bims-cesemi Biomed News
on Cellular senescence and mitochondria
Issue of 2024–11–17
sixteen papers selected by
Julio Cesar Cardenas, Universidad Mayor
  1. Mitochondrial calcium uptake orchestrates vertebrate pigmentation via transcriptional regulation of keratin filaments.
  2. Senescence as a therapeutic target in cancer and age-related diseases.
  3. Could senescent cells be the prescription for therapeutic cancer vaccines?
  4. Simultaneous detection of membrane contact dynamics and associated Ca2+ signals by reversible chemogenetic reporters.
  5. Radiation-induced senescence in glioblastoma: An overview of the mechanisms and eradication strategies.
  6. Knockdown of hepatic mitochondrial calcium uniporter mitigates MASH and fibrosis in mice.
  7. Hepatocellular senescence induces multi-organ senescence and dysfunction via TGFβ.
  8. Chronic social stress induces p16-mediated senescent cell accumulation in mice.
  9. A bright cyan fluorescence calcium indicator for mitochondrial calcium with minimal interference from physiological pH fluctuations.
  10. Cell type-divergent functions of senescence.
  11. PINK1-deficiency facilitates mitochondrial iron accumulation and colon tumorigenesis.
  12. Ketone ester-enriched diet ameliorates motor and dopamine release deficits in MitoPark mice.
  13. Clearance of p21 highly expressing senescent cells accelerates cutaneous wound healing.
  14. ALDH1A3 Contributes to Radiation-Induced Inhibition of Self-Renewal and Promotes Proliferative Activity of p53-Deficient Glioblastoma Stem Cells at the Onset of Differentiation.
  15. Targeting mitochondrial metabolism with CPI-613 in chemoresistant ovarian tumors.
  16. Liver knockout of MCU leads to greater dysregulation of lipid metabolism in MAFLD.
  1. PLoS Biol. 2024 Nov 11. 22(11): e3002895
    Mitochondrial calcium uptake orchestrates vertebrate pigmentation via transcriptional regulation of keratin filaments.
    Jyoti Tanwar, Kriti Ahuja, Akshay Sharma, Paras Sehgal, Gyan Ranjan, Farina Sultan, Anushka Agrawal, Donato D'Angelo, Anshu Priya, Vamsi K Yenamandra, Archana Singh, Anna Raffaello, Muniswamy Madesh, Rosario Rizzuto, Sridhar Sivasubbu, Rajender K Motiani.
      Mitochondria regulate several physiological functions through mitochondrial Ca2+ dynamics. However, role of mitochondrial Ca2+ signaling in melanosome biology remains unknown. Here, we show that pigmentation requires mitochondrial Ca2+ uptake. In vitro gain and loss of function studies demonstrate that mitochondrial Ca2+ uniporter (MCU) is crucial for melanogenesis while MCU rheostat, MCUb negatively control melanogenesis. Zebrafish, MCU+/- and MCUb-/- mice models show that MCU complex drives pigmentation in vivo. Mechanistically, MCU silencing activates transcription factor NFAT2 to induce expression of keratin (5, 7, and 8) filaments. Interestingly, keratin5 in turn augments mitochondrial Ca2+ uptake and potentiates melanogenesis by regulating melanosome biogenesis and maturation. Hence this signaling module acts as a negative feedback loop that fine-tunes both mitochondrial Ca2+ signaling and pigmentation. Notably, mitoxantrone, an FDA approved drug that inhibits MCU, reduces pigmentation thereby highlighting therapeutic potential of targeting mitochondrial Ca2+ uptake for clinical management of pigmentary disorders. Taken together, we reveal an MCU-NFAT2-Keratin5 driven signaling axis that acts as a critical determinant of mitochondrial Ca2+ uptake and pigmentation. Given the vital role of mitochondrial Ca2+ signaling and keratin filaments in cellular physiology, this feedback loop could be operational in a variety of other patho-physiological processes.
    DOI:  https://doi.org/10.1371/journal.pbio.3002895
  2. Nat Rev Drug Discov. 2024 Nov 15.
    Senescence as a therapeutic target in cancer and age-related diseases.
