protein and P300/CREB-binding-protein-associated factor. Consequently, PLD6 ablation reduces cancer stem cell-associated gene expression downstream of Wnt/β-catenin signaling, suppressing stem-like traits and chemoresistance to 5-fluorouracil. Furthermore, PLD6 depletion attenuates CRC tumorigenesis in both subcutaneous and orthotopic tumor models. Overall, PLD6 acts as an oncogenic switch by promoting mitochondria-mediated retrograde signaling, thereby regulating Wnt signaling in CRC.
    DOI:  https://doi.org/10.1038/s12276-025-01446-9
  6. Redox Biol. 2025 Apr 15. pii: S2213-2317(25)00150-8. [Epub ahead of print]83 103637
    OXPHOS inhibition overcomes chemoresistance in triple negative breast cancer.
    Cemile Uslu, Eda Kapan, Alex Lyakhovich.
      The hypothesis of a significant shift from oxidative phosphorylation (OXPHOS) to glycolysis in a number of solid tumors has been dominant for many years. Recently, however, evidence has begun to accumulate that OXPHOS is the major mode of energy production in many neoplasias, especially those that have undergone chemo- or radiotherapy, and especially in chemoresistant malignancies. In the present work, we demonstrated that chemoresistant triple-negative breast cancer cells prefer to obtain energy via OXPHOS to a greater extent than cells sensitive to chemotherapeutic agents, and therefore the former can be affected by some OXPHOS inhibitors. From a drug library containing several dozen antimicrobials, we selected those that inhibit OXPHOS in resistant TNBC cells and lead to mitochondrial dysfunction. We have also identified several pathways by which inhibition of growth suppression of chemoresistant cells occurs, including increased oxidative stress and mitophagy. Experiments in mice showed that selected OXPHOS inhibitors preferentially suppress tumor growth from chemoresistant but not from chemosensitive cells. The results of the present study suggest combinatorial therapy of such inhibitors and conventional anticancer drugs on resistant forms of tumors, if the latter show enhanced OXPHOS.
    Keywords:  Antimicrobials; Autophagy; Cancer resistance; Mitochondria; Oxidative phosphorylation; Triple negative breast tumors
    DOI:  https://doi.org/10.1016/j.redox.2025.103637
  7. Nat Commun. 2025 Apr 24. 16(1): 3867
    DHODH modulates immune evasion of cancer cells via CDP-Choline dependent regulation of phospholipid metabolism and ferroptosis.
    Da Teng, Kenneth D Swanson, Ruiheng Wang, Aojia Zhuang, Haofeng Wu, Zhixin Niu, Li Cai, Faith R Avritt, Lei Gu, John M Asara, Yaqing Zhang, Bin Zheng.
      The ability of cancer cells to evade immune destruction is governed by various intrinsic factors including their metabolic state. Here we demonstrate that inactivation of dihydroorotate dehydrogenase (DHODH), a pyrimidine synthesis enzyme, increases cancer cell sensitivity to T cell cytotoxicity through induction of ferroptosis. Lipidomic and metabolomic analyses reveal that DHODH inhibition reduces CDP-choline level and attenuates the synthesis of phosphatidylcholine (PC) via the CDP-choline-dependent Kennedy pathway. To compensate this loss, there is increased synthesis from phosphatidylethanolamine via the phospholipid methylation pathway resulting in increased generation of very long chain polyunsaturated fatty acid-containing PCs. Importantly, inactivation of Dhodh in cancer cells promotes the infiltration of interferon γ-secreting CD8+ T cells and enhances the anti-tumor activity of PD-1 blockade in female mouse models. Our findings reveal the importance of DHODH in regulating immune evasion through a CDP-choline dependent mechanism and implicate DHODH as a promising target to improve the efficacy of cancer immunotherapies.
    DOI:  https://doi.org/10.1038/s41467-025-59307-y
  8. Cell Rep. 2025 Apr 21. pii: S2211-1247(25)00381-X. [Epub ahead of print]44(5): 115610
    Mitochondrial protein OPA1 is required for the expansion of effector CD8 T cells.
