bims-midysc Biomed News
on Mitochondria dysfunction in cancer
Issue of 2025–01–12
sixteen papers selected by
Papachristodoulou Lab
  1. Targeting Mitochondria in Glioma: New Hopes for a Cure.
  2. Metabolic reprogramming, malignant transformation and metastasis: Lessons from chronic lymphocytic leukaemia and prostate cancer.
  3. Inosine monophosphate dehydrogenase 2 (IMPDH2) modulates response to therapy and chemo-resistance in triple negative breast cancer.
  4. ONC213: a novel strategy to resensitize resistant AML cells to venetoclax through induction of mitochondrial stress.
  5. Apoptotic priming in senescence predicts specific senolysis by quantitative analysis of mitochondrial dependencies.
  6. Mitochondria- and ER-associated actin are required for mitochondrial fusion.
  7. Mechanisms of metabolism-coupled protein modifications.
  8. Divide and conquer, mitochondrial edition: Subpopulations direct cellular energy and nutrient supply.
  9. CDK4 inactivation inhibits apoptosis via mitochondria-ER contact remodeling in triple-negative breast cancer.
  10. NAC regulates metabolism and cell fate in intestinal stem cells.
  11. Novel high-content and open-source image analysis tools for profiling mitochondrial morphology in neurological cell models.
  12. Triacylglycerol mobilization underpins mitochondrial stress recovery.
  13. Differential impacts of ribosomal protein haploinsufficiency on mitochondrial function.
  14. Mapping mitochondrial morphology and function: COX-SBFSEM reveals patterns in mitochondrial disease.
  15. Mitochondrial dysfunction in pancreatic acinar cells: mechanisms and therapeutic strategies in acute pancreatitis.
  16. Oxidative Phosphorylation is a Metabolic Vulnerability of Endocrine Therapy-Tolerant Persister Cells in ER+ Breast Cancer.
  1. Biomedicines. 2024 Nov 28. pii: 2730. [Epub ahead of print]12(12):
    Targeting Mitochondria in Glioma: New Hopes for a Cure.
    Lidia Gatto, Vincenzo Di Nunno, Anna Ghelardini, Alicia Tosoni, Stefania Bartolini, Sofia Asioli, Stefano Ratti, Anna Luisa Di Stefano, Enrico Franceschi.
      Drugs targeting mitochondrial energy metabolism are emerging as promising antitumor therapeutics. Glioma treatment is extremely challenging due to the high complexity of the tumor and the high cellular heterogeneity. From a metabolic perspective, glioma cancer cells can be classified into the oxidative metabolic phenotype (mainly depending on mitochondrial respiration for energy production) and glycolytic phenotype or "Warburg effect" (mainly depending on glycolysis). Herein, we reviewed the function of novel bio-active molecules targeting oxidative phosphorylation (OXPHOS), mitochondrial membrane potential and mitochondrial dynamics. These molecules exhibit intriguing preclinical and clinical results and have been proven to be promising candidates to be further developed for glioma therapy. However, despite these initial encouraging results, it is imperative to rigorously assess the side effects of these metabolic drugs, which have a non-negligible toxicity profile.
    Keywords:  IACS-010759; ONC201; OXPHOS; Warburg; metformin; mitochondria
    DOI:  https://doi.org/10.3390/biomedicines12122730
  2. Cancer Lett. 2025 Jan 02. pii: S0304-3835(25)00005-9. [Epub ahead of print]611 217441
    Metabolic reprogramming, malignant transformation and metastasis: Lessons from chronic lymphocytic leukaemia and prostate cancer.
    Madison T Hindes, Anthony M McElligott, Oliver G Best, Mark P Ward, Stavros Selemidis, Mark A Miles, Bukuru D Nturubika, Philip A Gregory, Paul H Anderson, Jessica M Logan, Lisa M Butler, David J Waugh, John J O'Leary, Shane M Hickey, Lauren A Thurgood, Douglas A Brooks.
