bims-midysc 2025-02-16 papers

bims-midysc

Biomed News

on Mitochondria dysfunction in cancer

Issue of 2025–02–16
eleven papers selected by
Papachristodoulou Lab

Lactoferrin-Encapsulated Dichloroacetophenone (DAP) nanoparticles enhance drug delivery and anti-tumor efficacy in prostate cancer.
A microscopy-based screen identifies cellular kinases modulating mitochondrial translation.
Publisher Correction: Immune evasion through mitochondrial transfer in the tumour microenvironment.
Mitochondrial DNA removal is essential for sperm development and activity.
ANO7 expression in the prostate modulates mitochondrial function and lipid metabolism.
Caloric Restriction and Telomere Preservation in TERT Knockout Adipocyte Progenitors Does Not Rescue Mice From Metabolic Dysfunction due to a TERT Function in Adipocyte Mitochondria.
Lactate controls cancer stemness and plasticity through epigenetic regulation.
Mitofusin 2 displays fusion-independent roles in proteostasis surveillance.
Effective Treatment of Disseminated Prostate Cancer Using CD46-Targeted 225Ac Therapy.
Combination of Low-Dose Sulforaphane and Docetaxel on Mitochondrial Function and Metabolic Reprogramming in Prostate Cancer Cell Lines.
Analysis of microarray and single-cell RNA-seq identifies gene co-expression, cell-cell communication, and tumor environment associated with metabolite interconversion enzyme in prostate cancer.

Cancer Lett. 2025 Feb 07. pii: S0304-3835(25)00086-2. [Epub ahead of print] 217522

Lactoferrin-Encapsulated Dichloroacetophenone (DAP) nanoparticles enhance drug delivery and anti-tumor efficacy in prostate cancer.

Sugarniya Subramaniam, Varinder Jeet, Jennifer H Gunter, Judith A Clements, Srilakshmi Srinivasan, Amirali Popat, Jyotsna Batra.

  Pyruvate Dehydrogenase Kinase 1 (PDK1) regulates glycolysis and oxidative phosphorylation pathways and is linked to prostate cancer metastasis and poor prognosis. The therapeutic application of 2,2-dichloroacetophenone (DAP), a PDK1 inhibitor, remains underexplored in prostate cancer. In this study we demonstrated that DAP exhibited a superior ability to inhibit prostate cancer cell proliferation, migration and colony formation at a lower concentration (20 μM) compared to a previously established inhibitor, dichloroacetate (DCA), which required concentrations of 30 mM or higher. However, poor aqueous solubility and lower stability of DAP limits its therapeutic application. Nano formulation of DAP with natural lactoferrin enhanced its dispersion and stability by increasing polydispersity index and intensity, and reduced zeta potential values upon conjugation that overcame the solubility limitations of DAP. The lactoferrin-DAP nanoparticles exhibited enhanced therapeutic efficacy by precisely targeting prostate cancer cells that express high lactoferrin receptors and high anti-tumor activity in vitro (at 1 μM) and in mouse prostate tumor xenografts (20 mg/kg). Mechanistically, these nanoparticles induce apoptosis in cancer cells by inducing caspase3/7 activity and disrupting the glycolytic and oxidative phosphorylation pathways. Moreover, lactoferrin-conjugated DAP nanoparticles suppressed the viability of docetaxel-resistant cells exhibiting a higher inhibitory efficacy compared to free DAP and DCA. Targeting PDK1 through lactoferrin-conjugated DAP nanoparticles represents a potent targeted therapeutic strategy for disrupting prostate tumor metabolism and offers promising implications for overcoming drug resistance.

Keywords:  Dichloroacetophenone; Lactoferrin nanoparticles; Metabolism; Prostate cancer; Pyruvate Dehydrogenase Kinase 1

DOI:  https://doi.org/10.1016/j.canlet.2025.217522
Cell Rep. 2025 Jan 28. pii: S2211-1247(24)01494-3. [Epub ahead of print]44(1): 115143

A microscopy-based screen identifies cellular kinases modulating mitochondrial translation.

