bims-midysc Biomed News
on Mitochondria dysfunction in cancer
Issue of 2025–02–23
fifteen papers selected by
Papachristodoulou Lab
  1. Lon protease 1-mediated metabolic reprogramming promotes the progression of prostate cancer.
  2. Putting the brakes on mitochondrial fusion to prevent escape of mitochondrial DNA.
  3. A Quantitative Approach to Mapping Mitochondrial Specialization and Plasticity.
  4. Analysis of fatty acid metabolism in prostate cancer and discovery of a new programmed cell death-associated luminal cell subpopulation.
  5. Heightened sensitivity to adverse effects of metformin in mtDNA mutant patient cells.
  6. Mapping the GDF15 Arm of the Integrated Stress Response in Human Cells and Tissues.
  7. Mitochondrial translation regulates terminal erythroid differentiation by maintaining iron homeostasis.
  8. How are mitochondrial nucleoids trafficked?
  9. PIM kinase inhibition counters resistance to radiotherapy and chemotherapy in human prostate cancer.
  10. CRISPR screening identifies regulators of enhancer-mediated androgen receptor transcription in advanced prostate cancer.
  11. Exploring the therapeutic potential of MOTS-c in age-related macular degeneration: from cellular responses to patient-derived cybrids.
  12. ECD, a novel androgen receptor target promotes prostate cancer tumorigenesis by regulating glycolysis.
  13. Blood mitochondrial health markers cf-mtDNA and GDF15 in human aging.
  14. Lactate Drives Senescence-Resistant Lineages in Hepatocellular Carcinoma via Histone H2B Lactylation of NDRG1.
  15. Mitochondrial fission produces a Warburg effect via the oxidative inhibition of prolyl hydroxylase domain-2.
  1. Cell Death Dis. 2025 Feb 19. 16(1): 116
    Lon protease 1-mediated metabolic reprogramming promotes the progression of prostate cancer.
    Mengfei Yao, Xingming Zhang, Tianqi Wu, Tao Feng, Xiaojie Bian, Mierxiati Abudurexiti, Wenfeng Wang, Guohai Shi, Gong-Hong Wei, Qin Zhang, Xiangyun Li, Gang Feng, Leilei Du, Jianhua Wang.
      Lon protease 1 (LONP1) is an ATP-dependent protease located in the mitochondrial matrix and plays a crucial role in regulating mitochondrial proteostasis, metabolism, and cellular stress responses et al. Aberrant LONP1 expression has been found in the progression of various tumors; however, the role and molecular mechanisms of LONP1 in prostate cancer (PCa) remain poorly understood. Here we show that overexpression of LONP1 is closely related to adverse clinic pathological features and poor prognosis in PCa patients. Mechanistically, the findings reveal that LONP1 is implicated in modulating the metabolic switch from oxidative phosphorylation (OXPHOS) to aerobic glycolysis, thereby promoting tumor proliferation, invasion, and metastasis both in vitro and in vivo. Meanwhile, we prove that LONP1 as a protease directly targets mitochondrial pyruvate carrier 1 (MPC1), a key metabolic protein in the process of glycolysis, and enhances its degradation, which in turn suppresses tricarboxylic acid (TCA) cycle and ultimately promotes the progression of PCa. Furthermore, using PCa in cancer-prone mice homozygous for a prostate-targeted conditional Pten knockout and Lonp1 knockin, we integrate transcriptomic and proteomic analyses of prostate tumors, upon which reveals that Lonp1 overexpression results in a significant downregulation of NADH: ubiquinone oxidoreductase activity, consequently impeding the electron transfer process and mitochondrial ATP synthesis, associated with metastasis of PCa. Collectively, our results highlight that metabolic reprogramming induced by LONP1 in PCa is closely coupled with disease progression, suggesting that targeting the LONP1-mediated cascade in the mitochondrial may provide therapeutic potential for PCa disease.
    DOI:  https://doi.org/10.1038/s41419-025-07449-8
  2. Nature. 2025 Feb 19.
    Putting the brakes on mitochondrial fusion to prevent escape of mitochondrial DNA.
    Kate McArthur, Michael T Ryan.
      
    Keywords:  Cell biology
    DOI:  https://doi.org/10.1038/d41586-025-00303-z
  3. bioRxiv. 2025 Feb 08. pii: 2025.02.03.635951. [Epub ahead of print]
    A Quantitative Approach to Mapping Mitochondrial Specialization and Plasticity.