      Metabolic reprogramming is a hallmark of cancer, crucial for malignant transformation and metastasis. Chronic lymphocytic leukaemia (CLL) and prostate cancer exhibit similar metabolic adaptations, particularly in glucose and lipid metabolism. Understanding this metabolic plasticity is crucial for identifying mechanisms contributing to metastasis. This review considers glucose and lipid metabolism in CLL and prostate cancer, exploring their roles in healthy and malignant states and during disease progression. In CLL, lipid metabolism supports cell survival and migration, with aggressive disease characterised by increased fatty acid oxidation and altered sphingolipids. Richter's transformation and aggressive lymphoma, however, exhibit a metabolic shift towards increased glycolysis. Similarly, prostate cell metabolism is unique, relying on citrate production in the healthy state and undergoing metabolic reprogramming during malignant transformation. Early-stage prostate cancer cells increase lipid synthesis and uptake, and decrease glycolysis, whereas metastatic cells re-adopt glucose metabolism, likely driven by interactions with the tumour microenvironment. Genetic drivers including TP53 and ATM mutations connect metabolic alterations to disease severity in these two malignancies. The bone microenvironment supports the metabolic demands of these malignancies, serving as an initiation niche for CLL and a homing site for prostate cancer metastases. By comparing these malignancies, this review underscores the importance of metabolic plasticity in cancer progression and highlights how CLL and prostate cancer may be models of circulating and solid tumours more broadly. The metabolic phenotypes throughout cancer cell transformation and metastasis, and the microenvironment in which these processes occur, present opportunities for interventions that could disrupt metastatic processes and improve patient outcomes.
    Keywords:  Chronic lymphocytic leukaemia; Malignant transformation; Metabolic reprogramming; Metastasis; Microenvironment; Prostate cancer
    DOI:  https://doi.org/10.1016/j.canlet.2025.217441
  3. Sci Rep. 2025 Jan 07. 15(1): 1061
    Inosine monophosphate dehydrogenase 2 (IMPDH2) modulates response to therapy and chemo-resistance in triple negative breast cancer.
    Tatiane da Silva Fernandes, Bryan M Gillard, Tao Dai, Jeffrey C Martin, Kanita A Chaudhry, Scott M Dugas, Alyssa A Fisher, Pia Sharma, RongRong Wu, Kristopher M Attwood, Subhamoy Dasgupta, Kazuaki Takabe, Spencer R Rosario, Anna Bianchi-Smiraglia.
      Triple negative breast cancer (TNBC) is one of the deadliest subtypes of breast cancer, whose high frequency of relapse is often due to resistance to chemotherapy. Here, we identify inosine monophosphate dehydrogenase 2 (IMPDH2) as a contributor to doxorubicin resistance, in multiple TNBC models. Analysis of publicly available datasets reveals elevated IMPDH2 expression to associate with worse overall TNBC prognosis in the clinic, including lower recurrence-free survival post adjuvant/neoadjuvant therapy. Importantly, both genetic depletion and pharmacological inhibition of IMPDH2 leads to reduction of pro-tumorigenic phenotypes in multiple doxorubicin-resistant TNBC models, both in vitro and in vivo. Overall, we propose IMPDH2 as a novel vulnerability that could be leveraged therapeutically to suppress and/or prevent the growth of chemo-resistant lesions.
    Keywords:  Chemo-resistance; Doxorubicin; GTP metabolism; IMPDH2; Paclitaxel; Ribavirin; TNBC
    DOI:  https://doi.org/10.1038/s41598-024-85094-5
  4. J Exp Clin Cancer Res. 2025 Jan 09. 44(1): 10
    ONC213: a novel strategy to resensitize resistant AML cells to venetoclax through induction of mitochondrial stress.
    Jenna L Carter, Yongwei Su, Eman T Al-Antary, Jianlei Zhao, Xinan Qiao, Guan Wang, Holly Edwards, Lisa Polin, Juiwanna Kushner, Sijana H Dzinic, Kathryn White, Steven A Buck, Maik Hüttemann, Joshua E Allen, Varun V Prabhu, Jay Yang, Jeffrey W Taub, Yubin Ge.