Roya Yousefi, Luis Daniel Cruz-Zaragoza, Anusha Valpadashi, Carina Hansohn, Drishan Dahal, Ricarda Richter-Dennerlein, Silvio Rizzoli, Henning Urlaub, Peter Rehling, David Pacheu-Grau.

  Mitochondrial DNA encodes 13 subunits of the oxidative phosphorylation (OXPHOS) system, which are synthesized inside the organelle and essential for cellular energy supply. How mitochondrial gene expression is regulated and integrated into cellular physiology is little understood. Here, we perform a high-throughput screen combining fluorescent labeling of mitochondrial translation products with small interfering RNA (siRNA)-mediated knockdown to identify cellular kinases regulating translation. As proof of principle, the screen identifies known kinases that affect mitochondrial translation, and it also reveals several kinases not yet linked to this process. Among the latter, we focus on the primarily cytosolic kinase, fructosamine 3 kinase (FN3K), which localizes partially to the mitochondria to support translation. FN3K interacts with the mitochondrial ribosome and modulates its assembly, thereby affecting translation. Overall, our work provides a reliable approach to identify protein functions for mitochondrial gene expression in a high-throughput manner.

Keywords:  CP: Metabolism; CP: Molecular biology; cellular kinases; click chemistry; mito-FUNCAT; mitochondrial translation; siRNA library

DOI:  https://doi.org/10.1016/j.celrep.2024.115143
Nature. 2025 Feb 13.

Publisher Correction: Immune evasion through mitochondrial transfer in the tumour microenvironment.

Hideki Ikeda, Katsushige Kawase, Tatsuya Nishi, Tomofumi Watanabe, Keizo Takenaga, Takashi Inozume, Takamasa Ishino, Sho Aki, Jason Lin, Shusuke Kawashima, Joji Nagasaki, Youki Ueda, Shinichiro Suzuki, Hideki Makinoshima, Makiko Itami, Yuki Nakamura, Yasutoshi Tatsumi, Yusuke Suenaga, Takao Morinaga, Akiko Honobe-Tabuchi, Takehiro Ohnuma, Tatsuyoshi Kawamura, Yoshiyasu Umeda, Yasuhiro Nakamura, Yukiko Kiniwa, Eiki Ichihara, Hidetoshi Hayashi, Jun-Ichiro Ikeda, Toyoyuki Hanazawa, Shinichi Toyooka, Hiroyuki Mano, Takuji Suzuki, Tsuyoshi Osawa, Masahito Kawazu, Yosuke Togashi.

DOI: https://doi.org/10.1038/s41586-025-08764-y
EMBO J. 2025 Feb 11.

Mitochondrial DNA removal is essential for sperm development and activity.

Zhe Chen, Fan Zhang, Annie Lee, Michaela Yamine, Zong-Heng Wang, Guofeng Zhang, Christian Combs, Hong Xu.

  Active mitochondrial DNA (mtDNA) elimination during spermatogenesis has emerged as a conserved mechanism ensuring the uniparental mitochondrial inheritance in animals. However, given the existence of post-fertilization processes degrading sperm mitochondria, the physiological significance of mtDNA removal during spermatogenesis is not clear. Here we show that mtDNA clearance is indispensable for sperm development and activity. We uncover a previously unappreciated role of Poldip2 as a mitochondrial exonuclease that is specifically expressed in late spermatogenesis and required for sperm mtDNA elimination in Drosophila. Loss of Poldip2 impairs mtDNA clearance in elongated spermatids and impedes the progression of individualization complexes that strip away cytoplasmic materials and organelles. Over time, poldip2 mutant sperm exhibit marked nuclear genome fragmentation, and the flies become completely sterile. Notably, these phenotypes were rescued by expressing a mitochondrially targeted bacterial exonuclease, which ectopically removes mtDNA. Our work illustrates the developmental necessity of mtDNA clearance for effective cytoplasm removal at the end of spermatid morphogenesis, and for preventing potential nuclear-mitochondrial genome imbalance in mature sperm, in which nuclear genome activity is shut down.

