bims-mibica Biomed News
on Mitochondrial bioenergetics in cancer
Issue of 2025–01–26
28 papers selected by
Kelsey Fisher-Wellman, Wake Forest University



  1. Nat Cancer. 2025 Jan 17.
      Cancer cells frequently rewire their metabolism to support proliferation and evade immune surveillance, but little is known about metabolic targets that could increase immune surveillance. Here we show a specific means of mitochondrial respiratory complex I (CI) inhibition that improves tumor immunogenicity and sensitivity to immune checkpoint blockade (ICB). Targeted genetic deletion of either Ndufs4 or Ndufs6, but not other CI subunits, induces an immune-dependent growth attenuation in melanoma and breast cancer models. We show that deletion of Ndufs4 induces expression of the major histocompatibility complex (MHC) class I co-activator Nlrc5 and antigen presentation machinery components, most notably H2-K1. This induction of MHC-related genes is driven by a pyruvate dehydrogenase-dependent accumulation of mitochondrial acetyl-CoA, which leads to an increase in histone H3K27 acetylation within the Nlrc5 and H2-K1 promoters. Taken together, this work shows that selective CI inhibition restricts tumor growth and that specific targeting of Ndufs4 or Ndufs6 increases T cell surveillance and ICB responsiveness.
    DOI:  https://doi.org/10.1038/s43018-024-00895-x
  2. bioRxiv. 2025 Jan 09. pii: 2025.01.08.631936. [Epub ahead of print]
      Metastasis causes most cancer deaths and reflects transitions from primary tumor escape to seeding and growth at metastatic sites. Epithelial-to-mesenchymal transition (EMT) is important early in metastasis to enable cancer cells to detach from neighboring cells, become migratory, and escape the primary tumor. While different phases of metastasis expose cells to variable nutrient environments and demands, the metabolic requirements and plasticity of each step are uncertain. Here we show that EMT and primary tumor escape are stimulated by disrupted oxidative metabolism. Using Renal Cell Carcinoma (RCC) patient samples, we identified the mitochondrial electron transport inhibitor NDUFA4L2 as upregulated in cells undergoing EMT. Deletion of NDUFA4L2 enhanced oxidative metabolism and prevented EMT and metastasis while NDUFA4L2 overexpression enhanced these processes. Mechanistically, NDUFA4L2 suppressed oxidative phosphorylation and caused citric acid cycle intermediates to accumulate, which modified chromatin accessibility of EMT-related loci to drive primary tumor escape. The effect of impaired mitochondrial metabolism to drive EMT appeared general, as renal cell carcinoma patient tumors driven by fumarate hydratase mutations with disrupted oxidative phosphorylation were highly metastatic and also had robust EMT. These findings highlight the importance of dynamic shifts in metabolism for cell migration and metastasis, with mitochondrial impairment driving early phases of this process. Understanding mitochondrial dynamics may have important implications in both basic and translational efforts to prevent cancer deaths.
    DOI:  https://doi.org/10.1101/2025.01.08.631936
  3. Cell Genom. 2025 Jan 16. pii: S2666-979X(24)00373-2. [Epub ahead of print] 100744
      The representation of driver mutations in preleukemic hematopoietic stem cells (pHSCs) provides a window into the somatic evolution that precedes acute myeloid leukemia (AML). Here, we isolate pHSCs from the bone marrow of 16 patients diagnosed with AML and perform single-cell DNA sequencing on thousands of cells to reconstruct phylogenetic trees of the major driver clones in each patient. We develop a computational framework that can infer levels of positive selection operating during preleukemic evolution from the statistical properties of these phylogenetic trees. Combining these data with 67 previously published phylogenetic trees, we find that the highly variable structures of preleukemic trees emerge naturally from a simple model of somatic evolution with pervasive positive selection typically in the range of 9%-24% per year. At these levels of positive selection, we show that the identification of early multiple-mutant clones could be used to identify individuals at risk of future AML.
    Keywords:  acute myeloid leukemia; cancer evolution; clonal hematopoiesis; early detection; evolutionary dynamics; pre-cancer; somatic mutation