       BACKGROUND: Venetoclax + azacitidine is a frontline treatment for older adult acute myeloid leukemia (AML) patients and a salvage therapy for relapsed/refractory patients who have been treated with intensive chemotherapy. While this is an important treatment option, many patients fail to achieve complete remission and of those that do, majority relapse. Leukemia stem cells (LSCs) are believed to be responsible for AML relapse and can be targeted through oxidative phosphorylation reduction. We previously reported that ONC213 disrupts oxidative phosphorylation and decreases Mcl-1 protein, which play a key role in venetoclax resistance. Here we investigated the antileukemic activity and underlying molecular mechanism of the combination of ONC213 + venetoclax against AML cells.
    METHODS: Flow cytometry was used to determine drug-induced apoptosis. Protein level changes were determined by western blot. An AML cell line-derived xenograft mouse model was used to determine the effects of ONC213 + venetoclax on survival. A patient-derived xenograft (PDX) mouse model was used to determine drug effects on CD45+/CD34+/CD38-/CD123 + cells. Colony formation assays were used to assess drug effects on AML progenitor cells. Mcl-1 and Bax/Bak knockdown and Mcl-1 overexpression were used to confirm their role in the mechanism of action. The effect of ONC213 + venetoclax on mitochondrial respiration was determined using a Seahorse bioanalyzer.
    RESULTS: ONC213 + venetoclax synergistically kills AML cells, including those resistant to venetoclax alone as well as venetoclax + azacitidine. The combination significantly reduced colony formation capacity of primary AML progenitors compared to the control and either treatment alone. Further, the combination prolonged survival in an AML cell line-derived xenograft model and significantly decreased LSCs in an AML PDX model.
    CONCLUSIONS: ONC213 can resensitize VEN + AZA-resistant AML cells to venetoclax therapy and target LSCs ex vivo and in vivo.
    Keywords:  Acute myeloid leukemia; Azacitidine; ONC213; Venetoclax
    DOI:  https://doi.org/10.1186/s13046-024-03267-6
  5. Cell Death Differ. 2025 Jan 06.
    Apoptotic priming in senescence predicts specific senolysis by quantitative analysis of mitochondrial dependencies.
    Julie A MacDonald, Gary A Bradshaw, Fleur Jochems, René Bernards, Anthony Letai.
      Cellular senescence contributes to a variety of pathologies associated with aging and is implicated as a cellular state in which cancer cells can survive treatment. Reported senolytic drug treatments act through varying molecular mechanisms, but heterogeneous efficacy across the diverse contexts of cellular senescence indicates a need for predictive biomarkers of senolytic activity. Using multi-parametric analyses of commonly reported molecular features of the senescent phenotype, we assayed a variety of models, including malignant and nonmalignant cells, using several triggers of senescence induction and found little univariate predictive power of these traditional senescence markers to identify senolytic drug sensitivity. We sought to identify novel drug targets in senescent cells that were insensitive to frequently implemented senolytic therapies, such as Navitoclax (ABT-263), using quantitative mass spectrometry to measure changes in the senescent proteome, compared to cells which acquire an acute sensitivity to ABT-263 with senescence induction. Inhibition of the antioxidant GPX4 or the Bcl-2 family member MCL-1 using small molecule compounds in combination with ABT-263 significantly increased the induction of apoptosis in some, but not all, previously insensitive senescent cells. We then asked if we could use BH3 profiling to measure differences in mitochondrial apoptotic priming in these models of cellular senescence and predict sensitivity to the senolytics ABT-263 or the combination of dasatinib and quercetin (D + Q). We found, despite being significantly less primed for apoptosis overall, the dependence of senescent mitochondria on BCL-XL was significantly correlated to senescent cell killing by both ABT-263 and D + Q, despite no significant changes in the gene or protein expression of BCL-XL. However, our data caution against broad classification of drugs as globally senolytic and instead provide impetus for context-specific senolytic targets and propose BH3 profiling as an effective predictive biomarker.
    DOI:  https://doi.org/10.1038/s41418-024-01431-1
  6. Nat Commun. 2025 Jan 07. 16(1): 451
    Mitochondria- and ER-associated actin are required for mitochondrial fusion.
    Priya Gatti, Cara Schiavon, Julien Cicero, Uri Manor, Marc Germain.