    Benjamin A S Willett, Scott B Thompson, Vincent Chen, Anza Dareshouri, Conner L Jackson, Tonya Brunetti, Angelo D'Alessandro, Jared Klarquist, Travis Nemkov, Ross M Kedl.
      Short-lived effector cells are characterized metabolically by a highly glycolytic state, driving energy and biomass acquisition, whereas memory-fated T cells have historically been described as meeting these requirements through mitochondrial metabolism. Here, we show that the mitochondrial protein optic atrophy 1 (OPA1) is critical for rapidly dividing CD8 T cells in vivo, the requirement for which is most pronounced in effector CD8 T cells. More specifically, OPA1 supports proper cell cycle initiation and progression and the viability and survival of CD8 T cells during clonal expansion. Use of mice deficient in the mitochondrial membrane fusion proteins Mitofusin 1 and 2 (MFN1/2) in both in vivo proliferation/differentiation assays and ex vivo metabolic analysis indicates that the requirement for OPA1 during cell division supersedes its role in mitochondrial fusion. We conclude that OPA1 is critical for the generation and accumulation of short-lived effector cells that arise during the response to infection.
    Keywords:  CD8; CP: Immunology; Mitofusins; Opa1; T cell; metabolism
    DOI:  https://doi.org/10.1016/j.celrep.2025.115610
  9. Cell Death Dis. 2025 Apr 21. 16(1): 321
    NADH:ubiquinone oxidoreductase core subunit S8 expression and functional significance in non-small cell lung cancer.
    Weihua Xu, Hongpeng Fang, Xianbao Cao, Min-Zhao Xu, Yubo Yan, Mingjing Shen, Yi Yang, Kanqiu Jiang.
      Hyperfunctional mitochondria provide a growth advantage by supporting the energy-intensive processes essential for non-small cell lung cancer (NSCLC). NADH:ubiquinone oxidoreductase core subunit S8 (NDUFS8) is a key subunit of mitochondrial complex I involved in oxidative phosphorylation (OXPHOS) and cellular energy production. Bioinformatics and local tissue examinations show that NDUFS8 expression is elevated in NSCLC compared to normal lung tissue. Both immortalized and primary human NSCLC cells exhibit higher NDUFS8 levels. Single-cell RNA sequencing confirmed NDUFS8 upregulation in cancerous cells of NSCLC tumor. Silencing NDUFS8 via shRNA or Cas9/sgRNA-mediated knockout (KO) disrupted mitochondrial functions, leading to decreased complex I activity, ATP depletion, mitochondrial depolarization, increased reactive oxygen species (ROS) production, and heightened lipid peroxidation. Furthermore, NDUFS8 silencing/KO triggered apoptosis and significantly reduced Akt-mTOR activation, cell viability, proliferation, and motility in various NSCLC cells. In contrast, ectopic overexpression of NDUFS8 boosted mitochondrial complex I activity and ATP levels, promoting Akt-mTOR activation, and enhancing NSCLC cell proliferation and motility. NDUFS8 also contributes to radioresistance in NSCLC; silencing or KO enhanced ionizing radiation (IR)-induced cytotoxicity, while overexpression mitigated it. Intratumoral injection of NDUFS8 shRNA-expressing adeno-associated virus significantly inhibited growth of primary NSCLC xenografts in nude mice, with observed NDUFS8 silencing, ATP reduction, oxidative damage, proliferation inhibition, Akt-mTOR inactivation and apoptosis in treated tissues. These findings highlight the pivotal pro-tumorigenic role of NDUFS8 in NSCLC.
    DOI:  https://doi.org/10.1038/s41419-025-07638-5
  10. Cell Rep. 2025 Apr 19. pii: S2211-1247(25)00367-5. [Epub ahead of print]44(5): 115596
    Combined inhibition of de novo glutathione and nucleotide biosynthesis is synthetically lethal in glioblastoma.
    Suresh Udutha, Céline Taglang, Georgios Batsios, Anne Marie Gillespie, Meryssa Tran, Johanna Ten Hoeve, Thomas G Graeber, Pavithra Viswanath.
