bims-midysc Biomed News
on Mitochondria dysfunction in cancer
Issue of 2025–03–23
twelve papers selected by
Papachristodoulou Lab
  1. Oxidative phosphorylation and breast cancer progression: insights into PGC-1α's role in mitochondrial function.
  2. TAK-901, a novel EPHA2 inhibitor as a therapeutic strategy against prostate cancer.
  3. Acute diacylglycerol production activates critical membrane-shaping proteins leading to mitochondrial tubulation and fission.
  4. Metabolic Reprogramming into a Glycolysis Phenotype Induced by Extracellular Vesicles Derived from Prostate Cancer Cells.
  5. Mitochondrial fission - changing perspectives for future progress.
  6. Small-molecule hypoxia therapy in mitochondrial disease.
  7. Wnt5a augments intracellular free cholesterol levels and promotes castration resistance in prostate cancer.
  8. Developmental mitochondrial complex I activity determines lifespan.
  9. Lactylation orchestrates ubiquitin-independent degradation of cGAS and promotes tumor growth.
  10. Small-molecule RNA therapeutics to target prostate cancer.
  11. Horizontal mitochondrial transfer in cancer biology: Potential clinical relevance.
  12. Whole genome sequencing of 378 prostate cancer metastases reveals tissue selectivity for mismatch deficiency with potential therapeutic implications.
  1. Naunyn Schmiedebergs Arch Pharmacol. 2025 Mar 17.
    Oxidative phosphorylation and breast cancer progression: insights into PGC-1α's role in mitochondrial function.
    Rihab Akasha, Jerlyn Apatan Enrera, Syeda Bushra Fatima, A M Hegazy, Weiam Hussein, Muhammad Nawaz, Maali D Alshammari, Sultan Almuntashiri, Najah Albadari, Mohammed Khaled Bin Break, Rahamat Unissa Syed.
      Breast cancer still ranks high as a leading cause of mortality in women due to its complex relationship with metabolic reprogramming and tumor progression. The peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α), a key transcriptional coactivator regulating mitochondrial biogenesis and oxidative phosphorylation (OXPHOS), plays a dual role in breast cancer metabolism. On the one hand, PGC-1α enhances mitochondrial function and energy production, facilitating tumor survival and metastasis, particularly in hypoxic environments. On the other hand, its suppression can limit tumor aggressiveness and energy metabolism. This dual functionality underscores its context-dependent role in cancer progression, where its activation or inhibition varies across tumor subtypes and microenvironmental conditions. The purpose of this review is to provide a comprehensive understanding of PGC-1α's dual roles in breast cancer, elucidating its regulation of mitochondrial function, its contribution to tumor progression, and the therapeutic implications of targeting this key metabolic regulator.
    Keywords:  Breast cancer; Metabolic reprogramming; Mitochondrial function; Oxidative phosphorylation; PGC-1α; Tumor progression
    DOI:  https://doi.org/10.1007/s00210-025-04018-w
  2. Cell Signal. 2025 Mar 16. pii: S0898-6568(25)00163-9. [Epub ahead of print]131 111750
    TAK-901, a novel EPHA2 inhibitor as a therapeutic strategy against prostate cancer.
    Shanhui Liu, Shengjun Fu, Xuewu Wu, Shan Wu, Youli Zhao, Xinyue Wu, Liting Yan, Jianzhong Lu, Lanlan Li, Yan Tao.
      Prostate cancer is the most common cancer and remains a leading cause of cancer-related deaths among men worldwide. Androgen deprivation therapy continues to be the cornerstone of treatment for prostate cancer. However, the efficacy of this treatments is often limited, leading to the emergence of drug resistance and tumor recurrence. TAK-901, an inhibitor of Aurora kinase B, has been shown to inhibit tumor growth both in vitro and in vivo models. To date, the effect of TAK-901 on prostate cancer and the underlying mechanism remain unknown. In this study, we found that TAK-901 could inhibit proliferation, colony formation and migration, while also inducing apoptosis in prostate cancer cells. We further demonstrated that TAK-901 activates the CHK1 signaling pathway, leading to G2/M-phase arrest in these cells. Additionally, we identified EPHA2 as a novel therapeutic target of TAK-901. By mutating the binding sites between EPHA2 and TAK-901, we discovered that these mutations could reverse the anti-proliferative effects of TAK-901 in prostate cancer models. Our study is the first to reveal that TAK-901 induces apoptosis in prostate cancer cells and inhibits cell growth by targeting EPHA2. These findings provide valuable insights into the underlying mechanisms of TAK-901 and may develop its therapeutic applications in prostate cancer.