      Mitochondria are crucial for cellular metabolism and signalling. Mitochondrial activity is modulated by mitochondrial fission and fusion, which are required to properly balance metabolic functions, transfer material between mitochondria, and remove defective mitochondria. Mitochondrial fission occurs at mitochondria-endoplasmic reticulum (ER) contact sites, and requires the formation of actin filaments that drive mitochondrial constriction and the recruitment of the fission protein DRP1. The role of actin in mitochondrial fusion remains entirely unexplored. Here we show that preventing actin polymerisation on either mitochondria or the ER disrupts both fission and fusion. We show that fusion but not fission is dependent on Arp2/3, whereas both fission and fusion require INF2 formin-dependent actin polymerization. We also show that mitochondria-associated actin marks fusion sites prior to the fusion protein MFN2. Together, our work introduces a method for perturbing organelle-associated actin and demonstrates a previously unknown role for actin in mitochondrial fusion.
    DOI:  https://doi.org/10.1038/s41467-024-55758-x
  7. Nat Chem Biol. 2025 Jan 07.
    Mechanisms of metabolism-coupled protein modifications.
    Bingsen Zhang, Frank C Schroeder.
      Intricate coupling between metabolism and protein post-translational modifications (PTMs) has emerged as a fundamental aspect of cellular regulation. Recent studies demonstrate that protein modifications can originate from diverse metabolites, and that their regulation is closely tied to the cellular metabolic state. Here we explore recently uncovered PTMs, including the concept of 'modification of a modification', as well as associated feedback and feedforward regulatory mechanisms, in which modified proteins impact not only related metabolic pathways but also other signaling cascades affecting physiology and diseases. The recently uncovered role of nucleus-localized metabolic enzymes for histone modifications additionally highlights the importance of cell-compartment-specific metabolic states. We further comment on the utility of untargeted metabolomics and proteomics for previously unrecognized PTMs and associated metabolic patterns. Together, these advances have uncovered a dynamic interplay between metabolism and PTMs, offering new perspectives for understanding metabolic regulation and developing targeted therapeutic strategies.
    DOI:  https://doi.org/10.1038/s41589-024-01805-z
  8. Cell Metab. 2025 Jan 07. pii: S1550-4131(24)00487-X. [Epub ahead of print]37(1): 5-6
    Divide and conquer, mitochondrial edition: Subpopulations direct cellular energy and nutrient supply.
    Sijie Tan, Nora Kory.
      Mitochondria produce energy and building blocks essential for cell growth. How these competing processes are balanced and sustained during nutrient scarcity remains unclear. Ryu et al. uncover distinct mitochondrial subpopulations, one dedicated to ATP production and another to macromolecule synthesis, enabling cell growth and proliferation under nutrient-limiting conditions.
    DOI:  https://doi.org/10.1016/j.cmet.2024.12.006
  9. Nat Commun. 2025 Jan 09. 16(1): 541
    CDK4 inactivation inhibits apoptosis via mitochondria-ER contact remodeling in triple-negative breast cancer.
    Dorian V Ziegler, Kanishka Parashar, Lucia Leal-Esteban, Jaime López-Alcalá, Wilson Castro, Nadège Zanou, Laia Martinez-Carreres, Katharina Huber, Xavier Pascal Berney, María M Malagón, Catherine Roger, Marie-Agnès Berger, Yves Gouriou, Giulia Paone, Hector Gallart-Ayala, George Sflomos, Carlos Ronchi, Julijana Ivanisevic, Cathrin Brisken, Jennifer Rieusset, Melita Irving, Lluis Fajas.
      The energetic demands of proliferating cells during tumorigenesis require close coordination between the cell cycle and metabolism. While CDK4 is known for its role in cell proliferation, its metabolic function in cancer, particularly in triple-negative breast cancer (TNBC), remains unclear. Our study, using genetic and pharmacological approaches, reveals that CDK4 inactivation only modestly impacts TNBC cell proliferation and tumor formation. Notably, CDK4 depletion or long-term CDK4/6 inhibition confers resistance to apoptosis in TNBC cells. Mechanistically, CDK4 enhances mitochondria-endoplasmic reticulum contact (MERCs) formation, promoting mitochondrial fission and ER-mitochondrial calcium signaling, which are crucial for TNBC metabolic flexibility. Phosphoproteomic analysis identified CDK4's role in regulating PKA activity at MERCs. In this work, we highlight CDK4's role in mitochondrial apoptosis inhibition and suggest that targeting MERCs-associated metabolic shifts could enhance TNBC therapy.