      Understanding the mechanisms by which oncogenic events alter metabolism will help identify metabolic weaknesses that can be targeted for therapy. Telomerase reverse transcriptase (TERT) is essential for telomere maintenance in most cancers. Here, we show that TERT acts via the transcription factor forkhead box O1 (FOXO1) to upregulate glutamate-cysteine ligase (GCLC), the rate-limiting enzyme for de novo biosynthesis of glutathione (GSH, reduced) in multiple cancer models, including glioblastoma (GBM). Genetic ablation of GCLC or pharmacological inhibition using buthionine sulfoximine (BSO) reduces GSH synthesis from [U-13C]-glutamine in GBMs. However, GCLC inhibition drives de novo pyrimidine nucleotide biosynthesis by upregulating the glutamine-utilizing enzymes glutaminase (GLS) and carbamoyl-phosphate synthetase 2, aspartate transcarbamoylase, and dihydroorotatase (CAD) in an MYC-driven manner. Combining BSO with the glutamine antagonist JHU-083 is synthetically lethal in vitro and in vivo and significantly extends the survival of mice bearing intracranial GBM xenografts. Collectively, our studies advance our understanding of oncogene-induced metabolic vulnerabilities in GBMs.
    Keywords:  CP: Cancer; CP: Metabolism; TERT; brain tumors; cancer; glioblastoma; glutamine metabolism; glutathione; in vivo stable isotope tracing; metabolic synthetic lethality; metabolomics; nucleotide biosynthesis; telomerase reverse transcriptase
    DOI:  https://doi.org/10.1016/j.celrep.2025.115596
  11. Metabolites. 2025 Apr 17. pii: 277. [Epub ahead of print]15(4):
    Metabolic Effects of the Cancer Metastasis Modulator MEMO1.
    Marziyeh Ghanbarian, Natalia Dolgova, Frederick S Vizeacoumar, Franco J Vizeacoumar, Deborah Michel, Anas El-Aneed, Oleg Y Dmitriev.
      Background/Objectives: Cancer cells often display altered energy metabolism. In particular, expression levels and activity of the tricarboxylic acid cycle (TCA cycle) enzymes may change in cancer, and dysregulation of the TCA cycle is a frequent hallmark of cancer cell metabolism. MEMO1, a modulator of cancer metastasis, has been shown to bind iron and regulate iron homeostasis in the cells. MEMO1 knockout changed mitochondrial morphology and iron content in breast cancer cells. Our previous genome-wide analysis of MEMO1 genetic interactions across multiple cancer cell lines revealed that gene sets involved in mitochondrial respiration and the TCA cycle are enriched among the gain-of-function interaction partners of MEMO1. Based on these findings, we measured the TCA cycle metabolite levels in breast cancer cells with varying levels of MEMO1 expression. Methods: ShRNA knockdown assay was performed to test essentiality of key TCA cycle enzymes. TCA metabolites were quantified using liquid chromatography-tandem mass spectrometry (LC-MS/MS) in MDA-MB-231 (high MEMO1), M67-2 (MEMO1 knockdown), and M67-9 (MEMO1 knockout) cells under iron-depleted, basal iron, and iron-supplemented conditions. Results:ACO2 and OGDH knockdowns inhibit cell proliferation, indicating an essential role of the TCA cycle in MDA-MB-231 metabolism. α-Ketoglutarate and citrate levels exhibited an inverse relationship with MEMO1 expression, increasing significantly in MEMO1 knockout cells regardless of iron availability. In contrast, fumarate, malate, and glutamate levels were elevated in MEMO1 knockout cells specifically under low iron conditions, suggesting an iron-dependent effect. Conclusions: Overall, our results indicate that MEMO1 plays a role in regulating the TCA in cancer cells in an iron-dependent manner.
    Keywords:  LC-MS/MS; MEMO1; breast cancer; cancer metastasis; energy metabolism; iron regulation; metal binding protein; tricarboxylic acid cycle
    DOI:  https://doi.org/10.3390/metabo15040277
  12. Nat Biotechnol. 2025 Apr 23.
    Treatment of acute myeloid leukemia models by targeting a cell surface RNA-binding protein.