    Domhnall McHugh, Imanol Durán, Jesús Gil.
      Cellular senescence is a stress response that restrains the growth of aged, damaged or abnormal cells. Thus, senescence has a crucial role in development, tissue maintenance and cancer prevention. However, lingering senescent cells fuel chronic inflammation through the acquisition of a senescence-associated secretory phenotype (SASP), which contributes to cancer and age-related tissue dysfunction. Recent progress in understanding senescence has spurred interest in the development of approaches to target senescent cells, known as senotherapies. In this Review, we evaluate the status of various types of senotherapies, including senolytics that eliminate senescent cells, senomorphics that suppress the SASP, interventions that mitigate senescence and strategies that harness the immune system to clear senescent cells. We also summarize how these approaches can be combined with cancer therapies, and we discuss the challenges and opportunities in moving senotherapies into clinical practice. Such therapies have the potential to address root causes of age-related diseases and thus open new avenues for preventive therapies and treating multimorbidities.
    DOI:  https://doi.org/10.1038/s41573-024-01074-4
  3. Immunotherapy. 2024 Nov 15. 1-3
    Could senescent cells be the prescription for therapeutic cancer vaccines?
    Yue Liu, Stephen J Kron.
      
    Keywords:  cancer vaccine; immune checkpoint blockade; immunotherapy; senescence; senescence-associated secretory phenotype (SASP)
    DOI:  https://doi.org/10.1080/1750743X.2024.2422813
  4. Nat Commun. 2024 Nov 12. 15(1): 9775
    Simultaneous detection of membrane contact dynamics and associated Ca2+ signals by reversible chemogenetic reporters.
    Paloma García Casas, Michela Rossini, Linnea Påvénius, Mezida Saeed, Nikita Arnst, Sonia Sonda, Tânia Fernandes, Irene D'Arsiè, Matteo Bruzzone, Valeria Berno, Andrea Raimondi, Maria Livia Sassano, Luana Naia, Elisa Barbieri, Sara Sigismund, Patrizia Agostinis, Mattia Sturlese, Barbara A Niemeyer, Hjalmar Brismar, Maria Ankarcrona, Arnaud Gautier, Paola Pizzo, Riccardo Filadi.
      Membrane contact sites (MCSs) are hubs allowing various cell organelles to coordinate their activities. The dynamic nature of these sites and their small size hinder analysis by current imaging techniques. To overcome these limitations, we here design a series of reversible chemogenetic reporters incorporating improved, low-affinity variants of splitFAST, and study the dynamics of different MCSs at high spatiotemporal resolution, both in vitro and in vivo. We demonstrate that these versatile reporters suit different experimental setups well, allowing one to address challenging biological questions. Using these probes, we identify a pathway in which calcium (Ca2+) signalling dynamically regulates endoplasmic reticulum-mitochondria juxtaposition, characterizing the underlying mechanism. Finally, by integrating Ca2+-sensing capabilities into the splitFAST technology, we introduce PRINCESS (PRobe for INterorganelle Ca2+-Exchange Sites based on SplitFAST), a class of reporters to simultaneously detect MCSs and measure the associated Ca2+ dynamics using a single biosensor.
    DOI:  https://doi.org/10.1038/s41467-024-52985-0
  5. Life Sci. 2024 Nov 05. pii: S0024-3205(24)00808-7. [Epub ahead of print]359 123218
    Radiation-induced senescence in glioblastoma: An overview of the mechanisms and eradication strategies.
    Neda Dehghan, Seyedeh Nasibeh Mousavikia, Younes Qasempour, Hosein Azimian.