    DOI:  https://doi.org/10.1038/s41467-024-55605-z
  10. Sci Adv. 2025 Jan 10. 11(2): eadn9750
    NAC regulates metabolism and cell fate in intestinal stem cells.
    Sofia Ramalho, Ferhat Alkan, Stefan Prekovic, Katarzyna Jastrzebski, Eric Pintó Barberà, Liesbeth Hoekman, Maarten Altelaar, Cecilia de Heus, Nalan Liv, Maria J Rodríguez-Colman, Mehmet Yilmaz, Rob van der Kammen, Juliette Fedry, Mark C de Gooijer, Saskia Jacoba Elisabeth Suijkerbuijk, William J Faller, Joana Silva.
      Intestinal stem cells (ISCs) face the challenge of integrating metabolic demands with unique regenerative functions. Studies have shown an intricate interplay between metabolism and stem cell capacity; however, it is still not understood how this process is regulated. Combining ribosome profiling and CRISPR screening in intestinal organoids, we identify the nascent polypeptide-associated complex (NAC) as a key mediator of this process. Our findings suggest that NAC is responsible for relocalizing ribosomes to the mitochondria and regulating ISC metabolism. Upon NAC inhibition, intestinal cells show decreased import of mitochondrial proteins, which are needed for oxidative phosphorylation, and, consequently, enable the cell to maintain a stem cell identity. Furthermore, we show that overexpression of NACα is sufficient to drive mitochondrial respiration and promote ISC identity. Ultimately, our results reveal the pivotal role of NAC in regulating ribosome localization, mitochondrial metabolism, and ISC function, providing insights into the potential mechanism behind it.
    DOI:  https://doi.org/10.1126/sciadv.adn9750
  11. SLAS Discov. 2025 Jan 06. pii: S2472-5552(25)00001-2. [Epub ahead of print] 100208
    Novel high-content and open-source image analysis tools for profiling mitochondrial morphology in neurological cell models.
    Marcus Y Chin, David A Joy, Madhuja Samaddar, Anil Rana, Johann Chow, Takashi Miyamoto, Meredith Calvert.
      Mitochondria undergo dynamic morphological changes depending on cellular cues, stress, genetic factors, or disease. The structural complexity and disease-relevance of mitochondria have stimulated efforts to generate image analysis tools for describing mitochondrial morphology for therapeutic development. Using high-content analysis, we measured multiple morphological parameters and employed unbiased feature clustering to identify the most robust pair of texture metrics that described mitochondrial state. Here, we introduce a novel image analysis pipeline to enable rapid and accurate profiling of mitochondrial morphology in various cell types and pharmacological perturbations. We applied a high-content adapted implementation of our tool, MitoProfilerHC, to quantify mitochondrial morphology changes in i) a mammalian cell dose response study and ii) compartment-specific drug effects in primary neurons. Next, we expanded the usability of our pipeline by using napari, a Python-powered image analysis tool, to build an open-source version of MitoProfiler and validated its performance and applicability. In conclusion, we introduce MitoProfiler as both a high-content-based and an open-source method to accurately quantify mitochondrial morphology in cells, which we anticipate to greatly facilitate mechanistic discoveries in mitochondrial biology and disease.
    Keywords:  Mitochondria; high-content imaging; high-throughput screening; image analysis; mitochondrial morphology; napari plugin; neurons; open-source
    DOI:  https://doi.org/10.1016/j.slasd.2025.100208
  12. Nat Cell Biol. 2025 Jan 08.
    Triacylglycerol mobilization underpins mitochondrial stress recovery.
    Zakery N Baker, Yunyun Zhu, Rachel M Guerra, Andrew J Smith, Aline Arra, Lia R Serrano, Katherine A Overmyer, Shankar Mukherji, Elizabeth A Craig, Joshua J Coon, David J Pagliarini.