    Benson M George, Maria Eleftheriou, Eliza Yankova, Jonathan Perr, Peiyuan Chai, Gianluca Nestola, Karim Almahayni, Siân Evans, Aristi Damaskou, Helena Hemberger, Charlotta G Lebedenko, Justyna Rak, Qi Yu, Ece Bapcum, James Russell, Jaana Bagri, Regan F Volk, Malte Spiekermann, Richard M Stone, George Giotopoulos, Brian J P Huntly, Joanna Baxter, Fernando Camargo, Jie Liu, Balyn W Zaro, George S Vassiliou, Leonhard Möckl, Jorge de la Rosa, Ryan A Flynn, Konstantinos Tzelepis.
      Immunotherapies for acute myeloid leukemia (AML) and other cancers are limited by a lack of tumor-specific targets. Here we discover that RNA-binding proteins and glycosylated RNAs (glycoRNAs) form precisely organized nanodomains on cancer cell surfaces. We characterize nucleophosmin (NPM1) as an abundant cell surface protein (csNPM1) on a variety of tumor types. With a focus on AML, we observe csNPM1 on blasts and leukemic stem cells but not on normal hematopoietic stem cells. We develop a monoclonal antibody to target csNPM1, which exhibits robust anti-tumor activity in multiple syngeneic and xenograft models of AML, including patient-derived xenografts, without observable toxicity. We find that csNPM1 is expressed in a mutation-agnostic manner on primary AML cells and may therefore offer a general strategy for detecting and treating AML. Surface profiling and in vivo work also demonstrate csNPM1 as a target on solid tumors. Our data suggest that csNPM1 and its neighboring glycoRNA-cell surface RNA-binding protein (csRBP) clusters may serve as an alternative antigen class for therapeutic targeting or cell identification.
    DOI:  https://doi.org/10.1038/s41587-025-02648-2
  13. Cell Death Dis. 2025 Apr 23. 16(1): 331
    Mechanisms of chemotherapy failure in refractory/relapsed acute myeloid leukemia: the role of cytarabine resistance and mitochondrial metabolism.
    Soo Yeon Chae, Se-Young Jang, Jinhui Kim, Sehyun Hwang, Disha Malani, Olli Kallioniemi, Seung Gyu Yun, Jong-Seo Kim, Hugh I Kim.
      Acute myeloid leukemia (AML) is an aggressive hematological malignancy. Patients with wild-type FLT3 relapsed or refractory (R/R) AML face significant therapeutic challenges due to the persistent lack of effective treatments. A comprehensive understanding of the mechanisms underlying chemotherapy resistance is needed to the development of effective treatment strategies. Therefore, we investigated the molecular mechanisms underlying cytarabine (Ara-C) resistance and daunorubicin (DNR) tolerance in Ara-C-resistant RHI-1 cells derived from the wild-type FLT3 AML cell line SHI-1. Quantitative analysis of intracellular drug concentrations, proteomics, and phosphoproteomics showed that DNR resistance in Ara-C-resistant RHI-1 cells is driven by metabolic remodeling toward mitochondrial metabolism, upregulation of DNA repair pathways, and enhanced reactive oxygen species (ROS) detoxification rather than reduced drug uptake. Moreover, targeting these compensatory mechanisms, particularly the OXPHOS complex I proteins, significantly improved the efficacy of both Ara-C and DNR. Conclusively, these findings highlight mitochondrial metabolism and DNA repair as critical factors in chemotherapy resistance and offer valuable insights into potential therapeutic targets for enhancing treatment outcomes in patients with wild-type FLT3 R/R AML.
    DOI:  https://doi.org/10.1038/s41419-025-07653-6
  14. Nat Chem Biol. 2025 Apr 22.
    TOM20-driven E3 ligase recruitment regulates mitochondrial dynamics through PLD6.
    Anat Raiff, Shidong Zhao, Aizat Bekturova, Colin Zenge, Shir Mazor, Xinyan Chen, Wenwen Ru, Yaara Makaros, Tslil Ast, Alban Ordureau, Chao Xu, Itay Koren.