Keywords:   Drosophila spermatogenesis; EndoG; Exonuclease; Male Sterile; Maternal Inheritance

DOI:  https://doi.org/10.1038/s44318-025-00377-5
Cell Commun Signal. 2025 Feb 08. 23(1): 71

ANO7 expression in the prostate modulates mitochondrial function and lipid metabolism.

Christoffer Löf, Nasrin Sultana, Neha Goel, Samuel Heron, Gudrun Wahlström, Andrew House, Minna Holopainen, Reijo Käkelä, Johanna Schleutker.

   BACKGROUND: Prostate cancer (PrCa) is a significant health concern, ranking as the second most common cancer in males globally. Genetic factors contribute substantially to PrCa risk, with up to 57% of the risk being attributed to genetic determinants. A major challenge in managing PrCa is the early identification of aggressive cases for targeted treatment, while avoiding unnecessary interventions in slow-progressing cases. Therefore, there is a critical need for genetic biomarkers that can distinguish between aggressive and non-aggressive PrCa cases. Previous research, including our own, has shown that germline variants in ANO7 are associated with aggressive PrCa. However, the function of ANO7 in the prostate remains unknown.
METHODS: We performed RNA-sequencing (RNA-seq) on RWPE1 cells engineered to express ANO7 protein, alongside the analysis of a single-cell RNA-sequencing (scRNA-seq) dataset and RNA-seq from prostate tissues. Differential gene expression analysis and gene set enrichment analysis (GSEA) were conducted to identify key pathways. Additionally, we assessed oxidative phosphorylation (OXPHOS), glycolysis, and targeted metabolomics. Image analysis of mitochondrial morphology and lipidomics were also performed to provide further insight into the functional role of ANO7 in prostate cells.
RESULTS: ANO7 expression resulted in the downregulation of metabolic pathways, particularly genes associated with the MYC pathway and oxidative phosphorylation (OXPHOS) in both prostate tissue and ANO7-expressing cells. Measurements of OXPHOS and glycolysis in the ANO7-expressing cells revealed a metabolic shift towards glycolysis. Targeted metabolomics showed reduced levels of the amino acid aspartate, indicating disrupted mitochondrial function in the ANO7-expressing cells. Image analysis demonstrated altered mitochondrial morphology in these cells. Additionally, ANO7 downregulated genes involved in fatty acid metabolism and induced changes in lipid composition of the cells, characterized by longer acyl chain lengths and increased unsaturation, suggesting a role for ANO7 in regulating lipid metabolism in the prostate.
CONCLUSIONS: This study provides new insights into the function of ANO7 in prostate cells, highlighting its involvement in metabolic pathways, particularly OXPHOS and lipid metabolism. The findings suggest that ANO7 may act as a key regulator of cellular lipid metabolism and mitochondrial function in the prostate, shedding light on a previously unknown aspect of ANO7's biology.

Keywords:  ANO7; Glycolysis; Lipid metabolism; MYC; Mitochondria; OXPHOS; Prostate cancer

DOI:  https://doi.org/10.1186/s12964-025-02081-7
Aging Cell. 2025 Feb 11. e14499

Caloric Restriction and Telomere Preservation in TERT Knockout Adipocyte Progenitors Does Not Rescue Mice From Metabolic Dysfunction due to a TERT Function in Adipocyte Mitochondria.

Zhanguo Gao, Yongmei Yu, Kristin Eckel-Mahan, Mikhail G Kolonin.