    DOI:  https://doi.org/10.1016/j.xgen.2024.100744
  4. Mol Oncol. 2025 Jan 23.
      Multiple myeloma (MM) is an incurable cancer of plasma cells with a 5-year survival rate of 59%. Dysregulation of fatty acid (FA) metabolism is associated with MM development and progression; however, the underlying mechanisms remain unclear. Herein, we explore the roles of long-chain fatty acid coenzyme A ligase (ACSL) family members in MM. ACSLs convert free long-chain fatty acids into fatty acyl-CoA esters and play key roles in catabolic and anabolic fatty acid metabolism. Analysis of the Multiple Myeloma Research Foundation (MMRF) CoMMpassSM study showed that high ACSL1 and ACSL4 expression in myeloma cells are both associated with worse clinical outcomes for MM patients. Cancer Dependency Map (DepMap) data showed that all five ACSLs have negative Chronos scores, and ACSL3 and ACSL4 were among the top 25% Hallmark Fatty Acid Metabolism genes that support myeloma cell line fitness. Inhibition of ACSLs in myeloma cell lines in vitro, using the pharmacological inhibitor Triacsin C (TriC), increased apoptosis, decreased proliferation, and decreased cell viability, in a dose- and time-dependent manner. RNA-sequencing analysis of MM.1S cells treated with TriC showed a significant enrichment in apoptosis, ferroptosis, and endoplasmic reticulum (ER) stress, and proteomic analysis of these cells revealed enriched pathways for mitochondrial dysfunction and oxidative phosphorylation. TriC also rewired mitochondrial metabolism by decreasing mitochondrial membrane potential, increasing mitochondrial superoxide levels, decreasing mitochondrial ATP production rates, and impairing cellular respiration. Overall, our data support the hypothesis that suppression of ACSLs in myeloma cells is a novel metabolic target in MM that inhibits their viability, implicating this family as a promising therapeutic target in treating myeloma.
    Keywords:  ACSL; Triacsin C; cell metabolism; fatty acid; hematological malignancies; multiple myeloma
    DOI:  https://doi.org/10.1002/1878-0261.13794
  5. Nature. 2025 Jan 22.
      Cancer cells in the tumour microenvironment use various mechanisms to evade the immune system, particularly T cell attack1. For example, metabolic reprogramming in the tumour microenvironment and mitochondrial dysfunction in tumour-infiltrating lymphocytes (TILs) impair antitumour immune responses2-4. However, detailed mechanisms of such processes remain unclear. Here we analyse clinical specimens and identify mitochondrial DNA (mtDNA) mutations in TILs that are shared with cancer cells. Moreover, mitochondria with mtDNA mutations from cancer cells are able to transfer to TILs. Typically, mitochondria in TILs readily undergo mitophagy through reactive oxygen species. However, mitochondria transferred from cancer cells do not undergo mitophagy, which we find is due to mitophagy-inhibitory molecules. These molecules attach to mitochondria and together are transferred to TILs, which results in homoplasmic replacement. T cells that acquire mtDNA mutations from cancer cells exhibit metabolic abnormalities and senescence, with defects in effector functions and memory formation. This in turn leads to impaired antitumour immunity both in vitro and in vivo. Accordingly, the presence of an mtDNA mutation in tumour tissue is a poor prognostic factor for immune checkpoint inhibitors in patients with melanoma or non-small-cell lung cancer. These findings reveal a previously unknown mechanism of cancer immune evasion through mitochondrial transfer and can contribute to the development of future cancer immunotherapies.
    DOI:  https://doi.org/10.1038/s41586-024-08439-0
  6. Nat Metab. 2025 Jan 20.
      Increased glycolytic flux is a hallmark of cancer; however, an increasing body of evidence indicates that glycolytic ATP production may be dispensable in cancer, as metabolic plasticity allows cancer cells to readily adapt to disruption of glycolysis by increasing ATP production via oxidative phosphorylation. Using functional genomic screening, we show here that liver cancer cells show a unique sensitivity toward aldolase A (ALDOA) depletion. Targeting glycolysis by disrupting the catalytic activity of ALDOA led to severe energy stress and cell cycle arrest in murine and human hepatocellular carcinoma cell lines. With a combination of metabolic flux analysis, metabolomics, stable-isotope tracing and mathematical modelling, we demonstrate that inhibiting ALDOA induced a state of imbalanced glycolysis in which the investment phase outpaced the payoff phase. Targeting ALDOA effectively converted glycolysis from an energy producing into an energy-consuming process. Moreover, we found that depletion of ALDOA extended survival and reduced cancer cell proliferation in an animal model of hepatocellular carcinoma. Thus, our findings indicate that induction of imbalanced glycolysis by targeting ALDOA presents a unique opportunity to overcome the inherent metabolic plasticity of cancer cells.