      Mitochondrial homeostasis is maintained through complex regulatory mechanisms, including the balance of mitochondrial dynamics involving fusion and fission processes. A central player in this regulation is the ubiquitin-proteasome system (UPS), which controls the degradation of pivotal mitochondrial proteins. In this study, we identified cullin-RING E3 ligase 2 (CRL2) and its substrate receptor, FEM1B, as critical regulators of mitochondrial dynamics. Through proteomic analysis, we demonstrate here that FEM1B controls the turnover of PLD6, a key regulator of mitochondrial dynamics. Using structural and biochemical approaches, we show that FEM1B physically interacts with PLD6 and that this interaction is facilitated by the direct association of FEM1B with the mitochondrial import receptor TOM20. Ablation of FEM1B or disruption of the FEM1B-TOM20 interaction impairs PLD6 degradation and induces mitochondrial defects, phenocopying PLD6 overexpression. These findings underscore the importance of FEM1B in maintaining mitochondrial morphology and provide further mechanistic insights into how the UPS regulates mitochondrial homeostasis.
    DOI:  https://doi.org/10.1038/s41589-025-01894-4
  15. Sci Adv. 2025 Apr 25. 11(17): eadv4410
    Conformational plasticity of mitochondrial VDAC2 controls the kinetics of its interaction with cytosolic proteins.
    William M Rosencrans, Harisankar Khuntia, Motahareh Ghahari Larimi, Radhakrishnan Mahalakshmi, Tsyr-Yan Yu, Sergey M Bezrukov, Tatiana K Rostovtseva.
      The voltage-dependent anion channel (VDAC) is a key conduit of the mitochondrial outer membrane for water-soluble metabolites and ions. Among the three mammalian isoforms, VDAC2 is unique because of its embryonic lethality upon knockout. Using single-molecule electrophysiology, we investigate the biophysical properties that distinguish VDAC2 from VDAC1 and VDAC3. Unlike the latter, VDAC2 exhibits dynamic switching between multiple high-conductance, anion-selective substates. Using α-synuclein (αSyn)-a known VDAC1 cytosolic regulator-we found that higher-conductance substates correlate with increased on-rates of αSyn-VDAC2 interaction but shorter blockage times, maintaining a consistent equilibrium constant across all substates. This suggests that αSyn detects VDAC2's dynamic structural variations before final binding. We explored the dependence of VDAC2's unique amino-terminal extension and cysteines on substate behavior, finding that both structural elements modulate substate occurrence. The discovered conformational flexibility enables VDAC2 recognition by diverse binding partners, explaining its critical physiological role via dynamical adaptation to mitochondrial metabolic conditions.
    DOI:  https://doi.org/10.1126/sciadv.adv4410
  16. Sci Rep. 2025 Apr 21. 15(1): 13811
    Human RCC1L is involved in the maintenance of mitochondrial nucleoids and mtDNA.
    Emi Matsumoto, Taeko Sasaki, Tetsuya Higashiyama, Narie Sasaki.
      Mitochondrial DNA (mtDNA) is organized with proteins into mitochondrial nucleoid (mt-nucleoid). The mt-nucleoid is a unit for the maintenance and function of mtDNA. The regulator of chromosome condensation 1-like protein (RCC1L) performs various functions in mitochondria, including translation, but its involvement in regulating mt-nucleoid maintenance is unknown. Herein, we found that human RCC1L was required to maintain mt-nucleoids and mtDNA. Human RCC1L has three splicing isoforms: RCC1LV1, RCC1LV2, and RCC1LV3. Knockout (KO) cells lacking all RCC1L isoforms, which were lethal without pyruvate and uridine, exhibited a decrease in mt-nucleoids and mtDNA, along with swollen and fragmented mitochondria. Among the three RCC1L isoforms, only RCC1LV1 recovered all phenotypes observed in RCC1L KO cells. As the treatment of wild-type cells with chloramphenicol, a mitochondrial translation inhibitor, did not lead to the decrease in mt-nucleoids accompanied by mtDNA depletion, the decrease in mt-nucleoids and mtDNA in RCC1L KO cells was not solely attributed to impaired mitochondrial translation. Using conditional RCC1L KO cells, we observed a rapid decrease in mt-nucleoids and mtDNA during a specific period following RCC1L loss. Our findings indicate that RCC1L regulates the maintenance of mt-nucleoids and mtDNA besides its role in mitochondrial translational regulation.