  Inactivation of telomerase (TERT) in adipocyte progenitor cells (APC) expedites telomere attrition, and the onset of diabetes in mice fed high-fat diet (HFD), which promotes APC over-proliferation and replicative senescence. Here, we show that time-restricted feeding or caloric restriction in the postnatal development of mice subsequently subjected to HFD prevents telomere attrition but not glucose intolerance. This metabolic effect of dietary intervention was not observed for mice with TERT KO in endothelial or myeloid cells. To characterize the telomere-independent effects of TERT in the APC lineage, we analyzed mice with TERT knockout in mature adipocytes (AD-TERT-KO), which do not proliferate and avoid telomere attrition. Analysis of adipocytes from AD-TERT-KO mice indicated reliance on glycolysis and decreased mitochondrial oxidative metabolism. We show that AD-TERT-KO mice have reduced cold tolerance and metabolism abnormality indicating a defect in adaptive thermogenesis, characteristic of aging. Conversely, ectopic TERT expression in brown adipocytes-induced mitochondrial oxidation and thermogenic gene expression. We conclude that TERT plays an important non-canonical function in the mitochondria of adipocytes.

Keywords:  TERT; adipocyte; mitochondria; progenitor; senescence; telomerase; telomere

DOI:  https://doi.org/10.1111/acel.14499
Cell Metab. 2025 Feb 04. pii: S1550-4131(25)00002-6. [Epub ahead of print]

Lactate controls cancer stemness and plasticity through epigenetic regulation.

Nguyen T B Nguyen, Sira Gevers, Rutger N U Kok, Lotte M Burgering, Hannah Neikes, Ninouk Akkerman, Max A Betjes, Marlies C Ludikhuize, Can Gulersonmez, Edwin C A Stigter, Yvonne Vercoulen, Jarno Drost, Hans Clevers, Michiel Vermeulen, Jeroen S van Zon, Sander J Tans, Boudewijn M T Burgering, Maria J Rodríguez Colman.

  Tumors arise from uncontrolled cell proliferation driven by mutations in genes that regulate stem cell renewal and differentiation. Intestinal tumors, however, retain some hierarchical organization, maintaining both cancer stem cells (CSCs) and cancer differentiated cells (CDCs). This heterogeneity, coupled with cellular plasticity enabling CDCs to revert to CSCs, contributes to therapy resistance and relapse. Using genetically encoded fluorescent reporters in human tumor organoids, combined with our machine-learning-based cell tracker, CellPhenTracker, we simultaneously traced cell-type specification, metabolic changes, and reconstructed cell lineage trajectories during tumor organoid development. Our findings reveal distinctive metabolic phenotypes in CSCs and CDCs. We find that lactate regulates tumor dynamics, suppressing CSC differentiation and inducing dedifferentiation into a proliferative CSC state. Mechanistically, lactate increases histone acetylation, epigenetically activating MYC. Given that lactate's regulation of MYC depends on the bromodomain-containing protein 4 (BRD4), targeting cancer metabolism and BRD4 inhibitors emerge as a promising strategy to prevent tumor relapse.

Keywords:  cancer metabolism; cell plasticity; cell types; cell-cell interactions; differentiation; heterogeneity; live imaging; organoids; single-cell tracking; stem cells

DOI:  https://doi.org/10.1016/j.cmet.2025.01.002
Nat Commun. 2025 Feb 10. 16(1): 1501

Mitofusin 2 displays fusion-independent roles in proteostasis surveillance.

Mariana Joaquim, Selver Altin, Maria-Bianca Bulimaga, Tânia Simões, Hendrik Nolte, Verian Bader, Camilla Aurora Franchino, Solenn Plouzennec, Karolina Szczepanowska, Elena Marchesan, Kay Hofmann, Marcus Krüger, Elena Ziviani, Aleksandra Trifunovic, Arnaud Chevrollier, Konstanze F Winklhofer, Elisa Motori, Margarete Odenthal, Mafalda Escobar-Henriques.