    DOI:  https://doi.org/10.1038/s42255-024-01201-w
  7. Am J Physiol Cell Physiol. 2025 Jan 24.
      Resistance to drugs is one of the major issues affecting the response to pharmacological treatments for tumors. Different mechanisms have been proposed to explain the development of cancer drug resistance (CDR), and several approaches to overcome it have been suggested. However, the biological basis of CDR remains unclear. Here, we investigated whether mitochondrial damage and consequent mitochondrial dysfunction are major causes of drug resistance in different tumors. To this end, we used cell lines from three tumors: hepatocellular carcinoma, breast cancer, and colon cancer. We then applied a protocol that recapitulates chemotherapy regimens in patients, rendering each cell line resistant to the drug commonly used in their respective treatments. The combination of cellular respiration analysis, gene expression analysis of cytochrome c oxidase isoforms, and mass spectrometry assessment of cardiolipin reveals that mitochondrial dysfunction is the underlying cause of the resistant phenotype. Importantly, we disclosed for the first time the rapid inhibition of oxidative phosphorylation (OXPHOS) by L-lactate, the major product of fermentation. Finally, we demonstrated that inhibition of lactic acid fermentation and activation of OXPHOS can increase drug sensitivity in all tested drug-resistant cancer cells. Taken together, our results suggest that inhibiting fermentation and enhancing mitochondrial function in cancer cells may be a concrete option to control the worrisome phenomenon of CDR.
    Keywords:  Cancer drug resistance; L-lactate; cardiolipin; mitochondria; oxidative phosphorylation
    DOI:  https://doi.org/10.1152/ajpcell.00538.2024
  8. Blood. 2025 Jan 22. pii: blood.2024027207. [Epub ahead of print]
      Recurrent IDH mutations catalyze NADPH-dependent production of oncometabolite R-2HG for tumorigenesis. IDH inhibition provides clinical response in a subset of acute myeloid leukemia (AML) cases; however, most patients develop resistance, highlighting the need for more effective IDH-targeting therapies. By comparing transcriptomic alterations in isogenic leukemia cells harboring CRISPR base-edited IDH mutations, we identify the activation of adhesion molecules including CD44, a transmembrane glycoprotein, as a shared feature of IDH-mutant leukemia, consistent with elevated CD44 expression in IDH-mutant AML patients. CD44 is indispensable for IDH-mutant leukemia cells through activating pentose phosphate pathway and inhibiting glycolysis by phosphorylating G6PD and PKM2, respectively. This metabolic rewiring ensures efficient NADPH generation for mutant IDH-catalyzed R-2HG production. Combining IDH inhibition with CD44 blockade enhances the elimination of IDH-mutant leukemia cells. Hence, we describe an oncogenic feedforward pathway involving CD44-mediated metabolic rewiring for oncometabolite production, representing a targetable dependency of IDH-mutant malignancies.
    DOI:  https://doi.org/10.1182/blood.2024027207
  9. Free Radic Res. 2025 Jan 20. 1-14
      PurposeThe concept of dual-state hyper-energy metabolism characterized by elevated glycolysis and OxPhos has gained considerable attention during tumor growth and metastasis in different malignancies. However, it is largely unknown how such metabolic phenotypes influence the radiation response in aggressive cancers. Therefore, the present study aimed to investigate the impact of hyper-energy metabolism (increased glycolysis and OxPhos) on the radiation response of a human glioma cell line.MethodsModulation of the mitochondrial electron transport chain was carried out using a 2,4-dinitrophenol (DNP). Metabolic characterization was carried out by assessing glucose uptake, lactate production, mitochondrial mass, membrane potential, and ATP production. The radiation response was examined by cell growth, clonogenic survival, and cell death assays. Macromolecular oxidation was assessed by DNA damage, lipid peroxidation, and protein carbonylation assay.ResultsHypermetabolic OPM-BMG cells exhibited a significant increase in glycolysis and OxPhos following irradiation as compared to the parental BMG-1 cells. Enhanced radioresistance of OPM-BMG cells was evidenced by the increase in α/β ratio (9.58) and D1 dose (4.18 Gy) as compared to 4.36 and 2.19 Gy in BMG-1 cells respectively. Moreover, OPM-BMG cells were found to exhibit increased resistance against radiation-induced cell death, and macromolecular oxidation as compared to BMG-1 cells. Inhibition of glycolysis and mitochondrial complex-II significantly enhanced the radiosensitivity of OPM-BMG cells compared to BMG-1 cells.ConclusionOur results demonstrate that the hyper-energy metabolism of increased glycolysis and OxPhos confer radioresistance. Consequently targeting glycolysis and OxPhos in combination with radiation may overcome therapeutic resistance in aggressive cancers like glioma.
    Keywords:  2-DG; Cancer bioenergetics; Glioma; Hyper-energy metabolism; Malonate; OXPHOS; Radioresistance Glycolysis
    DOI:  https://doi.org/10.1080/10715762.2025.2456740
  10. Diseases. 2025 Jan 08. pii: 10. [Epub ahead of print]13(1):
       BACKGROUND: Acute myeloid leukemia (AML) is a common and aggressive form of leukemia, yet current treatment strategies remain insufficient. Venetoclax, a BH3-mimetic approved for AML treatment, induces Bcl-2-dependent apoptosis, though its therapeutic efficacy is still limited. Therefore, new strategies to enhance the effect of venetoclax are highly sought. Valproic acid (VPA), commonly used for epilepsy, has also been studied for potential applications in AML treatment.