    Anna S Monzel, Jack Devine, Darshana Kapri, Jose Antonio Enriquez, Caroline Trumpff, Martin Picard.
      Mitochondria are a diverse family of organelles that specialize to accomplish complimentary functions 1-3 . All mitochondria share general features, but not all mitochondria are created equal 4 .Here we develop a quantitative pipeline to define the degree of molecular specialization among different mitochondrial phenotypes - or mitotypes . By distilling hundreds of validated mitochondrial genes/proteins into 149 biologically interpretable MitoPathway scores (MitoCarta 3.0 5 ) the simple mitotyping pipeline allows investigators to quantify and interpret mitochondrial diversity and plasticity from transcriptomics or proteomics data across a variety of natural and experimental contexts. We show that mouse and human multi-organ mitotypes segregate along two main axes of mitochondrial specialization, contrasting anabolic (liver) and catabolic (brain) tissues. In cultured primary human fibroblasts exhibiting robust time-dependent and treatment-induced metabolic plasticity 6-8 , we demonstrate how the mitotype of a given cell type recalibrates i) over time in parallel with hallmarks of aging, and ii) in response to genetic, pharmacological, and metabolic perturbations. Investigators can now use MitotypeExplorer.org and the associated code to visualize, quantify and interpret the multivariate space of mitochondrial biology.
    DOI:  https://doi.org/10.1101/2025.02.03.635951
  4. Discov Oncol. 2025 Feb 17. 16(1): 194
    Analysis of fatty acid metabolism in prostate cancer and discovery of a new programmed cell death-associated luminal cell subpopulation.
    Yan Zeng, Zhaolin Jiang.
       INTRODUCTION: This study focuses on the role of fatty acid metabolism in prostate cancer, particularly in oncogenic luminal cells associated with programmed cell death under the influence of metabolic reprogramming.
    MATERIALS AND METHODS: Prostate cancer was analyzed using single-cell transcriptomics and spatial transcriptomics data. Fatty acid metabolism levels in the tumor microenvironment were quantified by multiple gene set scoring methods, and data were processed using NMF and deconvolution methods to identify different cell populations and their interactions in the tumor microenvironment.
    RESULTS: Luminal cells have significantly increased activity in fatty acid metabolism, which is associated with the aggressiveness and metastatic capability of tumors. Luminal cell subpopulations have been found to play a key role in the development of prostate cancer, especially their close association with programmed cell death.
    CONCLUSION: This study deepens the understanding of the role of fatty acid metabolism in prostate cancer, identifies fatty acid metabolism-related luminal cell subtypes, and proposes new therapeutic targets, providing new insights into prostate cancer treatment.
    Keywords:  Fatty acid metabolism; Luminal cells; Programmed cell death; Prostate cancer; Therapeutic targets; Tumor microenvironment
    DOI:  https://doi.org/10.1007/s12672-025-01982-w
  5. Life Sci. 2025 Feb 19. pii: S0024-3205(25)00119-5. [Epub ahead of print]366-367 123486
    Heightened sensitivity to adverse effects of metformin in mtDNA mutant patient cells.
    Sanna Ryytty, Katriina Nurminen, Petri Mäkinen, Anu Suomalainen, Riikka H Hämäläinen.
       AIMS: Metformin (Met) is a widely used, cost-effective, and relatively safe drug, primarily prescribed for diabetes, that also exhibits beneficial effects in other conditions, such as in cardiovascular diseases, neurological disorders, and cancer. Despite its common use, the safety of Met in patients with primary mitochondrial disease remains uncertain, as both Met and mitochondrial dysfunction increase the risk of lactic acidosis. Here we have examined the effects of Met in patient cells with m.3243A>G mitochondrial DNA mutation.
    MATERIALS AND METHODS: We utilized induced pluripotent stem cells (iPSCs) derived from two m.3243A>G patients, alongside cardiomyocytes differentiated from these iPSCs (iPSC-CMs). The cells were exposed to 10, 100, and 1000 μM Met for 24 h, and the effects on cellular metabolism and mitochondrial function were evaluated.
    KEY FINDINGS: While low concentrations, relative to common therapeutic plasma levels, increased mitochondrial respiration, higher concentrations decreased respiration in both patient and control cells. Furthermore, cells with high level of the m.3243A>G mutation were more sensitive to Met than control cells. Additionally, we observed a clear patient-specific response to Met in cardiomyocytes.
    SIGNIFICANCE: The findings emphasize the critical importance of selecting appropriate Met concentrations in cellular experiments and demonstrate the variability in Met's effects between individuals. Moreover, the results highlight the need for caution when considering Met use in patients with primary mitochondrial disorders.