      Radiotherapy as a treatment method for glioblastoma is limited due to the intrinsic apoptosis resistance mechanisms of the tumor. Administration of higher radiation doses contributes to toxicities in normal tissues and organs at risk, like optic chiasma. Cellular senescence represents an alternative mechanism to apoptosis following radiotherapy in glioblastoma, occurring in both normal and neoplastic cells. Although it impedes the growth of tumors and sustains cells in their cycle, it can also act as a cause of tumor development and recurrence following treatment. In this review, we discuss detailed insights into the significance of radiation-induced senescence in glioblastoma and the underlying mechanisms that lead to radioresistance. We also discuss senescence biomarkers and the role of senescence-associated secretory phenotype (SASP) in tumor recurrence. Finally, we review the studies that have administered potential interventions to eradicate or inhibit senescent cells in glioblastoma after treatment with radiation.
    Keywords:  Cell signal pathway; Glioblastoma; Radiation-induced senescence; Senescence associated secretory phenotype (SASP); Tumor recurrence
    DOI:  https://doi.org/10.1016/j.lfs.2024.123218
  6. Cell Biosci. 2024 Nov 10. 14(1): 135
    Knockdown of hepatic mitochondrial calcium uniporter mitigates MASH and fibrosis in mice.
    Shuyu Li, Fangyuan Chen, Min Liu, Yajun Zhang, Jingjing Xu, Xi Li, Zhiyin Shang, Shaoping Huang, Shu Song, Chuantao Tu.
       BACKGROUND: Mitochondrial calcium uniporter (MCU) plays pleiotropic roles in cellular physiology and pathology that contributes to a variety of diseases, but the role and potential mechanism of MCU in the pathogenesis of metabolic dysfunction-associated steatohepatitis (MASH) remain poorly understood.
    METHODS AND RESULTS: Here, hepatic knockdown of MCU in C57BL/6J mice was achieved by tail vein injection of AAV8-mediated the CRISPR/Cas9. Mice were fed a Choline-deficient, L-amino acid-defined high-fat diet (CDAHFD) for 8 weeks to induce MASH and fibrosis. We find that expression of MCU enhanced in MASH livers of humans and mice. MCU knockdown robustly limits lipid droplet accumulation, steatosis, inflammation, and hepatocyte apoptotic death during MASH development both in vivo in mice and in vitro in cellular models. MCU-deficient mice strikingly mitigate MASH-related fibrosis. Moreover, the protective effects of MCU knockdown against MASH progression are accompanied by a reduced level of mitochondrial calcium, limiting hepatic oxidative stress, and attenuating mitochondrial dysfunction. Mechanically, RNA sequencing analysis and protein immunoblotting indicate that knockdown MCU inhibited the Hippo/YAP pathway activation and restored the AMP-activated protein kinase (AMPK) activity during MASH development both in vitro and in vivo.
    CONCLUSIONS: MCU is up-regulated in MASH livers in humans and mice; and hepatic MCU knockdown protects against diet-induced MASH and fibrosis in mice. Thus, targeting MCU may represent a novel therapeutic strategy for MASH and fibrosis.
    Keywords:  Liver fibrosis; MCU; Mitochondrial dysfunction; Oxidative stress; Steatohepatitis
    DOI:  https://doi.org/10.1186/s13578-024-01315-4
  7. Nat Cell Biol. 2024 Nov 13.
    Hepatocellular senescence induces multi-organ senescence and dysfunction via TGFβ.
    Christos Kiourtis, Maria Terradas-Terradas, Lucy M Gee, Stephanie May, Anastasia Georgakopoulou, Amy L Collins, Eoin D O'Sullivan, David P Baird, Mohsin Hassan, Robin Shaw, Ee Hong Tan, Miryam Müller, Cornelius Engelmann, Fausto Andreola, Ya-Ching Hsieh, Lee H Reed, Lee A Borthwick, Colin Nixon, William Clark, Peter S Hanson, David Sumpton, Gillian Mackay, Toshiyasu Suzuki, Arafath K Najumudeen, Gareth J Inman, Andrew Campbell, Simon T Barry, Alberto Quaglia, Christopher M Morris, Fiona E N LeBeau, Owen J Sansom, Kristina Kirschner, Rajiv Jalan, Fiona Oakley, Thomas G Bird.