    Keywords:  Mitochondrial DNA; Mitochondrial nucleoid; RCC1L
    DOI:  https://doi.org/10.1038/s41598-025-98397-y
  17. Immunol Cell Biol. 2025 Apr 23.
    A new method to measure cell metabolism of rare cells in vivo reveals a high oxidative phosphorylation dependence of lung T cells.
    Aristeidis Roubanis, Morgane Hilaire, Morgane Le Teuff, Odile Devergne, Tim Sparwasser, Luciana Berod, Benoît L Salomon.
      Regulation of cellular metabolism is a central element governing the fate and function of T cells. However, the in vivo metabolic characteristics of rare cells, such as nonlymphoid tissue T cells, are poorly understood because of experimental limitations. Most techniques measuring cell metabolism require large cell numbers. The recent SCENITH method allows for studying the metabolism of rare cells by flow cytometry. However, this technique requires cells to be isolated and cultured ex vivo, which may alter their metabolism. Here, we propose a new experimental approach, called in vivo SCENITH, to investigate the cellular metabolism of T cells in vivo at a steady state in the spleen and lungs. For this purpose, we administered the metabolic modulators directly in mice, instead of applying these reagents ex vivo, as in the classical SCENITH method. Whereas ex vivo manipulation impacted the viability and phenotype of T cells, this toxic effect was not observed in the in vivo SCENITH. We observed that conventional and regulatory T cells shared similar metabolic profiles. Importantly, whereas spleen T cells used both oxidative phosphorylation and glycolysis, the metabolism of T cells in the lungs was mainly based on oxidative phosphorylation. Finally, metabolic inhibitors that interfere with protein translation and energy availability downregulated Foxp3 expression in regulatory T cells. These results describe an expansion of SCENITH that allows to measure the metabolic profile of rare cells in vivo, revealing a high dependence on oxidative phosphorylation of lung T cells.
    Keywords:  Cell metabolism; Foxp3; Treg; in vivo SCENITH; lung T cells
    DOI:  https://doi.org/10.1111/imcb.70018
  18. J Inflamm Res. 2025 ;18 5205-5216
    Mitochondrial Dysfunction and Reduced TCA Cycle Metabolite Levels in Inflammatory Bowel Disease Patients.
    Ewa Dudzińska, Agnieszka Madro, Ann Katrin Sauer, Andreas M Grabrucker, Aneta Strachecka.
       Introduction: Inflammatory bowel disease (IBD) mainly includes ulcerative colitis (UC) and Crohn's disease (CD). These diseases are classified as chronic and recurrent inflammatory diseases affecting the digestive tract. An energy deficiency in intestinal cells is believed to be associated with IBD pathology.
    Methods: Our study investigated the bioenergetic functionality of mitochondria using the plasma of patients with CD and UC by determining the concentration of intermediates of the tricarboxylic acid cycle (TCA), such as acetyl coenzyme A, succinate, fumarate, α-ketoglutarate, NADH2, IDH2, Cytochrome C Oxidase, Cytochrome C Reductase, and ATP.
    Results: Our results show an imbalance in mitochondrial homeostasis and bioenergetics, demonstrated by reduced activity of respiratory complexes and reduced production of TCA intermediates in the plasma of patients with CD and UC. In the group of patients with CD, treatment with corticosteroids had a significant positive effect, as significantly higher IDH2 and succinate levels were found. Correlation analyses of mitochondrial functionality biomarkers with other blood markers revealed a significant relationship between CRP and ATP levels, with higher CRP significantly linked to lower ATP and a similar trend for succinate levels. Using the disease activity scale, we show that biomarkers such as IDH2, α-ketoglutarate, and succinate levels are significantly lower in patients with higher disease activity.