    Keywords:  Apoptosis; Cell cycle arrest; EPHA2; Prostate cancer; TAK-901
    DOI:  https://doi.org/10.1016/j.cellsig.2025.111750
  3. Nat Commun. 2025 Mar 19. 16(1): 2685
    Acute diacylglycerol production activates critical membrane-shaping proteins leading to mitochondrial tubulation and fission.
    Joshua G Pemberton, Krishnendu Roy, Yeun Ju Kim, Tara D Fischer, Vijay Joshi, Elizabeth Ferrer, Richard J Youle, Thomas J Pucadyil, Tamas Balla.
      Mitochondrial dynamics are orchestrated by protein assemblies that directly remodel membrane structure, however the influence of specific lipids on these processes remains poorly understood. Here, using an inducible heterodimerization system to selectively modulate the lipid composition of the outer mitochondrial membrane (OMM), we show that local production of diacylglycerol (DAG) directly leads to transient tubulation and rapid fragmentation of the mitochondrial network, which are mediated by isoforms of endophilin B (EndoB) and dynamin-related protein 1 (Drp1), respectively. Reconstitution experiments on cardiolipin-containing membrane templates mimicking the planar and constricted OMM topologies reveal that DAG facilitates the membrane binding and remodeling activities of both EndoB and Drp1, thereby independently potentiating membrane tubulation and fission events. EndoB and Drp1 do not directly interact with each other, suggesting that DAG production activates multiple pathways for membrane remodeling in parallel. Together, our data emphasizes the importance of OMM lipid composition in regulating mitochondrial dynamics.
    DOI:  https://doi.org/10.1038/s41467-025-57439-9
  4. Mol Cell Proteomics. 2025 Mar 13. pii: S1535-9476(25)00042-8. [Epub ahead of print] 100944
    Metabolic Reprogramming into a Glycolysis Phenotype Induced by Extracellular Vesicles Derived from Prostate Cancer Cells.
    Yoon-Jin Lee, Chul Won Seo, Shinwon Chae, Chang Yeol Lee, Sang Soo Kim, Yoon-Hee Shin, Hyun-Mee Park, Yong Song Gho, Seongho Ryu, Sang-Han Lee, Dongsic Choi.
      Most cancer cells adopt a less efficient metabolic process of aerobic glycolysis with high level of glucose uptake followed by lactic acid production, known as the Warburg effect. This phenotypic transition enables cancer cells to achieve increased cellular survival and proliferation in a harsh low-oxygen tumor microenvironment. Also, the resulting acidic microenvironment causes inactivation of the immune system such as T-cell impairment that favors escape by immune surveillance. While lots of studies have revealed that tumor-derived EVs can deliver parental materials to adjacent cells and contribute to oncogenic reprogramming, their functionality in energy metabolism is not well addressed. In this study, we established prostate cancer cells PC3-AcT resistant to cellular death in an acidic culture medium driven by lactic acid. Quantitative proteomics between EVs derived from PC-3 and PC-3AcT cells identified 935 confident EV proteins. According to cellular adaptation to lactic acidosis, we revealed 159 regulated EV proteins related to energy metabolism, cellular shape, and extracellular matrix. These EVs contained a high abundance of glycolytic enzymes. In particular, PC-3AcT EVs were enriched with apolipoproteins including apolipoprotein B100 (APOB). APOB on PC-3AcT EVs could facilitate their endocytic uptake depending on low density lipoprotein receptor of recipient PC-3 cells, encouraging increases of cellular proliferation and survival in acidic culture media via increased activity and expression of hexokinases and phosphofructokinase. The activation of recipient PC-3 cells can increase glucose consumption and ATP generation, representing an acquired metabolic reprogramming into the Warburg phenotype. Our study first revealed that EVs derived from prostate cancer cells could contribute to energy metabolic reprogramming and that the acquired metabolic phenotypic transition of recipient cells could favor cellular survival in tumor microenvironment.
    DOI:  https://doi.org/10.1016/j.mcpro.2025.100944
  5. J Cell Sci. 2025 May 01. pii: jcs263640. [Epub ahead of print]138(9):
    Mitochondrial fission - changing perspectives for future progress.
    Sukrut C Kamerkar, Ao Liu, Henry N Higgs.