      Cellular senescence is not only associated with ageing but also impacts physiological and pathological processes, such as embryonic development and wound healing. Factors secreted by senescent cells affect their microenvironment and can induce spreading of senescence locally. Acute severe liver disease is associated with hepatocyte senescence and frequently progresses to multi-organ failure. Why the latter occurs is poorly understood. Here we demonstrate senescence development in extrahepatic organs and associated organ dysfunction in response to liver senescence using liver injury models and genetic models of hepatocyte-specific senescence. In patients with severe acute liver failure, we show that the extent of hepatocellular senescence predicts disease outcome, the need for liver transplantation and the occurrence of extrahepatic organ failure. We identify the TGFβ pathway as a critical mediator of systemic spread of senescence and demonstrate that TGFβ inhibition in vivo blocks senescence transmission to other organs, preventing liver senescence induced renal dysfunction. Our results highlight the systemic consequences of organ-specific senescence, which, independent of ageing, contributes to multi-organ dysfunction.
    DOI:  https://doi.org/10.1038/s41556-024-01543-3
  8. Nat Aging. 2024 Nov 11.
    Chronic social stress induces p16-mediated senescent cell accumulation in mice.
    Carey E Lyons, Jean Pierre Pallais, Seth McGonigle, Rachel P Mansk, Charles W Collinge, Matthew J Yousefzadeh, Darren J Baker, Patricia R Schrank, Jesse W Williams, Laura J Niedernhofer, Jan M van Deursen, Maria Razzoli, Alessandro Bartolomucci.
      Life stress can shorten lifespan and increase risk for aging-related diseases, but the biology underlying this phenomenon remains unclear. Here we assessed the effect of chronic stress on cellular senescence-a hallmark of aging. Exposure to restraint stress, a psychological non-social stress model, increased p21Cip1 exclusively in the brains of male, but not female mice, and in a p16Ink4a-independent manner. Conversely, exposure to chronic subordination stress (only males were tested) increased key senescent cell markers in peripheral blood mononuclear cells, adipose tissue and brain, in a p16Ink4a-dependent manner. p16Ink4a-positive cells in the brain of chronic subordination stress-exposed mice were primarily hippocampal and cortical neurons with evidence of DNA damage that could be reduced by p16Ink4a cell clearance. Clearance of p16Ink4a-positive cells was not sufficient to ameliorate the adverse effects of social stress on measured metrics of healthspan. Overall, our findings indicate that social stress induces an organ-specific and p16Ink4a-dependent accumulation of senescent cells, illuminating a fundamental way by which the social environment can contribute to aging.
    DOI:  https://doi.org/10.1038/s43587-024-00743-8
  9. Biophys Rep. 2024 Oct 31. 10(5): 315-327
    A bright cyan fluorescence calcium indicator for mitochondrial calcium with minimal interference from physiological pH fluctuations.
    Wenjia Gu, Yuqin Yang, Yuqing Wang, Jia Li, Wanjie Li, Xiaoyan Zhang, Hao Dong, Youjun Wang.
      Genetically Encoded Calcium (Ca2+) indicators (GECIs) are indispensable tools for dissecting intracellular Ca2+ signaling and monitoring cellular activities. Mitochondrion acts as a Ca2+ sink and a central player for maintaining Ca2+ homeostasis. Accurately monitoring Ca2+ transients within the mitochondrial matrix that undergo constant pH fluctuations is challenging, as signals of most currently available GECIs suffer from artifacts induced by physiological pH variations. Multiplexed monitoring of optophysiology is also hindered by the limited availability of GECIs with cyan fluorescence. Based on the bright variant of cyan fluorescence protein (CFP), mTurquoise2, we developed a GECI designated as TurCaMP. Results from molecular dynamics simulations and ab initio calculations revealed that the deprotonation of the chromophore may be responsible for the Ca2+-dependent changes in TurCaMP signals. TurCaMP sensors showed inverse response to Ca2+ transients, and their responses were not affected by pH changes within the range of pH 6-9. The high basal fluorescence and insensitivity to physiological pH fluctuations enabled TurCaMP to faithfully monitor mitochondrial Ca2+ responses with a high signal-to-noise ratio. TurCaMP sensors allow simultaneous multi-colored imaging of intracellular Ca2+ signals, expanding the possibility of multiplexed monitoring of Ca2+-dependent physiological events.