    Keywords:  Cardiomyocytes; Induced pluripotent stem cells; Metformin; Mitochondrial disease; m.3243A>G
    DOI:  https://doi.org/10.1016/j.lfs.2025.123486
  6. bioRxiv. 2025 Feb 01. pii: 2025.01.31.635929. [Epub ahead of print]
    Mapping the GDF15 Arm of the Integrated Stress Response in Human Cells and Tissues.
    Janell Lm Smith, Kamaryn Tanner, Jack Devine, Anna S Monzel, Alan A Cohen, Martin Picard.
      Mitochondrial stress activates the integrated stress response (ISR) and triggers cell-cell communication through secretion of the metabokine growth differentiation factor 15 (GDF15). However, the gene network underlying the ISR remains poorly defined, particularly across metabolically diverse cellular states and tissues. Using RNAseq data from fibroblasts subjected to metabolic perturbations, we develop an ISR GDF15 index quantifying the GDF15 arm of the ISR activation in human cells. Validation of ISR GDF15 index across 44 postmortem human tissues illustrates how this index can be applied to investigate tissue-specific and age-related ISR activation.
    DOI:  https://doi.org/10.1101/2025.01.31.635929
  7. Sci Adv. 2025 Feb 21. 11(8): eadu3011
    Mitochondrial translation regulates terminal erythroid differentiation by maintaining iron homeostasis.
    Tatsuya Morishima, Md Fakruddin, Yohei Kanamori, Takeshi Masuda, Akiko Ogawa, Yuxin Wang, Vivien A C Schoonenberg, Falk Butter, Yuichiro Arima, Takaaki Akaike, Toshiro Moroishi, Kazuhito Tomizawa, Toshio Suda, Fan-Yan Wei, Hitoshi Takizawa.
      Mitochondrial tRNA taurine modifications mediated by mitochondrial tRNA translation optimization 1 (Mto1) is essential for the mitochondrial protein translation. Mto1 deficiency was shown to induce proteostress in embryonic stem cells. A recent finding that a patient with MTO1 gene mutation showed severe anemia led us to hypothesize that Mto1 dysfunctions may result in defective erythropoiesis. Hematopoietic-specific Mto1 conditional knockout (cKO) mice were embryonic lethal and showed niche-independent defect in erythroblast proliferation and terminal differentiation. Mechanistically, mitochondrial oxidative phosphorylation complexes were severely impaired in the Mto1 cKO fetal liver, and this was followed by cytosolic iron accumulation. Overloaded cytosolic iron promoted heme biosynthesis, which induced an unfolded protein response (UPR) in Mto1 cKO erythroblasts. An iron chelator or UPR inhibitor rescued erythroid terminal differentiation in the Mto1 cKO fetal liver in vitro. This mitochondrial regulation of iron homeostasis revealed the indispensable role of mitochondrial tRNA modification in fetal hematopoiesis.
    DOI:  https://doi.org/10.1126/sciadv.adu3011
  8. Trends Cell Biol. 2025 Feb 20. pii: S0962-8924(24)00272-1. [Epub ahead of print]
    How are mitochondrial nucleoids trafficked?
    Josefa Macuada, Isidora Molina-Riquelme, Verónica Eisner.
      Mitochondria harbor their own DNA (mtDNA), which codifies essential proteins of the oxidative phosphorylation (OXPHOS) system and locally feeds them to their surrounding inner mitochondrial membrane (IMM), according to the 'sphere of influence' theory. mtDNA is compacted into nucleoids, which are tethered to the IMM and distributed throughout the mitochondrial network. Some nucleoid subpopulations present distinct intramitochondrial positioning during fission and their correct positioning is associated with mtDNA segregation and selective degradation. This opinion article focuses on different mechanisms that could control nucleoid positioning through intramitochondrial trafficking, either by cristae reshaping or by intercompartment-driven mechanisms involving the mitochondrial membranes and extramitochondrial elements. Understanding nucleoid trafficking promises insights into mitochondrial dysfunction in pathologies with mtDNA distribution and segregation issues.
    Keywords:  cristae reshaping; mitochondrial nucleoid; mtDNA inheritance; nucleoid dynamics; sphere of influence
    DOI:  https://doi.org/10.1016/j.tcb.2024.12.007
  9. Radiother Oncol. 2025 Feb 18. pii: S0167-8140(25)00089-1. [Epub ahead of print] 110794
    PIM kinase inhibition counters resistance to radiotherapy and chemotherapy in human prostate cancer.