      Mitochondrial fission is important for many aspects of cellular homeostasis, including mitochondrial distribution, stress response, mitophagy, mitochondrially derived vesicle production and metabolic regulation. Several decades of research has revealed much about fission, including identification of a key division protein - the dynamin Drp1 (also known as DNM1L) - receptors for Drp1 on the outer mitochondrial membrane (OMM), including Mff, MiD49 and MiD51 (also known as MIEF2 and MIEF1, respectively) and Fis1, and important Drp1 regulators, including post-translational modifications, actin filaments and the phospholipid cardiolipin. In addition, it is now appreciated that other organelles, including the endoplasmic reticulum, lysosomes and Golgi-derived vesicles, can participate in mitochondrial fission. However, a more holistic understanding of the process is lacking. In this Review, we address three questions that highlight knowledge gaps. First, how do we quantify mitochondrial fission? Second, how does the inner mitochondrial membrane (IMM) divide? Third, how many 'types' of fission exist? We also introduce a model that integrates multiple regulatory factors in mammalian mitochondrial fission. In this model, three possible pathways (cellular stimulation, metabolic switching or mitochondrial dysfunction) independently initiate Drp1 recruitment at the fission site, followed by a shared second step in which Mff mediates subsequent assembly of a contractile Drp1 ring. We conclude by discussing some perplexing issues in fission regulation, including the effects of Drp1 phosphorylation and the multiple Drp1 isoforms.
    Keywords:  Drp1 receptors; Dynamin related protein-1; Inner mitochondrial membrane division; Mitochondrial fission
    DOI:  https://doi.org/10.1242/jcs.263640
  6. Cell. 2025 Mar 20. pii: S0092-8674(25)00207-7. [Epub ahead of print]188(6): 1462-1465
    Small-molecule hypoxia therapy in mitochondrial disease.
    Marni J Falk.
      In this issue of Cell, Blume et al. provide compelling rationale for pursuing pharmacologic optimization of a small-molecule "HypoxyStat," which left-shifts the oxyhemoglobin dissociation curve in red blood cells in an attempt to induce an effective and sustained reduction of chronic tissue hyperoxia in primary mitochondrial disease (PMD) and was well-tolerated and effective for both pre-symptomatic and advanced disease treatment to extend survival and improve neurologic outcomes in a mouse model of Leigh syndrome spectrum.
    DOI:  https://doi.org/10.1016/j.cell.2025.02.019
  7. J Transl Med. 2025 Mar 18. 23(1): 347
    Wnt5a augments intracellular free cholesterol levels and promotes castration resistance in prostate cancer.
    Yuqi Guo, Zhiyuan Zhang, Lintao Dong, Xinyi Shi, Xiaohan Li, Mingxiu Luo, Yajuan Fu, Yujing Gao.
       BACKGROUND: Prostate cancer (PCa) is a leading cause of cancer-related mortality in men globally. While androgen deprivation therapy (ADT) can extend the asymptomatic phase and overall survival of patients with metastatic PCa, prolonged ADT often leads to the development of castration-resistant prostate cancer (CRPC) within 18-24 months. The mechanisms underlying CRPC remain incompletely understood, presenting a significant challenge in clinical prostate cancer treatment.
    METHODS: In this study, we investigated the role of Wnt5a, a member of the Wnt family, in CRPC. Tumor tissues from CRPC patients were analyzed to assess the expression levels of Wnt5a. Prostate cancer cells were used to examine the impact of Wnt5a on androgen-dependent and -independent growth, as well as sensitivity to bicalutamide. RNA-seq analysis, qRT-PCR, intracellular cholesterol content and the activation of the androgen receptor (AR) signaling pathway were evaluated to elucidate the mechanistic role of Wnt5a in CRPC progression. Drug target Mendelian randomization analysis was performed to investigate the effect of PCSK9 inhibitor on prostate cancer.
    RESULTS: Our study revealed a significant overexpression of Wnt5a in tissues from CRPC tumors. Wnt5a was found to enhance both androgen-dependent and -independent growth in prostate cancer cells while reducing their sensitivity to bicalutamide. Mechanistically, Wnt5a was shown to upregulate intracellular free cholesterol content and activate the AR signaling pathway, contributing to hormone therapy resistance in CRPC. PCSK9 inhibitor significantly reduced the risk of PCa.