Mitochondria are essential organelles and their functional state dictates cellular proteostasis. However, little is known about the molecular gatekeepers involved, especially in absence of external stress. Here we identify a role of MFN2 in quality control independent of its function in organellar shape remodeling. MFN2 ablation alters the cellular proteome, marked for example by decreased levels of the import machinery and accumulation of the kinase PINK1. Moreover, MFN2 interacts with the proteasome and cytosolic chaperones, thereby preventing aggregation of newly translated proteins. Similarly to MFN2-KO cells, patient fibroblasts with MFN2-disease variants recapitulate excessive protein aggregation defects. Restoring MFN2 levels re-establishes proteostasis in MFN2-KO cells and rescues fusion defects of MFN1-KO cells. In contrast, MFN1 loss or mitochondrial shape alterations do not alter protein aggregation, consistent with a fusion-independent role of MFN2 in cellular homeostasis. In sum, our findings open new possibilities for therapeutic strategies by modulation of MFN2 levels.

DOI: https://doi.org/10.1038/s41467-025-56673-5
Clin Cancer Res. 2025 Feb 13.

Effective Treatment of Disseminated Prostate Cancer Using CD46-Targeted 225Ac Therapy.

Anil P Bidkar, Robin Peter, Anju Wadhwa, Kondapa Naidu Bobba, Scott Bidlingmaier, Niranjan Meher, Jonathan Chou, Nancy Greenland, Chandrashekhar Dasari, Shubhankar Naik, Athira Raveendran, Megha Basak, Juan Antonio Camara Serrano, Veronica Steri, Scott Kogan, Adam Oskowitz, Jiang He, David M Wilson, Rahul Aggarwal, Renuka Sriram, Henry F VanBrocklin, Youngho Seo, Bin Liu, Robert R Flavell.

PURPOSE: Metastatic castration-resistant prostate cancer (mCRPC) has limited treatment options and a poor prognosis. Recently, PSMA-targeted alpha particle therapy agents using Actinium-225 (225Ac) have shown promising results for prostate cancer treatment, but a significant fraction of patients with advanced mCRPC demonstrate loss of PSMA expression. We have previously reported that PSMA-null and PSMA-positive tumors can be detected and treated effectively with CD46-targeted radiopharmaceuticals. This study evaluates the CD46-targeting PET imaging agent [89Zr]DFO-YS5 and the radioimmunotherapy agent [225Ac]Macropa-PEG4-YS5 in disseminated prostate cancer tumors.
EXPERIMENTAL DESIGN: Microtumor lesions, primarily observed in the liver, kidneys, and lungs, were successfully detected with [89Zr]DFO-YS5 PET imaging. We used disseminated 22Rv1 tumors for biodistribution studies, dosimetry assessments, and therapeutic efficacy evaluations of [225Ac]Macropa-PEG4-YS5.
RESULTS: Quantitative digital alpha-particle autoradiography revealed high radiation dose deposition from [225Ac]Macropa-PEG4-YS5 in microtumors compared to surrounding liver tissues, although in larger lesions (>1 mm diameter) the dose distribution was heterogeneous. Early treatment of smaller disseminated tumors with uniform radiation dose was more effective in ablating tumors and promoting survival. In late-stage lesions of large size, heterogeneous dose deposition limited therapeutic efficacy, requiring higher administered activity to achieve a complete response.
CONCLUSIONS: Our findings highlight that [225Ac]Macropa-PEG4-YS5 holds the potential for clinical translation for metastatic prostate cancer and reinforces the value of microdosimetry in understanding the efficacy of and resistance to targeted alpha therapy.

DOI: https://doi.org/10.1158/1078-0432.CCR-24-2850
Int J Mol Sci. 2025 Jan 24. pii: 1013. [Epub ahead of print]26(3):

Combination of Low-Dose Sulforaphane and Docetaxel on Mitochondrial Function and Metabolic Reprogramming in Prostate Cancer Cell Lines.