    Anne Rajkumar-Calkins, Vinay Sagar, Jian Wang, Shania Bailey, Philip Anderson, Sarki A Abdulkadir, Austin N Kirschner.
       PURPOSE: PIM kinases are associated with treatment resistance and poor prognosis in prostate cancer through roles in DNA damage response, cellular metabolism, proliferation, and survival. We hypothesized PIM inhibition addresses treatment resistance to radiotherapy and docetaxel in prostate cancer.
    METHODS: PIM inhibition in prostate cancer cell lines was examined by phosphorylated H2AX and colony formations assays. In normal and castrated mice with prostate tumor xenografts, tumor growth was monitored with daily oral PIM inhibition +/- fractionated radiotherapy (RT) or docetaxel. Radiotherapy was given 30 Gy in 15 treatments, mimicking clinical conventional daily treatment over 3 weeks in a translational murine model system.
    RESULTS: PIM inhibition decreased radiotherapy-induced DNA-damage repair and decreased cell proliferation and survival. In mice, PIM inhibition increased the efficacy of both radiation and docetaxel to reduce tumor size in hormone-dependent and -independent xenografts. Xenografts showed altered gene expression changes, including downregulation of ribosomal pathways and upregulation of cardiomyocyte signaling pathways, due to PIM inhibition as analyzed by RNA-Seq. Immunostaining of multiple proteins, including COX-2 and MDM2, was altered by PIM inhibition.
    CONCLUSIONS: PIM inhibition addresses treatment resistance to docetaxel and radiotherapy in multiple prostate cancer models. Our data provide a strong rationale for testing PIM inhibitors in combination with standard therapies for treatment-resistant high-risk localized or metastatic prostate cancer in clinical trials.
    Keywords:  Docetaxel; Model organisms/animal models of cancer; PIM kinase; Prostate cancer; Radiation; Radiosensitization
    DOI:  https://doi.org/10.1016/j.radonc.2025.110794
  10. Cell Rep. 2025 Feb 14. pii: S2211-1247(25)00083-X. [Epub ahead of print]44(2): 115312
    CRISPR screening identifies regulators of enhancer-mediated androgen receptor transcription in advanced prostate cancer.
    Rachel R Xiang, Shin-Ai Lee, Caroline F Tyndall, Anusha R Bhatia, JuanJuan Yin, Cassandra Singler, Benjamin J Hauk, Matthew P Kipp, David Y Takeda.
      Amplification of the androgen receptor (AR) locus is the most frequent alteration in metastatic castration-resistant prostate cancer (CRPC). Recently, it was discovered that an enhancer of the AR is co-amplified with the AR gene body and contributes to increased AR transcription and resistance to androgen deprivation therapy. However, the mechanism of enhancer activation in advanced disease is unknown. Here, we used CRISPR-Cas9 screening to identify transcription factors that bind to the AR enhancer and modulate enhancer-mediated AR transcription. We demonstrate that HOXB13, GATA2, and TFAP2C bind the AR enhancer in patient-derived xenografts and directly impact features associated with an active chromatin state. Interestingly, the AR enhancer belongs to a set of regulatory elements that require HOXB13 to maintain FOXA1 binding, further delineating the role of HOXB13 in CRPC. This work provides a framework to functionally identify trans-acting factors required for the activation of disease-related noncoding regulatory elements.
    Keywords:  CP: Cancer; CP: Molecular biology; CRISPR; CRPC; androgen receptor; enhancer; epigenetics; functional genomics; prostate cancer
    DOI:  https://doi.org/10.1016/j.celrep.2025.115312
  11. Hum Cell. 2025 Feb 17. 38(2): 57
    Exploring the therapeutic potential of MOTS-c in age-related macular degeneration: from cellular responses to patient-derived cybrids.
    Zahra Mohtashami, Kevin Schneider, Reza Azimi, Shari Atilano, Marilyn Chwa, M Cristina Kenney, Mithalesh Kumar Singh.