    CONCLUSIONS: The findings of this study highlight a novel molecular mechanism underlying endocrine therapy resistance in CRPC mediated by Wnt5a. Targeting Wnt5a or reducing cholesterol level would be a promising therapeutic strategy for the treatment of CRPC, providing new insights into potential avenues for combating this challenging form of prostate cancer.
    Keywords:  Androgen receptor signaling; Castration resistance; Cholesterol; Prostate cancer
    DOI:  https://doi.org/10.1186/s12967-025-06322-8
  8. EMBO Rep. 2025 Mar 17.
    Developmental mitochondrial complex I activity determines lifespan.
    Rhoda Stefanatos, Fiona Robertson, Beatriz Castejon-Vega, Yizhou Yu, Alejandro Huerta Uribe, Kevin Myers, Tetsushi Kataura, Viktor I Korolchuk, Oliver D K Maddocks, L Miguel Martins, Alberto Sanz.
      Aberrant mitochondrial function has been associated with an increasingly large number of human disease states. Observations from in vivo models where mitochondrial function is altered suggest that maladaptations to mitochondrial dysfunction may underpin disease pathology. We hypothesized that the severity of this maladaptation could be shaped by the plasticity of the system when mitochondrial dysfunction manifests. To investigate this, we have used inducible fly models of mitochondrial complex I (CI) dysfunction to reduce mitochondrial function at two stages of the fly lifecycle, from early development and adult eclosion. Here, we show that in early life (developmental) mitochondrial dysfunction results in severe reductions in survival and stress resistance in adulthood, while flies where mitochondrial function is perturbed from adulthood, are long-lived and stress resistant despite having up to a 75% reduction in CI activity. After excluding developmental defects as a cause, we went on to molecularly characterize these two populations of mitochondrially compromised flies, short- and long-lived. We find that our short-lived flies have unique transcriptomic, proteomic and metabolomic responses, which overlap significantly in discrete models of CI dysfunction. Our data demonstrate that early mitochondrial dysfunction via CI depletion elicits a maladaptive response, which severely reduces survival, while CI depletion from adulthood is insufficient to reduce survival and stress resistance.
    Keywords:  Ageing; Complex I; Drosophila; Mitochondria; Mitochondrial Disease
    DOI:  https://doi.org/10.1038/s44319-025-00416-6
  9. Cell Rep. 2025 Mar 18. pii: S2211-1247(25)00212-8. [Epub ahead of print]44(4): 115441
    Lactylation orchestrates ubiquitin-independent degradation of cGAS and promotes tumor growth.
    Keqiang Rao, Xinchao Zhang, Yi Luo, Qiang Xia, Yuting Jin, Jing He.
      Lactate extensively associates with metabolic reprogramming, signal transduction, and immune modulation. Nevertheless, the regulatory role of lactate in immune sensing of cytosolic DNA remains uncertain. Here, we report that lactate serves as an initiator to facilitate proteasomal degradation of cyclic GMP-AMP synthase (cGAS) independent of ubiquitin, thus repressing the production of interferon and contributing to tumor growth. Mechanistically, lactylation of K21 stimulates cGAS translocation from the nucleus to the proteasome for degradation, which is compromised by phosphorylation of PSMA4 S188 via disrupting its association with cGAS. Concurrently, lactylation of K415 rewires PIK3CB activity and impairs ULK1-driven phosphorylation of PSMA4 S188. Physiologically, lactylation of cGAS sustains tumor growth. Expression of cGAS correlates with the antitumor effect of the LDHA inhibitor FX11. Finally, the lactate-cGAS axis indicates a prognostic outcome of lung adenocarcinoma. Collectively, these findings not only put forth a mechanism of cGAS degradation but also unravel the clinical relevance of cGAS lactylation.
    Keywords:  CP: Cancer; PIK3CB; PSMA4; ULK1; cGAS; innate immune system; lactylation; tumor growth; ubiquitin-independent degradation
    DOI:  https://doi.org/10.1016/j.celrep.2025.115441
  10. Cancer Cell. 2025 Mar 18. pii: S1535-6108(25)00079-0. [Epub ahead of print]
    Small-molecule RNA therapeutics to target prostate cancer.
    Duygu Kuzuoglu-Ozturk, Hao G Nguyen, Lingru Xue, Emma Figueredo, Vishvak Subramanyam, Isabelle Liu, Kenya Bonitto, Ashish Noronha, Adrianna Dabrowska, Janet E Cowan, Juan A Oses-Prieto, Alma L Burlingame, Stephen T Worland, Peter R Carroll, Davide Ruggero.