    Conclusion: We conclude that reduced metabolites and respiratory complexes associated with the TCA indicate mitochondrial bioenergetic failure in IBD patients. Besides, Krebs cycle metabolites can be a good marker of predisposition to the disease and the course of IBD. They can be easily determined in a blood sample taken from the patient. Pharmacological protection of mitochondria in individuals predisposed to IBD development and compensation for the changed function of mitochondria in persons with the developed disease may become a new approach to personalized therapies focused on restoring the proper activity of mitochondrial enzymes.
    Keywords:  Krebs cycle; inflammatory bowel disease; respiratory complexes
    DOI:  https://doi.org/10.2147/JIR.S487349
  19. J Cell Sci. 2025 May 01. pii: jcs263780. [Epub ahead of print]138(9):
    Origin and evolution of mitochondrial inner membrane composition.
    Kailash Venkatraman, Nicolas-Frédéric Lipp, Itay Budin.
      Unique membrane architectures and lipid building blocks underlie the metabolic and non-metabolic functions of mitochondria. During eukaryogenesis, mitochondria likely arose from an alphaproteobacterial symbiont of an Asgard archaea-related host cell. Subsequently, mitochondria evolved inner membrane folds known as cristae alongside a specialized lipid composition supported by metabolic and transport machinery. Advancements in phylogenetic methods and genomic and metagenomic data have suggested potential origins for cristae-shaping protein complexes, such as the mitochondrial contact site and cristae-organizing system (MICOS). MICOS protein homologs function in the formation of cristae-like intracytoplasmic membranes (ICMs) in diverse extant alphaproteobacteria. The machinery responsible for synthesizing key mitochondrial phospholipids - which cooperate with cristae-shaping proteins to establish inner membrane architecture - could have also evolved from a bacterial ancestor, but its origins have been less explored. In this Review, we examine the current understanding of mitochondrial membrane evolution, highlighting distinctions between prokaryotic and eukaryotic mitochondrial-specific proteins and lipids and their differing roles in shaping cristae and ICM architecture, and propose a model explaining the concurrent specialization of the mitochondrial lipidome and inner membrane structure in eukaryogenesis. We discuss how advancements across a range of disciplines are shedding light on how multiple membrane components co-evolved to support the central functions of eukaryotic mitochondria.
    Keywords:  Cardiolipin; Cristae; Curvature; Evolution; Mitochondria; Phospholipids
    DOI:  https://doi.org/10.1242/jcs.263780
  20. Nature. 2025 Apr 23.
    Blood cancer driven by 'one hit' mutation event undergoes rapid growth.
      
    Keywords:  Cancer; Genetics
    DOI:  https://doi.org/10.1038/d41586-025-01170-4
  21. Autophagy. 2025 Apr 25. 1-3
    SMAD3 and PINK1 constitute a new positive feedback loop in regulation of mitophagy.
    Mingzhu Tang, Guang Lu, Han-Ming Shen.
      Mitophagy, selective degradation of dysfunctional mitochondria by the autophagy-lysosome pathway, is critical for maintaining cellular homeostasis. In recent years, significant progress has been made in understanding how PINK1 (PTEN-induced kinase 1)-mediated phosphorylation and the E3 ubiquitin (Ub) ligase (PRKN/parkin)-mediated ubiquitination form a positive feedforward loop in control of mitophagy. Nevertheless, a fundamental question remains: How is PINK1 transcriptionally modulated under mitochondrial stress to finely support mitophagy? Recently, we unveiled a novel mechanism in control of PINK1 transcription by SMAD3 (SMAD family member 3), an essential component of the TGFB/TGFβ (transforming growth factor beta)-SMAD signaling pathway. Upon mitochondrial depolarization, SMAD3 is activated through PINK1-mediated phosphorylation of SMAD3 at serine 423/425 independent of canonical TGFB signaling. More importantly, the SMAD3-PINK1 regulatory axis appears to functionally provide a pro-survival mechanism against mitochondrial stress. Therefore, PINK1 and SMAD3 constitute a newly discovered positive feedforward loop to regulate mitophagy, highlighting the need for further exploring the crosstalk between TGFB-SMAD signaling and mitophagy.