    METHODS: AML cells were treated with venetoclax, with or without VPA. Cell viability was assessed using the trypan blue dye exclusion assay, while cell cycle progression was analyzed by flow cytometry. The expression of pro-apoptotic proteins Bax and Bak was measured by RT-qPCR.
    RESULTS: Venetoclax and VPA individually had only mild effects on AML cell proliferation. However, their combination significantly inhibited cell growth and triggered pronounced cell death. This combination also led to the cleavage of poly (ADP-ribose) polymerase (PARP), a substrate of caspases, indicating activation of apoptosis. VPA treatment upregulated the expression of Bax and Bak, further supporting apoptosis induction. The cell death induced by the venetoclax-VPA combination was predominantly apoptotic, as confirmed by the near-complete blockade of cell death by a pan-caspase inhibitor.
    CONCLUSIONS: Our study demonstrates that VPA enhances venetoclax-induced apoptosis in AML cell lines, providing a novel role for VPA and suggesting a promising combinatory strategy for AML treatment. These findings offer valuable insights into potential clinical applications of venetoclax and VPA in AML management.
    Keywords:  Bak; Bax; Bcl-2; acute myeloid leukemia; apoptosis; valproic acid
    DOI:  https://doi.org/10.3390/diseases13010010
  11. Nat Cell Biol. 2025 Jan 22.
      Mitochondria have to import a large number of precursor proteins from the cytosol. Chaperones keep these proteins in a largely unfolded state and guide them to the mitochondrial import sites. Premature folding, mitochondrial stress and import defects can cause clogging of import sites and accumulation of non-imported precursors, representing a critical burden for cellular proteostasis. Here we discuss how cells respond to mitochondrial protein import stress by regenerating clogged import sites and inducing stress responses. The mitochondrial protein import machinery has a dual role by serving as sensor for detecting mitochondrial dysfunction and inducing stress-response pathways. The production of chaperones that fold or sequester precursor proteins in deposits is induced and the proteasomal activity is increased to remove the excess precursor proteins. Together, these pathways reveal how mitochondria are tightly integrated into a cellular proteostasis and stress response network to maintain cell viability.
    DOI:  https://doi.org/10.1038/s41556-024-01590-w
  12. Blood Adv. 2025 Jan 18. pii: bloodadvances.2024014900. [Epub ahead of print]
      Venetoclax plus azacitidine represents a key advance for older, unfit patients with acute myeloid leukemia (AML). The chemotherapy and venetoclax in elderly AML trial (CAVEAT) was first to combine venetoclax with intensive chemotherapy in newly diagnosed patients ≥65 years. In this final analysis, 85 patients (median age 71 years) were followed for a median of 41.8 months. The CAVEAT induction combined cytarabine and idarubicin with 5 dose levels of venetoclax (50-600 mg) for up to 14 days. Two additional cohorts explored adjusted-dose venetoclax (50 mg, 100 mg) with posaconazole. CAVEAT induction was well tolerated, with low mortality (4%) and limited high-grade gastrointestinal toxicity (4%). Delayed hematological recovery after consolidation was ameliorated by omitting idarubicin from post-remission therapy. The overall response rate (ORR: CR + CRh + CRi) was 75% with a median overall survival (OS) of 19.3 months (95% CI 11.1-31.3). Among de novo AML, ORR was 88% and median OS 33.1 months (95% CI 19.3-54.3). Almost one-third have not relapsed, many benefiting from prolonged treatment-free remission (median 17.9 months). CAVEAT induction was well tolerated and associated with high ORR that was durable, particularly for de novo AML. CAVEAT represents an effective time-limited treatment option for fit older patients with AML. (https://www.anzctr.org.au; ACTRN12616000445471).