      Age-related macular degeneration (AMD), the leading cause of irreversible vision loss in the US, is on the rise among the elderly. Uncontrolled mitochondria-derived peptide production from mtDNA disruption and 16S or 12S rRNA damage could worsen AMD. Our previous work has shown that Humanin G possesses cytoprotective effects in retinal pigment epithelial (RPE) cells. However, MOTS-c, a highly efficient mitochondrial peptide, has yet to be evaluated on retinal cell survival. In this study, we show that there are differences in effects between wild-type (wt-) and differentiated ARPE19 cells (diff-ARPE19), implying that the cellular differentiation status may influence how cells respond to MOTS-c. MOTS-c has dose-dependent effects on apoptosis, inflammation, and mitochondrial biogenesis in diff-ARPE19 cells. Lower doses (500 nM) have more significant impacts than 5 µM concentrations. In diff-ARPE19 cells, a lower dose of MOTS-c can reduce the negative impact of hypoxia on cellular survival and gene expression, including apoptosis (CASP3, CASP9), mitochondrial biogenesis (TFAM, PGC-1α), and metabolic sensor (AMPK). However, it had no significant effect on ROS levels or NRF1 expression, regardless of MOTS-c dose. Exposing diff-ARPE19 cells to varied MOTS-c dosages before and after therapy in a chemically induced hypoxic environment yields no extra benefits as compared to MOTS-c treatment alone. MOTS-c had different effects on the expression of genes linked with apoptosis, mitochondrial biogenesis, and antioxidant activity in AMD patients versus age-matched control cybrids. The MOTS-c peptide appears to enhance cellular metabolism and regulate gene expression, which could potentially provide therapeutic benefits in AMD.
    Keywords:  Age-related macular degeneration; Apoptosis; Cybrids; Differentiated ARPE19; Hypoxia; MOTS-c; Mitochondrial biogenesis
    DOI:  https://doi.org/10.1007/s13577-025-01188-w
  12. bioRxiv. 2025 Feb 05. pii: 2025.01.30.635534. [Epub ahead of print]
    ECD, a novel androgen receptor target promotes prostate cancer tumorigenesis by regulating glycolysis.
    Mohsin Raza, Asher Rajkumar Rajan, Benjamin B Kennedy, Timothy E Reznicek, Farshid Oruji, Sameer Mirza, M Jordan Rowley, Glen Kristiansen, Kaustubh Datta, Bhopal C Mohapatra, Hamid Band, Vimla Band.
      Androgen receptor (AR)-mediated signaling is essential for PC tumorigenesis. In TCGA database we observed a positive correlation between ECD and AR expression. Consistently, Dihydrotestosterone (DHT) treatment of PC cell lines increased ECD mRNA and protein levels, and AR knockdown (KD) reduced ECD expression. Bioinformatic analysis predicted three consensus androgen response elements in the ECD promoter, and DHT treatment increased AR occupancy at the ECD promoter, and enhanced ECD promoter activity. Enzalutamide treatment decreased ECD levels, and ECD knockout (KO) in PC cells reduced oncogenic traits, suggesting a functional role of ECD to maintain PC oncogenesis. ECD mRNA and protein are overexpressed in PC patient tissues, and its overexpression predicts shorter survival. Overexpression of ECD in PC cell lines enhanced the oncogenic traits in vitro and developed faster and larger highly proliferative xenograft tumors. RNA-seq analysis of mouse tumors revealed increase mRNA levels of several glycolytic genes. ECD associates with mRNA of several key glycolytic genes and is required for their stability, consistent with our recent demonstration of ECD as an RNA binding protein. Higher glucose uptake and glycolysis was seen upon ECD OE in PC cells. Together, we demonstrate role of a novel AR target gene ECD in PC tumorigenesis.
    DOI:  https://doi.org/10.1101/2025.01.30.635534
  13. bioRxiv. 2025 Jan 31. pii: 2025.01.28.635306. [Epub ahead of print]
    Blood mitochondrial health markers cf-mtDNA and GDF15 in human aging.
    Caroline Trumpff, Qiuhan Huang, Jeremy Michelson, Cynthia C Liu, David Shire, Christian G Habeck, Yaakov Stern, Martin Picard.