      Tuning protein expression by targeting RNA structure using small molecules is an unexplored avenue for cancer treatment. To understand whether this vulnerability could be therapeutically targeted in the most lethal form of prostate cancer, castration-resistant prostate cancer (CRPC), we use a clinical small molecule, zotatifin, that targets the RNA helicase and translation factor eukaryotic initiation factor 4A (eIF4A). Zotatifin represses tumorigenesis in patient-derived and xenograft models and prolonged survival in vivo alongside hormone therapy. Genome-wide transcriptome, translatome, and proteomic analysis reveals two important translational targets: androgen receptor (AR), a key oncogene in CRPC, and hypoxia-inducible factor 1A (HIF1A), an essential cancer modulator in hypoxia. We solve the structure of the 5' UTRs of these oncogenic mRNAs and strikingly observe complex structural remodeling of these select mRNAs by this small molecule. Remarkably, tumors treated with zotatifin become more sensitive to anti-androgen therapy and radiotherapy. Therefore, "translatome therapy" provides additional strategies to treat the deadliest cancers.
    Keywords:  5′ UTR; AR; HIF1A; RNA structure; combinational therapy; eIF4A; mCRPC; prostate cancer; translational control; zotatifin
    DOI:  https://doi.org/10.1016/j.ccell.2025.02.027
  11. Cancer Cell. 2025 Mar 18. pii: S1535-6108(25)00081-9. [Epub ahead of print]
    Horizontal mitochondrial transfer in cancer biology: Potential clinical relevance.
    Michael V Berridge, Renata Zobalova, Stepana Boukalova, Andrés Caicedo, Stuart A Rushworth, Jiri Neuzil.
      Recent research highlights horizontal mitochondrial transfer as a key biological phenomenon linked to cancer onset and progression. The transfer of mitochondria and their genomes between cancer and non-cancer cells shifts our understanding of intercellular gene trafficking, increasing the metabolic fitness of cancer cells and modulating antitumor immune responses. This process not only facilitates tumor progression but also presents potential therapeutic opportunities.
    DOI:  https://doi.org/10.1016/j.ccell.2025.03.002
  12. Genome Med. 2025 Mar 20. 17(1): 24
    Whole genome sequencing of 378 prostate cancer metastases reveals tissue selectivity for mismatch deficiency with potential therapeutic implications.
    Daniel J Vis, Sander A L Palit, Marie Corradi, Edwin Cuppen, Niven Mehra, Martijn P Lolkema, Lodewyk F A Wessels, Michiel S van der Heijden, Wilbert Zwart, Andries M Bergman.
       BACKGROUND: Survival of patients with metastatic castration-resistant prostate cancer (mCRPC) depends on the site of metastatic dissemination.
    METHODS: Patients with mCRPC were prospectively included in the CPCT-02 metastatic site biopsy study. We evaluated whole genome sequencing (WGS) of 378 mCRPC metastases to understand the genetic traits that affect metastatic site distribution.
    RESULTS: Our findings revealed that RB1, PIK3CA, JAK1, RNF43, and TP53 mutations are the most frequent genetic determinants associated with site selectivity for metastatic outgrowth. Furthermore, we explored mutations in the non-coding genome and found that androgen receptor (AR) chromatin binding sites implicated in metastatic prostate cancer differ in mutation frequencies between metastatic sites, converging on pathways that impact DNA repair. Notably, liver and visceral metastases have a higher tumor mutational load (TML) than bone and lymph node metastases, independent of genetic traits associated with neuroendocrine differentiation. We found that TML is strongly associated with DNA mismatch repair (MMR)-deficiency features in these organs.
    CONCLUSIONS: Our results revealed gene mutations that are significantly associated with metastatic site selectivity and that frequencies of non-coding mutations at AR chromatin binding sites differ between metastatic sites. Immunotherapeutics are thus far unsuccessful in unselected mCRPC patients. We found a higher TML in liver and visceral metastases compared to bone and lymph node metastases. As immunotherapeutics response is associated with mutational burden, these findings may assist in selecting mCRPC patients for immunotherapy treatment based on organs affected by metastatic disease.
    TRIAL REGISTRATION NUMBER: NCT01855477.
    Keywords:  Coding DNA; Immunotherapeutics; Metastases; Mutations; Non-coding DNA; Prostate cancer; Site selectivity; Tumor mutational load
    DOI:  https://doi.org/10.1186/s13073-025-01445-5
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