    Keywords:  Mitophagy; PINK1; SMAD3; phosphorylation; transcription
    DOI:  https://doi.org/10.1080/15548627.2025.2496364
  22. Nat Nanotechnol. 2025 Apr 23.
    An orally administered gene editing nanoparticle boosts chemo-immunotherapy in colorectal cancer.
    Kai Zhao, Yu Yan, Xiao-Kang Jin, Ting Pan, Shi-Man Zhang, Chi-Hui Yang, Zhi-Yong Rao, Xian-Zheng Zhang.
      Chemoresistance and immunosuppression are common obstacles to the efficacy of chemo-immunotherapy in colorectal cancer (CRC) and are regulated by mitochondrial chaperone proteins. Here we show that the disruption of the tumour necrosis factor receptor-associated protein 1 (TRAP1) gene, which encodes a mitochondrial chaperone in tumour cells, causes the translocation of cyclophilin D in tumour cells. This process results in the continuous opening of the mitochondrial permeability transition pore, which enhances chemotherapy-induced cell necrosis and promotes immune responses. On the basis of this discovery we developed an oral CRISPR-Cas9 delivery system based on zwitterionic and polysaccharide polymer-coated nanocomplexes that disrupts the TRAP1 gene in CRC. This system penetrates the intestinal mucus layer and undergoes epithelial transcytosis, accumulating in CRC tissues. It enhances chemotherapeutic efficacy by overcoming chemoresistance and activating the tumour immune microenvironment in orthotopic, chemoresistant and spontaneous CRC models, with remarkable synergistic antitumour effects. This oral CRISPR-Cas9 delivery system represents a promising therapeutic strategy for the clinical management of CRC.
    DOI:  https://doi.org/10.1038/s41565-025-01904-5
  23. iScience. 2025 May 16. 28(5): 112333
    Downregulation of rRNA synthesis by BCL-2 induces chemoresistance in diffuse large B cell lymphoma.
    Alessandra Rossi, Saveria Mazzara, Dorotea Salemi, Simone Zanetti, Maria Rosaria Sapienza, Stefania Orecchioni, Giovanna Talarico, Paolo Falvo, Alessandro Davini, Claudio Ceccarelli, Giovanna Motta, Federica Melle, Valentina Tabanelli, Claudio Agostinelli, Davide Trerè, Marianna Penzo, Chiara Corsini, Elena Baiardi, Angelica Calleri, Umberto Vitolo, Francesco Bertolini, Pier Luigi Zinzani, Roberto Chiarle, Corrado Tarella, Stefano Pileri, Enrico Derenzini.
      Overexpression of the antiapoptotic oncogene BCL-2 predicts poor prognosis in diffuse large B cell lymphoma (DLBCL) treated with anthracycline-based chemoimmunotherapy. Anthracyclines exert antitumor effects by multiple mechanisms including inhibition of ribosome biogenesis (RiBi) through rRNA synthesis blockade. RiBi inhibitors induce p53 stabilization through the ribosomal proteins-MDM2-p53 pathway, with stabilized p53 levels depending on baseline rRNA synthesis rate. We found that the BH3-mimetic venetoclax could not fully reverse BCL-2-mediated resistance to RiBi inhibitors in DLBCL cells. BCL-2 overexpression was associated with decreased baseline rRNA synthesis rate, attenuating p53 stabilization by RiBi inhibitors. Drugs stabilizing p53 irrespective of RiBi inhibition reversed BCL-2-induced resistance in vitro and in vivo, restoring p53 activation and apoptosis. A small nucleolar size, indicative of low baseline rRNA synthesis, correlated with high BCL-2 levels and poor outcomes in DLBCL patients. These findings uncover alternative BCL-2-dependent chemoresistance mechanisms, providing a rationale for specific combination strategies in BCL-2 positive lymphomas.
    Keywords:  Cancer; Cell biology
    DOI:  https://doi.org/10.1016/j.isci.2025.112333
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