      Mitochondria are central to myriad biochemical processes, and thus even their moderate impairment could have drastic cellular consequences if not rectified. Here, to explore cellular strategies for surmounting mitochondrial stress, we conducted a series of chemical and genetic perturbations to Saccharomyces cerevisiae and analysed the cellular responses using deep multiomic mass spectrometry profiling. We discovered that mobilization of lipid droplet triacylglycerol stores was necessary for strains to mount a successful recovery response. In particular, acyl chains from these stores were liberated by triacylglycerol lipases and used to fuel biosynthesis of the quintessential mitochondrial membrane lipid cardiolipin to support new mitochondrial biogenesis. We demonstrate that a comparable recovery pathway exists in mammalian cells, which fail to recover from doxycycline treatment when lacking the ATGL lipase. Collectively, our work reveals a key component of mitochondrial stress recovery and offers a rich resource for further exploration of the broad cellular responses to mitochondrial dysfunction.
    DOI:  https://doi.org/10.1038/s41556-024-01586-6
  13. J Cell Biol. 2025 Mar 03. pii: e202404084. [Epub ahead of print]224(3):
    Differential impacts of ribosomal protein haploinsufficiency on mitochondrial function.
    Agustian Surya, Blythe Marie Bolton, Reed Rothe, Raquel Mejia-Trujillo, Amanda Leonita, Qiuxia Zhao, Alia Arya, Yue Liu, Rekha Rangan, Yasash Gorusu, Pamela Nguyen, Can Cenik, Elif Sarinay Cenik.
      The interplay between ribosomal protein (RP) composition and mitochondrial function is essential for energy homeostasis. Balanced RP production optimizes protein synthesis while minimizing energy costs, but its impact on mitochondrial functionality remains unclear. Here, we investigated haploinsufficiency for RP genes (rps-10, rpl-5, rpl-33, and rps-23) in Caenorhabditis elegans and corresponding reductions in human lymphoblast cells. Significant mitochondrial morphological differences, upregulation of glutathione transferases, and SKN-1-dependent oxidative stress resistance were observed across mutants. Loss of a Datasingle rps-10 copy reduced mitochondrial activity, energy levels, and oxygen consumption, mirrored by similar reductions in mitochondrial activity and energy levels in lymphoblast cells with 50% lower RPS10 transcripts. Both systems exhibited altered translation efficiency (TE) of mitochondrial electron transport chain components, suggesting a conserved mechanism to adjust mitochondrial protein synthesis under ribosomal stress. Finally, mitochondrial membrane and cytosolic RPs showed significant RNA and TE covariation in lymphoblastoid cells, highlighting the interplay between protein synthesis machinery and mitochondrial energy production.
    DOI:  https://doi.org/10.1083/jcb.202404084
  14. Commun Biol. 2025 Jan 09. 8(1): 24
    Mapping mitochondrial morphology and function: COX-SBFSEM reveals patterns in mitochondrial disease.
    Julie Faitg, Tracey Davey, Ross Laws, Conor Lawless, Helen Tuppen, Eric Fitton, Doug Turnbull, Amy E Vincent.
      Mitochondria play a crucial role in maintaining cellular health. It is interesting that the shape of mitochondria can vary depending on the type of cell, mitochondrial function, and other cellular conditions. However, there are limited studies that link functional assessment with mitochondrial morphology evaluation at high magnification, even fewer that do so in situ and none in human muscle biopsies. Therefore, we have developed a method which combines functional assessment of mitochondria through Cytochrome c Oxidase (COX) histochemistry, with a 3D electron microscopy (EM) technique, serial block-face scanning electron microscopy (SBFSEM). Here we apply COX-SBFSEM to muscle samples from patients with single, large-scale mtDNA deletions, a cause of mitochondrial disease. These deletions cause oxidative phosphorylation deficiency, which can be observed through changes in COX activity. One of the main advantages of combining 3D-EM with the COX reaction is the ability to look at how per-mitochondrion oxidative phosphorylation status is spatially distributed within muscle fibres. Here we show a robust spatial pattern in COX-positive and intermediate-fibres and that the spatial pattern is less clear in COX-deficient fibres.