      Altered mitochondria biology can accelerate biological aging, but scalable biomarkers of mitochondrial health for population studies are lacking. We examined two potential candidates: 1) cell-free mitochondrial DNA (cf-mtDNA), a marker of mitochondrial signaling elevated with disease states accessible as distinct biological entities from plasma or serum; and 2) growth differentiation factor 15 (GDF15), an established biomarker of biological aging downstream of mitochondrial energy transformation defects and stress signaling. In a cohort of 430 participants aged 24-84 (54.2% women), we measured plasma and serum cf-mtDNA, and plasma GDF15 levels at two timepoints 5 years apart, then assessed their associations with age, BMI, diabetes, sex, health-related behaviors, and psychosocial factors. As expected, GDF15 showed a positive, exponential association with age (r=0.66, p<0.0001) and increased by 33% over five years. cf-mtDNA was not correlated with GDF15 or age. BMI and sex were also not related to cf-mtDNA nor GDF15. Type 2 diabetes was only positively associated with GDF15. Exploring potential drivers of systemic mitochondrial stress signaling, we report a novel association linking higher education to lower age-adjusted GDF15 (r=-0.14, p<0.0034), both at baseline and the 5-year follow up, highlighting a potential influence of psychosocial factors on mitochondrial health. Overall, our findings among adults spanning six decades of lifespan establish associations between age, diabetes and GDF15, an emerging marker of mitochondrial stress signaling. Further studies are needed to determine if the associations of blood GDF15 with age and metabolic stress can be moderated by psychosocial factors or health-related behaviors.
    DOI:  https://doi.org/10.1101/2025.01.28.635306
  14. Cancer Lett. 2025 Feb 18. pii: S0304-3835(25)00131-4. [Epub ahead of print] 217567
    Lactate Drives Senescence-Resistant Lineages in Hepatocellular Carcinoma via Histone H2B Lactylation of NDRG1.
    Lu Li, Jinyun Dong, Chunwei Xu, Shiqun Wang.
      Hepatocellular carcinoma (HCC) treatment options remain limited despite advances in targeted therapies for molecularly-defined cancers. To address tumor heterogeneity, we reconstructed HCC clonal evolution through single-cell RNA sequencing trajectory analysis, identifying 902 signature genes across seven cellular states. Weighted gene co-expression network analysis of public HCC datasets revealed tumor-grade-associated modules and established a 14-gene prognostic model linked to clonal evolution. Central to this model is the LDHA-NDRG1 axis - two hypoxia-responsive regulators showing coordinated spatiotemporal expression patterns during cancer progression. Dual-expressing cell lineages correlated with poor prognosis and senescence resistance through LDHA-mediated lactylation of histone H2B at K58 on NDRG1, an epigenetic mechanism connecting metabolic reprogramming to senescence evasion. Therapeutically, dual inhibition of this axis extended survival in metastatic HCC murine models. Our findings reveal that lactate-driven epigenetic modification via the LDHA-NDRG1 axis creates a molecularly distinct subpopulation enabling senescence resistance, providing mechanistic insights into HCC heterogeneity. This work proposes a precision medicine strategy targeting lactylation-mediated epigenetic regulation, with implications for developing combination therapies and patient stratification based on clonal evolution patterns.
    Keywords:  Cellular Senescence; Hepatocellular Carcinoma; Lactate Metabolism; Lactylation; N-Myc Downstream Regulated 1
    DOI:  https://doi.org/10.1016/j.canlet.2025.217567
  15. Redox Biol. 2025 Feb 04. pii: S2213-2317(25)00042-4. [Epub ahead of print]81 103529
    Mitochondrial fission produces a Warburg effect via the oxidative inhibition of prolyl hydroxylase domain-2.
    Xutong Sun, Manivannan Yegambaram, Qing Lu, Alejandro E Garcia Flores, Marissa D Pokharel, Jamie Soto, Saurabh Aggarwal, Ting Wang, Jeffrey R Fineman, Stephen M Black.
      Excessive mitochondrial fission and a shift to a Warburg phenotype are hallmarks of pulmonary hypertension (PH), although the mechanistic link between these processes remains unclear. We show that in pulmonary arterial endothelial cells (PAEC), Drp1 overexpression induces mitochondrial fission and increases glycolytic ATP production and glycolysis. This is due to mitochondrial reactive oxygen species (mito-ROS)-mediated activation of hypoxia-inducible factor-1α (HIF-1α) signaling, and this is linked to hydrogen peroxide (H2O2)-mediated inhibition of prolyl hydroxylase domain-2 (PHD2) due to its cysteine 326 oxidation and dimerization. Furthermore, these findings are validated in PAEC isolated from a lamb model of PH, which are glycolytic (Shunt PAEC), exhibit increases in both H2O2 and PHD2 dimer levels. The overexpression of catalase reversed the PHD2 dimerization, decreased HIF-1α levels, and attenuated glycolysis in Shunt PAEC. Our data suggest that reducing PHD2 dimerization could be a potential therapeutic target for PH.
    Keywords:  Drp1; HIF-1 alpha; Hydrogen peroxide; Mitochondrial fission; PHD2; ROS; Warburg effect
    DOI:  https://doi.org/10.1016/j.redox.2025.103529
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