    DOI:  https://doi.org/10.1182/bloodadvances.2024014900
  13. Nature. 2025 Jan 22.
      
    Keywords:  Cancer; Cell biology; Immunology
    DOI:  https://doi.org/10.1038/d41586-025-00176-2
  14. Blood. 2025 Jan 22. pii: blood.2024025886. [Epub ahead of print]
      Leukemic stem cells (LSCs) fuel acute myeloid leukemia (AML) growth and relapse, but therapies tailored towards eradicating LSCs without harming normal hematopoietic stem cells (HSCs) are lacking. FLT3 is considered an important therapeutic target due to frequent mutation in AML and association with relapse. However, there has been limited clinical success with FLT3 drug targeting, suggesting either that FLT3 is not a vulnerability in LSC, or that more potent inhibition is required, a scenario where HSC toxicity could become limiting. We tested these possibilities by ablating FLT3 using CRISPR/Cas9-mediated FLT3 knock-out (FLT3-KO) in human LSCs and HSCs followed by functional xenograft assays. FLT3-KO in LSCs from FLT3-ITD mutated, but not FLT3-wild type (WT) AMLs, resulted in short-term leukemic grafts of FLT3-KO edited cells that disappeared by 12 weeks. By contrast, FLT3-KO in HSCs from fetal liver, cord blood and adult bone marrow did not impair multilineage hematopoiesis in primary and secondary xenografts. Our study establishes FLT3 as an ideal therapeutic target where ITD+ LSC are eradicated upon FLT3 deletion, while HSCs are spared. These findings support the development of more potent FLT3-targeting drugs or gene-editing approaches for LSC eradication to improve clinical outcomes.
    DOI:  https://doi.org/10.1182/blood.2024025886
  15. Dis Model Mech. 2025 Jan 20. pii: dmm.052063. [Epub ahead of print]
      Mitochondria contribute to cellular metabolism by providing a specialised milieu for energising cells by incorporating and processing the metabolites. However, heterogeneity in the mitochondria within is only partially elucidated. Mitochondria dynamically alter their morphology and functions during the life of animals, in which cells proliferate and grow. We here show that Kntc1, a highly evolutionarily conserved protein, translocates from the Golgi apparatus to linear mitochondrial segments (LMS) upon glutamine deprivation and plays an essential role in maintaining LMS. The LMS with Kntc1 localisation exhibits an increase in the membrane potential, suggesting the role of Kntc1 in functioning as a reservoir for the energy-generating potential. Suppression of Kntc1 leads to glutamine consumption and lactate production, thus impacting cellular metabolism, eventually leading to anchorage-independent growth of cells. Indeed, the KNTC1 variant was identified in a patient with ovarian cancer, suggesting that segmental regulation of the mitochondrial function is essential for maintaining tissue integrity.
    Keywords:  Bent mitochondrial segment (BMS); Glutamine metabolism; KNTC1; Linear mitochondrial segment (LMS); Mitochondrial structural heterogeneity
    DOI:  https://doi.org/10.1242/dmm.052063
  16. Biochim Biophys Acta Bioenerg. 2025 Jan 17. pii: S0005-2728(25)00006-4. [Epub ahead of print] 149540
      The human mitochondrial nicotinamide nucleotide transhydrogenase (NNT) uses the proton motive force to drive hydride transfer from NADH to NADP+ and is a major contributor to the generation of mitochondrial NADPH. NNT plays a critical role in maintaining cellular redox balance. NNT-deficiency results in oxidative damage and its absence results in familial glucocorticoid deficiency. Recently it has also become clear that NNT is a tumor promoter whose presence in mouse models of non-small cell lung cancer results in enhanced tumor growth and aggressiveness. The presence of NNT mitigates the effects of oxidative stress and facilitates cancer cell proliferation, suggesting NNT-inhibition as a promising therapeutic strategy. The human NNT is a homodimer in which each subunit has a molecular weight of 114 kDa and 14 transmembrane spans. Here we report on the development of a system for isolating full-length recombinant human NNT using Escherichia coli. The purified enzyme is catalytically active, and the enzyme reconstituted into proteoliposomes pumps protons and generates a proton motive force capable of driving ATP synthesis by E. coli ATP synthase. The recombinant human NNT will facilitate structural and biochemical studies as well as provide a useful tool to develop and characterize potential anti-cancer therapeutics.
    Keywords:  Cancer; Familial glucocorticoid deficiency; Heterologous overexpression; Human nicotinamide nucleotide transhydrogenase; Integral membrane protein
    DOI:  https://doi.org/10.1016/j.bbabio.2025.149540
  17. Front Oncol. 2024 ;14 1414950
       Introduction: Progressing myelodysplastic syndrome (MDS) into acute myeloid leukemia (AML) is an indication for hypomethylating therapy (HMA, 5-Azacytidine (AZA)) and a BCL2 inhibitor (Venetoclax, VEN) for intensive chemotherapy ineligible patients. Mouse models that engraft primary AML samples may further advance VEN + AZA resistance research.
    Methods: We generated a set of transplantable murine PDX models from MDS/AML patients who developed resistance to VEN + AZA and compared the differences in hematopoiesis of the PDX models with primary bone marrow samples at the genetic level. PDX were created in NSGS mice via intraosseal injection of luciferase-encoding Lentivirus-infected MDS/AML primary cells from patient bone marrow. We validated the resistance of PDX-leukemia to VEN and AZA and further tested candidate agents that inhibit the growth of VEN/AZA-resistant AML.