    Keywords:  Ab initio calculations; Genetically encoded calcium indicator; MD simulations; Mitochondria; mTurquoise2; pH
    DOI:  https://doi.org/10.52601/bpr.2024.240001
  10. Nat Aging. 2024 Nov;4(11): 1520
    Cell type-divergent functions of senescence.
    Hannah Walters.
      
    DOI:  https://doi.org/10.1038/s43587-024-00764-3
  11. Autophagy. 2024 Nov 08.
    PINK1-deficiency facilitates mitochondrial iron accumulation and colon tumorigenesis.
    Mariella Arcos, Lavanya Goodla, Hyeoncheol Kim, Sharina P Desai, Rui Liu, Kunlun Yin, Zhaoli Liu, David R Martin, Xiang Xue.
      Mitophagy, the process by which cells eliminate damaged mitochondria, is mediated by PINK1 (PTEN induced kinase 1). Our recent research indicates that PINK1 functions as a tumor suppressor in colorectal cancer by regulating cellular metabolism. Interestingly, PINK1 ablation activated the NLRP3 (NLR family pyrin domain containing 3) inflammasome, releasing IL1B (interleukin 1 beta). However, inhibiting the NLRP3-IL1B signaling pathway with an IL1R (interleukin 1 receptor) antagonist or NLRP3 inhibitor did not hinder colon tumor growth after PINK1 loss. To identify druggable targets in PINK1-deficient tumors, ribonucleic acid sequencing analysis was performed on colon tumors from pink1 knockout and wild-type mice. Gene Set Enrichment Analysis highlighted the enrichment of iron ion transmembrane transporter activity. Subsequent qualitative polymerase chain reaction and western blot analysis revealed an increase in mitochondrial iron transporters, including mitochondrial calcium uniporter, in PINK1-deficient colon tumor cells and tissues. Live-cell iron staining demonstrated elevated cellular and mitochondrial iron levels in PINK1-deficient cells. Clinically used drugs deferiprone and minocycline reduced mitochondrial iron and superoxide levels, resulting in decreased colon tumor cell growth in vitro and in vivo. Manipulating the mitochondrial iron uptake protein MCU (mitochondrial calcium uniporter) also affected cell and xenograft tumor growth. This study suggests that therapies aimed at reducing mitochondrial iron levels may effectively inhibit colon tumor growth, particularly in patients with low PINK1 expression.
    Keywords:  Colorectal cancer; deferiprone; iron chelation; minocycline; mitochondrial iron; mitophagy
    DOI:  https://doi.org/10.1080/15548627.2024.2425594
  12. Eur J Neurosci. 2024 Nov 11.
    Ketone ester-enriched diet ameliorates motor and dopamine release deficits in MitoPark mice.
    Vikrant R Mahajan, Jacob A Nadel, M Todd King, Robert J Pawlosky, Margaret I Davis, Richard L Veech, David M Lovinger, Armando G Salinas.
      Parkinson's disease (PD) is a progressive, neurodegenerative disease characterized by motor dysfunction and dopamine deficits. The MitoPark (MP) mouse model of PD recapitulates several facets of Parkinson's disease, including gradual development of motor deficits, which enables the study of potential therapeutic interventions. One therapeutic strategy involves decreasing the mitochondrial metabolic load by inducing ketosis and providing an alternative energy source for neurons, leading to decreased neuronal oxidative stress. Thus, we hypothesized that administration of a ketone ester-enriched diet (KEED) would improve motor and dopamine release deficits in MP mice. Motor function (rotarod and open field tests), dopamine release (fast-scan cyclic voltammetry), tissue dopamine levels (gas chromatography-mass spectrometry) and dopamine neurons and axons (immunofluorescence) were assessed in MP, and control mice fed either the standard or a KEED. When started on the ketone diet before motor dysfunction onset, MP mice had improved motor function relative to standard diet (SD) MP mice. While the KEED did not preserve dopamine neurons or striatal dopamine axons, dopamine release in ketone diet MP mice was greater than SD MP mice but less than control mice. In a follow-up experiment, we began the ketone diet after motor dysfunction onset and observed a modest preservation of motor function in ketone diet MP mice relative to SD MP mice. The improvement in motor dysfunction indicates that a KEED or ketone supplement may have a beneficial effect on delaying motor deficit progression in Parkinson's disease.