Ana Peñata-Taborda, Pedro Espitia-Pérez, Lyda Espitia-Pérez, Andrés Coneo-Pretelt, Hugo Brango, Dina Ricardo-Caldera, Gean Arteaga-Arroyo, Luisa Jiménez-Vidal, Claudia Galeano-Páez, Karina Pastor-Sierra, Alicia Humanez-Alvarez, Osnamir Bru-Cordero, Nathalia Jones-Cifuentes, Bladimiro Rincón-Orozco, Stelia Mendez-Sanchez, Mario Negrette-Guzmán.

  Considering the limitations of monotherapies due to chemoresistance and side effects, this research aimed to determine whether low doses of sulforaphane (SFN) combined with docetaxel (DCT) could enhance therapeutic efficacy. Prostate cancer cell lines LNCaP and PC-3 were treated with individual IC50 doses of SFN and DCT and half-reduced IC50 values for the SFN:DCT combination. Metabolic markers, including glucose consumption, lactate production, reactive oxygen species (ROS), mitochondrial mass, and caspase activity, were assessed. In LNCaP cells, the SFN:DCT combination reduced cell viability to 50%, comparable to DCT monotherapy (48%). Caspase 3 activation was also higher with SFN:DCT (2.4 ± 0.75 RFU) than DCT alone (2.1 ± 0.47 RFU), while caspase 8 activation remained comparable, indicating equivalent effectiveness at lower concentrations. In PC-3 cells, the combination induced caspase 3 activation (1.16 ± 0.0484 RFU) at levels slightly lower than DCT (1.51 ± 0.2062 RFU) but achieved greater reductions in mitochondrial mass, reflecting its ability to target metabolic vulnerabilities in aggressive phenotypes. Our findings suggest that the SFN:DCT combination is a promising strategy for early-stage prostate cancer. By achieving comparable efficacy to DCT monotherapy at low doses, the SFN:DCT combination maintains the therapeutic impact, mitigating the adverse effects of conventional DCT treatment.

Keywords:  combination therapy; docetaxel; glycolysis; mitochondrial function; prostate cancer; redox status; sulforaphane

DOI:  https://doi.org/10.3390/ijms26031013
Discov Oncol. 2025 Feb 13. 16(1): 177

Analysis of microarray and single-cell RNA-seq identifies gene co-expression, cell-cell communication, and tumor environment associated with metabolite interconversion enzyme in prostate cancer.

Danial Hashemi Karoii, Ali Shakeri Abroudi, Nadia Forghani, Sobhan Bavandi, Melika Djamali, Hamoon Baghaei, Sana Shafaeitilaki, Ehsan HasanZadeh.

   BACKGROUND: Prostate cancer (PCa) is the second most common malignant neoplasm in males and is the fifth leading cause of cancer-related mortality. Due to the use of prostate-specific antigen (PSA) screening and improved biopsy techniques, persons identified with early-stage prostate cancer often have a positive prognosis after comprehensive treatment. Nonetheless, prostate cancer is a latent illness that may present as an asymptomatic tumor in individuals aged 20-30. The overall survival (OS) of men with advanced PCa is significantly diminished. Consequently, there is an immediate want for innovative, accurate biomarkers to detect early prostate cancer.
METHODS: This research analyzed the interaction network of differentially expressed genes (DEGs) related to metabolite interconversion enzymes in PCa by gene expression microarray data, single-cell RNA sequencing, oncogenes, and tumor suppressor genes (TSGs) utilizing bioinformatics techniques. This kind of analysis has not been documented in prior studies.
RESULTS: We then used a dataset acquired by the Cancer Genome Atlas (TCGA) to confirm our findings. Genes including CYP3A5, PDE8B, AOX1, BNIPL, FADS2, RRM2, ALDH3B2, and GSTM2 may be significant in the diagnosis and treatment of PCa.
CONCLUSION: Our objective was to provide new perspectives on the molecular properties and pathways of DEGs in PCa and to uncover potential biomarkers that play a crucial role in the genesis and progression of PCa.

Keywords:  Cell–cell communication; Metabolite interconversion enzyme; Microarray; Prostate cancer

DOI:  https://doi.org/10.1007/s12672-025-01926-4