    Results and discussion: Transplantable PDX models for MDS/AML arise with 31 % frequency. The lower frequency of transplantable PDX models is not related to peritransplant lethality of the graft, but rather to the loss of the ability of short-term proliferation of leukemic progenitors after 10 weeks of engraftment. There exist subtle genetic and cytological changes between primary and PDX-AML samples however, the PDX models retain therapy resistance observed in patients. Based on in vitro testing and in vivo validation in PDX models, Panobinostat and Dinaciclib are very promising candidate agents that overcome dual VEN + AZA resistance.
    Keywords:  5-Azacytidine; PDX (patient derived xenograft); Venetoclax (BCL2 inhibitor); myelodysplastic syndrome; therapeutic targets
    DOI:  https://doi.org/10.3389/fonc.2024.1414950
  18. Transl Lung Cancer Res. 2024 Dec 31. 13(12): 3692-3717
      For over a century, we have appreciated that the biochemical processes through which micro- and macronutrients are anabolized and catabolized-collectively referred to as "cellular metabolism"-are reprogrammed in malignancies. Cancer cells in lung tumors rewire pathways of nutrient acquisition and metabolism to meet the bioenergetic demands for unchecked proliferation. Advances in precision medicine have ushered in routine genotyping of patient lung tumors, enabling a deeper understanding of the contribution of altered metabolism to tumor biology and patient outcomes. This paradigm shift in thoracic oncology has spawned a new enthusiasm for dissecting oncogenotype-specific metabolic phenotypes and creates opportunity for selective targeting of essential tumor metabolic pathways. In this review, we discuss metabolic states across histologic and molecular subtypes of lung cancers and the additional changes in tumor metabolic pathways that occur during acquired therapeutic resistance. We summarize the clinical investigation of metabolism-specific therapies, addressing successes and limitations to guide the evaluation of these novel strategies in the clinic. Beyond changes in tumor metabolism, we also highlight how non-cellular autonomous processes merit particular consideration when manipulating metabolic processes systemically, such as efforts to disentangle how lung tumor cells influence immunometabolism. As the future of metabolic therapeutics hinges on use of models that faithfully recapitulate metabolic rewiring in lung cancer, we also discuss best practices for harmonizing workflows to capture patient specimens for translational metabolic analyses.
    Keywords:  Lung cancer; immunometabolism; metabolism; resistance
    DOI:  https://doi.org/10.21037/tlcr-24-662
  19. Sci Adv. 2025 Jan 24. 11(4): eadq7307
      The cytokine interleukin-10 (IL-10) limits the immune response and promotes resolution of acute inflammation. Because of its immunosuppressive effects, IL-10 up-regulation is a common feature of tumor progression and metastasis. Recently, IL-10 regulation has been shown to depend on mitochondria and redox-sensitive signals. We have found that Suppressor of site IIIQo Electron Leak 1.2 (S3QEL 1.2), a specific inhibitor of reactive oxygen species (ROS) production from mitochondrial complex III, and myxothiazol, a complex III inhibitor, decrease IL-10 in lipopolysaccharide (LPS)-activated macrophages. IL-10 down-regulation is likely to be mediated by suppression of c-Fos, which is a subunit of activator protein 1 (AP1), a transcription factor required for IL-10 gene expression. S3QEL 1.2 impairs IL-10 production in vivo after LPS challenge and promotes the survival of mice bearing B16F10 melanoma by lowering tumor growth. Our data identify a link between complex III-dependent ROS generation and IL-10 production in macrophages, the targeting of which could have potential in boosting antitumor immunity.
    DOI:  https://doi.org/10.1126/sciadv.adq7307
  20. FEBS J. 2025 Jan 19.
      Lactate dehydrogenase A (LDHA) is upregulated in multiple cancer types and contributes to the Warburg effect. Several studies have found that many tumor-related genes have subtypes and play important roles in promoting cancer development. Here, we identified a novel LDHA transcript, which produced a new protein 3 kDa larger than LDHA, which we named LDHAα. We found that multiple cancer cell lines express LDHAα, and ectopic expression of LDHAα led to a higher proliferation and migration rate in vitro. Ectopic expression of LDHAα could also promote tumor cell growth in vivo. Conversely, deletion of LDHAα by CRISPR-sgRNA significantly inhibited the growth of tumor cells. LDHAα was found to be mainly located in the cytoplasm, and overexpression or deletion of LDHAα could significantly affect the glucose uptake and lactate production of tumor cells. Further investigation showed that c-MYC and FOXM1 could markedly modulate the expression of both LDHA and LDHAα, especially c-MYC. We found that a small molecular compound targeting LDHA could also inhibit the enzyme activity of LDHAα. LDHAα, LDHA and c-MYC expression was significantly higher in human acute lymphocytic leukemia and colorectal cancer tissue specimens compared to normal controls. In conclusion, our study identified LDHAα as a subtype of LDHA and highlighted its critical role in tumor metabolism, providing a potential new therapeutic target for tumor diagnosis and treatment.