    Keywords:  Parkinson's disease; dopamine neurons; ketosis; neuroprotection; striatum
    DOI:  https://doi.org/10.1111/ejn.16601
  13. Nat Aging. 2024 Nov 13.
    Clearance of p21 highly expressing senescent cells accelerates cutaneous wound healing.
    Nathan S Gasek, Pengyi Yan, Junyu Zhu, K-Raman Purushothaman, Taewan Kim, Lichao Wang, Binsheng Wang, William F Flynn, Mingda Sun, Chun Guo, Billy Huggins, Roshanak Sharafieh, Yueying Zhou, Vojtech Parizek, Tamar Tchkonia, James L Kirkland, Saranya P Wyles, Ming Xu.
      While senescent cells have detrimental roles in several contexts, they are highly heterogeneous. p16 highly expressing senescent cells have been reported to exert beneficial functions in wound healing. Here we use Xenium spatial transcriptomics to identify a distinct p21 highly expressing senescent population induced on wounding, with a pro-inflammatory profile. We find that clearing p21 highly expressing cells expedites wound closure and is partially mediated by NF-κB inhibition, thus enhancing our understanding of the multifaceted functions of senescence in tissue remodeling.
    DOI:  https://doi.org/10.1038/s43587-024-00755-4
  14. Cells. 2024 Oct 31. pii: 1802. [Epub ahead of print]13(21):
    ALDH1A3 Contributes to Radiation-Induced Inhibition of Self-Renewal and Promotes Proliferative Activity of p53-Deficient Glioblastoma Stem Cells at the Onset of Differentiation.
    Andreas Müller, Bogdan Lyubarskyy, Jurij Tchoumakov, Maike Wagner, Bettina Sprang, Florian Ringel, Ella L Kim.
      ALDH1A3 is a marker for mesenchymal glioblastomas characterized by a greater degree of aggressiveness compared to other major subtypes. ADH1A3 has been implicated in the regulation of stemness and radioresistance mediated by glioblastoma stem cells. Mechanisms by which ALDH1A3 promotes malignant progression of glioblastoma remain elusive posing a challenge for rationalization of ALDH1A3 targeting in glioblastoma, and it is also unclear how ALDH1A3 regulates glioblastoma cells stemness. Usage of different models with diverse genetic backgrounds and often unknown degree of stemness is one possible reason for discrepant views on the role of ALDH1A3 in glioblastoma stem cells. This study clarifies ALDH1A3 impacts on glioblastoma stem cells by modelling ALDH1A3 expression in an otherwise invariable genetic background with consideration of the impacts of inherent plasticity and proliferative changes associated with transitions between cell states. Our main finding is that ALDH1A3 exerts cell-state dependent impact on proliferation of glioblastoma stem cells. We provide evidence that ALDH1A3 augments radiation-induced inhibition of self-renewal and promotes the proliferation of differentiated GSC progenies. Congruent effects ALDH1A3 and radiation on self-renewal and proliferation provides a framework for promoting glioblastoma growth under radiation treatment.
    Keywords:  ALDH1A3; glioblastoma stem cells; radioresistance
    DOI:  https://doi.org/10.3390/cells13211802
  15. J Ovarian Res. 2024 Nov 14. 17(1): 226
    Targeting mitochondrial metabolism with CPI-613 in chemoresistant ovarian tumors.