    DOI:  https://doi.org/10.1038/s42003-024-07389-7
  15. Front Immunol. 2024 ;15 1503087
    Mitochondrial dysfunction in pancreatic acinar cells: mechanisms and therapeutic strategies in acute pancreatitis.
    Fan Chen, Kedong Xu, Yimin Han, Jiachun Ding, Jiaqiang Ren, Yaochun Wang, Zhenhua Ma, Fang Cao.
      Acute pancreatitis (AP) is an inflammatory disease of the pancreas and a complex process involving multiple factors, with mitochondrial damage playing a crucial role. Mitochondrial dysfunction is now considered a key driver in the development of AP. This dysfunction often presents as increased oxidative stress, altered membrane potential and permeability, and mitochondrial DNA damage and mutations. Under stress conditions, mitochondrial dynamics and mitochondrial ROS production increase, leading to decreased mitochondrial membrane potential, imbalanced calcium homeostasis, and activation of the mitochondrial permeability transition pore. The release of mitochondrial DNA (mtDNA), recognized as damage-associated molecular patterns, can activate the cGAS-STING1 and NF-κB pathway and induce pro-inflammatory factor expression. Additionally, mtDNA can activate inflammasomes, leading to interleukin release and subsequent tissue damage and inflammation. This review summarizes the relationship between mitochondria and AP and explores mitochondrial protective strategies in the diagnosis and treatment of this disease. Future research on the treatment of acute pancreatitis can benefit from exploring promising avenues such as antioxidants, mitochondrial inhibitors, and new therapies that target mitochondrial dysfunction.
    Keywords:  acute pancreatitis; calcium overload; mitochondrial; mitochondrial permeability transition pore; regulated cell death
    DOI:  https://doi.org/10.3389/fimmu.2024.1503087
  16. Cancer Res. 2025 Jan 09.
    Oxidative Phosphorylation is a Metabolic Vulnerability of Endocrine Therapy-Tolerant Persister Cells in ER+ Breast Cancer.
    Steven Tau, Mary D Chamberlin, Huijuan Yang, Jonathan D Marotti, Patricia C Muskus, Alyssa M Roberts, Melissa M Carmichael, Lauren Cressey, Christo Philip C Dragnev, Eugene Demidenko, Riley A Hampsch, Shannon M Soucy, Fred W Kolling, Kimberley S Samkoe, James V Alvarez, Arminja N Kettenbach, Todd W Miller.
      Despite adjuvant treatment with endocrine therapies, estrogen receptor-positive (ER+) breast cancers recur in a significant proportion of patients. Recurrences are attributable to clinically undetectable endocrine-tolerant persister cancer cells that retain tumor-forming potential. Therefore, strategies targeting such persister cells may prevent recurrent disease. Using CRISPR-Cas9 genome-wide knockout screening in ER+ breast cancer cells, we identified a survival mechanism involving metabolic reprogramming with reliance upon mitochondrial respiration in endocrine-tolerant persister cells. Quantitative proteomic profiling showed reduced levels of glycolytic proteins in persisters. Metabolic tracing of glucose revealed an energy-depleted state in persisters where oxidative phosphorylation was required to generate ATP. A phase II clinical trial was conducted to evaluate changes in mitochondrial markers in primary ER+/HER2- breast tumors induced by neoadjuvant endocrine therapy (NCT04568616). In an analysis of tumor specimens from 32 patients, tumors exhibiting residual cell proliferation after aromatase inhibitor-induced estrogen deprivation with letrozole showed increased mitochondrial content. Genetic profiling and barcode lineage tracing showed that endocrine-tolerant persistence occurred stochastically without genetic predisposition. Pharmacological inhibition of mitochondrial complex I suppressed the tumor-forming potential of persisters in mice and synergized with the anti-estrogen fulvestrant to induce regression of patient-derived xenografts. These findings indicate that mitochondrial metabolism is essential in endocrine-tolerant persister ER+ breast cancer cells and warrant the development of treatment strategies to leverage this vulnerability for treating breast cancer.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-24-1204
This page is being maintained by Thomas Krichel. It was last updated on 2025‒01‒13 at 14:12.