    Keywords:  glycolysis; isoform; lactate dehydrogenase A; metabolism; tumor
    DOI:  https://doi.org/10.1111/febs.17374
  21. Nat Commun. 2025 Jan 20. 16(1): 867
      S-palmitoylation is a reversible and widespread post-translational modification, but its role in the regulation of ferroptosis has been poorly understood. Here, we elucidate that GPX4, an essential regulator of ferroptosis, is reversibly palmitoylated on cysteine 66. The acyltransferase ZDHHC20 palmitoylates GPX4 and increases its protein stability. ZDHHC20 depletion or inhibition of protein palmitoylation by 2-BP sensitizes cancer cells to ferroptosis. Moreover, we identify APT2 as the depalmitoylase of GPX4. Genetic silencing or pharmacological inhibition of APT2 with ML349 increases GPX4 palmitoylation, thereby stabilizing the protein and conferring resistance to ferroptosis. Notably, disrupting GPX4 palmitoylation markedly potentiates ferroptosis in xenografted and orthotopically implanted tumor models, and inhibits tumor metastasis through blood vessels. In the chemically induced colorectal cancer model, knockout of APT2 significantly aggravates cancer progression. Furthermore, pharmacologically modulating GPX4 palmitoylation impacts liver ischemia-reperfusion injury. Overall, our findings uncover the intricate network regulating GPX4 palmitoylation, highlighting its pivotal role in modulating ferroptosis sensitivity.
    DOI:  https://doi.org/10.1038/s41467-025-56344-5
  22. Biol Chem. 2025 Jan 21.
      Most mitochondrial proteins are synthesized in the cytosol and post-translationally imported into mitochondria. If the rate of protein synthesis exceeds the capacity of the mitochondrial import machinery, precursor proteins can transiently accumulate in the cytosol. The cytosolic accumulation of mitochondrial precursors jeopardizes cellular protein homeostasis (proteostasis) and can be the cause of diseases. In order to prevent these toxic effects, most non-imported precursors are rapidly degraded by the ubiquitin-proteasome system. However, cells employ a second layer of defense which is the facilitated sequestration of mitochondrial precursor proteins in transient protein aggregates. The formation of such structures is triggered by nucleation factors such as small heat shock proteins. Disaggregases and chaperones can liberate precursors from cytosolic aggregates to pass them on to the mitochondrial import machinery or, under persistent stress conditions, to the proteasome for degradation. Owing to their role as transient buffering systems, these aggregates were referred to as MitoStores. This review articles provides a general overview about the MitoStore concept and the early stages in mitochondrial protein biogenesis in yeast and, in cases where aspects differ, in mammalian cells.
    Keywords:  aggregates; mitochondria; mitostores; proteasome; protein targeting; quality control
    DOI:  https://doi.org/10.1515/hsz-2024-0148
  23. bioRxiv. 2025 Jan 06. pii: 2025.01.06.631511. [Epub ahead of print]
      Aging is characterized by extensive metabolic dysregulation. Redox coenzyme nicotinamide adenine dinucleotide (NAD) can exist in oxidized (NAD+) or reduced (NADH) states, which together form a key NADH/NAD+ redox pair. Total levels of NAD decline with age in a tissue-specific manner, thereby playing a significant role in the aging process. Supplementation with NAD precursors boosts total cellular NAD levels and provides some therapeutic benefits in human clinical trials. However, supplementation studies cannot determine tissue-specific effects of an altered NADH/NAD+ ratio. Here, we created transgenic Drosophila expressing a genetically encoded xenotopic tool LbNOX to directly manipulate the cellular NADH/NAD+ ratio. We found that LbNOX expression in Drosophila impacts both NAD(H) and NADP(H) metabolites in a sex-specific manner. LbNOX rescues neuronal cell death induced by the expression of mutated alpha-B crystallin in the Drosophila eye, a widely used system to study reductive stress. Utilizing LbNOX, we demonstrate that targeting redox NAD metabolism in different tissues may have drastically different outcomes, as the expression of LbNOX solely in the muscle is much more effective for rescuing paraquat-induced oxidative stress compared to whole-body expression. Excitingly, we demonstrate that perturbing NAD(P) metabolism in non-neuronal tissues is sufficient to rejuvenate sleep profiles in aged flies to a youthful state. In summary, we used xenotopic tool LbNOX to identify tissues and metabolic processes which benefited the most from the modulation of the NAD metabolism thereby highlighting important aspects of rebalancing the NAD and NADP pools, all of which can be translated into novel designs of NAD-related human clinical trials.