    Mary P Udumula, Faraz Rashid, Harshit Singh, Tim Pardee, Sanjeev Luther, Tanya Bhardwaj, Km Anjaly, Sofia Piloni, Miriana Hijaz, Radhika Gogoi, Philip A Philip, Adnan R Munkarah, Shailendra Giri, Ramandeep Rattan.
       BACKGROUND: There is evidence indicating that chemoresistance in tumor cells is mediated by the reconfiguration of the tricarboxylic acid cycle, leading to heightened mitochondrial activity and oxidative phosphorylation (OXPHOS). Previously, we have shown that ovarian cancer cells that are resistant to chemotherapy display increased OXPHOS, mitochondrial function, and metabolic flexibility. To exploit this weakness in chemoresistant ovarian cancer cells, we examined the effectiveness of the mitochondrial inhibitor CPI-613 in treating preclinical ovarian cancer.
    METHODS: Chemosensitive OVCAR3, and chemoresistant CAOV3 and F2 ovarian cancer cells lines and their xenografts in nude mice were used. Functional metabolic studies were performed using Seahorse instrument. Metabolite quantification was performed using LC/MS/MS.
    RESULTS: Mice treated with CPI-613 exhibited a notable increase in overall survival and a reduction in tumor development and burden in OVCAR3, F2, and CAOV3 xenografts. CPI-613 suppressed the activity of pyruvate dehydrogenase and alpha-ketoglutarate dehydrogenase complex, which are two of its targets. This led to a reduction in OXPHOS and tricarboxylic acid cycle activity in all 3 xenografts. The addition of CPI-613 enhanced the responsiveness of chemotherapy in the chemoresistant F2 and CAOV3 tumors, resulting in a notable improvement in survival rates and a reduction in tumor size as compared to using chemotherapy alone. CPI-613 reduced the chemotherapy-induced OXPHOS in chemoresistant tumors. The study revealed that the mechanism by which CPI-613 inhibits tumor growth is through mitochondrial collapse. This is evidenced by an increase in superoxide production within the mitochondria, a decrease in ATP generation, and the release of cytochrome C, which triggers mitochondria-induced apoptosis.
    CONCLUSION: Our study demonstrates the translational potential of CPI-613 against chemoresistant ovarian tumors.
    Keywords:  Apoptosis; CPI-613; Mitochondria; Ovarian cancer
    DOI:  https://doi.org/10.1186/s13048-024-01546-6
  16. Sci Rep. 2024 Nov 15. 14(1): 28167
    Liver knockout of MCU leads to greater dysregulation of lipid metabolism in MAFLD.
    Qichao Liao, Yurou Zhang, Tingli Pan, Yu Sun, Siqi Liu, Zhiwang Zhang, Yixing Li, Lin Yu, Zupeng Luo, Yang Xiao, Xinyi Qi, Tianyu Jiang, Songtao Su, Shi Liu, Xinyu Qi, Xiangling Li, Turtushikh Damba, Khongorzul Batchuluun, Yunxiao Liang, Suosu Wei, Lei Zhou.
      Metabolic-associated fatty liver disease (MAFLD) is a common chronic condition that poses a significant threat to human health. Mitochondrial dysfunction, particularly involving the mitochondrial Ca2+ uniporter (MCU), plays a key role in its pathogenesis. This study aimed to investigate the impact of the MCU gene on hepatic lipid metabolism in mice fed a high-fat diet. Using MCU knockout and wild-type mice, subjected to either a high-fat or normal diet for 14 weeks, we observed notable Steatosis and liver weight gain in MCU-deficient mice. Liver function markers, serum triglycerides, very low-density lipoprotein (VLDL) levels, and ApoB protein expression were all significantly elevated. Mechanistic studies revealed that MCU deletion led to mitochondrial dysfunction, increased oxidative stress. These findings highlight the critical role of the MCU gene in maintaining hepatic lipid balance and suggest its potential as a therapeutic target for managing nonalcoholic fatty liver disease.
    Keywords:  Fat liver; Lipid dysregulation; Lipid transport-associated; MAFLD; MCU
    DOI:  https://doi.org/10.1038/s41598-024-78935-w
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