    Keywords:  B-mediated reductive stress; Drosophila; LbNOX; NAD+; NADH; NADP+; NADPH; aging; mitochondria; mutated α-crystallin; xenotopic tool
    DOI:  https://doi.org/10.1101/2025.01.06.631511
  24. Biomed Pharmacother. 2025 Jan 21. pii: S0753-3322(25)00034-4. [Epub ahead of print]183 117840
      Platelet inhibition is a fundamental objective to prevent and treat thrombus formation. Platelet activation depends on mitochondrial function. This study aims to identify a new mitochondria-targeting compound with antiplatelet activity at safe concentrations in vitro. Cytotoxicity and viability tests were performed on human platelets from volunteer donors, together with experiments on aggregation, platelet activation, mitochondrial function, mitochondrial respiration, and thioredoxin reductase 2 (TrxR2) enzymatic activity in isolated platelet mitochondria. The compound MitoCDNB, corresponding to the molecule 5-chloro-2,4-dinitrophenylamino linked with triphenylphosphonium cation (TPP+) by a butyl chain and methanesulfonate as the counterion, was evaluated. MitoCDNB demonstrates potent, high mitochondria-selective antiplatelet effects that provide a novel approach to platelet inhibition with potentially minimized systemic risks. Here, we describe the first compound that inhibits platelet activation by decreasing TrxR2 enzymatic activity and collagen-stimulated maximal mitochondrial respiration, preventing aggregation and platelet activation. These results can be used to develop new antiplatelet drugs targeting mitochondria.
    Keywords:  Antiplatelet; Mitochondrial Targeting; Platelet Bioenergetics; Thioredoxin Reductase 2; Triphenylphosphonium Cation
    DOI:  https://doi.org/10.1016/j.biopha.2025.117840
  25. Biochim Biophys Acta Bioenerg. 2025 Jan 17. pii: S0005-2728(25)00007-6. [Epub ahead of print]1866(2): 149541
      To professional bioenergeticists, the thermodynamic and kinetic constraints on mitochondrial function are self-evident. It is therefore profoundly concerning that high-profile cell biology papers continue to appear containing fundamental bioenergetic errors that appear to have evaded the scrutiny of the principal investigator, co-authors, editors and, apparently, at least some of the referees. The problem is not new, and seems to stem from a perception that bioenergetics is a 'difficult' subject, both at undergraduate level, if it is taught in any depth, and in research, where cell biologists are faced with biophysical concepts such as protonmotive force, ion flux, redox potential and Gibbs free energy.
    Keywords:  Commentary; Proton circuit; Protonmotive force; Thermodynamics
    DOI:  https://doi.org/10.1016/j.bbabio.2025.149541
  26. Nature. 2025 Jan 22.
      The development of animal models is crucial for studying and treating mitochondrial diseases. Here we optimized adenine and cytosine deaminases to reduce off-target effects on the transcriptome and the mitochondrial genome, improving the accuracy and efficiency of our newly developed mitochondrial base editors (mitoBEs)1. Using these upgraded mitoBEs (version 2 (v2)), we targeted 70 mouse mitochondrial DNA mutations analogous to human pathogenic variants2, establishing a foundation for mitochondrial disease mouse models. Circular RNA-encoded mitoBEs v2 achieved up to 82% editing efficiency in mice without detectable off-target effects in the nuclear genome. The edited mitochondrial DNA persisted across various tissues and was maternally inherited, resulting in F1 generation mice with mutation loads as high as 100% and some mice exhibiting editing only at the target site. By optimizing the transcription activator-like effector (TALE) binding site, we developed a single-base-editing mouse model for the mt-Nd5 A12784G mutation. Phenotypic evaluations led to the creation of mouse models for the mt-Atp6 T8591C and mt-Nd5 A12784G mutations, exhibiting phenotypes corresponding to the reduced heart rate seen in Leigh syndrome and the vision loss characteristic of Leber's hereditary optic neuropathy, respectively. Moreover, the mt-Atp6 T8591C mutation proved to be more deleterious than mt-Nd5 A12784G, affecting embryonic development and rapidly diminishing through successive generations. These upgraded mitoBEs offer a highly efficient and precise strategy for constructing mitochondrial disease models, laying a foundation for further research in this field.
    DOI:  https://doi.org/10.1038/s41586-024-08469-8