bims-cesemi Biomed News
on Cellular senescence and mitochondria
Issue of 2024–04–28
seventeen papers selected by
Julio Cesar Cardenas, Universidad Mayor
  1. Cellular senescence in cancer: molecular mechanisms and therapeutic targets.
  2. The senescence-associated secretory phenotype and its physiological and pathological implications.
  3. Network model of skeletal muscle cell signalling predicts differential responses to endurance and resistance exercise training.
  4. Loss of AMPK activity induces organelle dysfunction and oxidative stress during oocyte aging.
  5. Cell Senescence-Independent Changes of Human Skin Fibroblasts with Age.
  6. Profiling microRNA expression during senescence and aging: mining for a diagnostic tool of senescent-cell burden.
  7. Mitochondrial Transplantation's Role in Rodent Skeletal Muscle Bioenergetics: Recharging the Engine of Aging.
  8. Wound care in older people: overcoming the challenges of assessment and management.
  9. Sedentary behavior in mice induces metabolic inflexibility by suppressing skeletal muscle pyruvate metabolism.
  10. Mutant RAS-driven secretome causes skeletal muscle defects in breast cancer.
  11. Transcription factor Nrf1 regulates proteotoxic stress-induced autophagy.
  12. Wild-type IDH2 is a therapeutic target for triple-negative breast cancer.
  13. The Role and Prospects of Mesenchymal Stem Cells in Skin Repair and Regeneration.
  14. Beta hydroxybutyrate induces lung cancer cell death, mitochondrial impairment and oxidative stress in a long term glucose-restricted condition.
  15. Mitochondrial sites of contact with the nucleus.
  16. Neuronal Mitochondrial Calcium Uniporter (MCU) Deficiency Is Neuroprotective in Hyperexcitability by Modulation of Metabolic Pathways and ROS Balance.
  17. Inflammation and mitophagy are mitochondrial checkpoints to aging.
  1. MedComm (2020). 2024 May;5(5): e542
    Cellular senescence in cancer: molecular mechanisms and therapeutic targets.
    Ping Jin, Xirui Duan, Lei Li, Ping Zhou, Cheng-Gang Zou, Ke Xie.
      Aging exhibits several hallmarks in common with cancer, such as cellular senescence, dysbiosis, inflammation, genomic instability, and epigenetic changes. In recent decades, research into the role of cellular senescence on tumor progression has received widespread attention. While how senescence limits the course of cancer is well established, senescence has also been found to promote certain malignant phenotypes. The tumor-promoting effect of senescence is mainly elicited by a senescence-associated secretory phenotype, which facilitates the interaction of senescent tumor cells with their surroundings. Targeting senescent cells therefore offers a promising technique for cancer therapy. Drugs that pharmacologically restore the normal function of senescent cells or eliminate them would assist in reestablishing homeostasis of cell signaling. Here, we describe cell senescence, its occurrence, phenotype, and impact on tumor biology. A "one-two-punch" therapeutic strategy in which cancer cell senescence is first induced, followed by the use of senotherapeutics for eliminating the senescent cells is introduced. The advances in the application of senotherapeutics for targeting senescent cells to assist cancer treatment are outlined, with an emphasis on drug categories, and the strategies for their screening, design, and efficient targeting. This work will foster a thorough comprehension and encourage additional research within this field.
    Keywords:  immunosenescence; senescence; senescence‐associated secretory phenotype (SASP); senotherapeutics; tumor
    DOI:  https://doi.org/10.1002/mco2.542
  2. Nat Rev Mol Cell Biol. 2024 Apr 23.
    The senescence-associated secretory phenotype and its physiological and pathological implications.
    Boshi Wang, Jin Han, Jennifer H Elisseeff, Marco Demaria.
      Cellular senescence is a state of terminal growth arrest associated with the upregulation of different cell cycle inhibitors, mainly p16 and p21, structural and metabolic alterations, chronic DNA damage responses, and a hypersecretory state known as the senescence-associated secretory phenotype (SASP). The SASP is the major mediator of the paracrine effects of senescent cells in their tissue microenvironment and of various local and systemic biological functions. In this Review, we discuss the composition, dynamics and heterogeneity of the SASP as well as the mechanisms underlying its induction and regulation. We describe the various biological properties of the SASP, its beneficial and detrimental effects in different physiological and pathological settings, and its impact on overall health span. Finally, we discuss the use of the SASP as a biomarker and of SASP inhibitors as senomorphic interventions to treat cancer and other age-related conditions.
    DOI:  https://doi.org/10.1038/s41580-024-00727-x
  3. Exp Physiol. 2024 Apr 21.
    Network model of skeletal muscle cell signalling predicts differential responses to endurance and resistance exercise training.
    Annabelle Fowler, Katherine R Knaus, Stephanie Khuu, Ali Khalilimeybodi, Simon Schenk, Samuel R Ward, Andrew C Fry, Padmini Rangamani, Andrew D McCulloch.
      Exercise-induced muscle adaptations vary based on exercise modality and intensity. We constructed a signalling network model from 87 published studies of human or rodent skeletal muscle cell responses to endurance or resistance exercise in vivo or simulated exercise in vitro. The network comprises 259 signalling interactions between 120 nodes, representing eight membrane receptors and eight canonical signalling pathways regulating 14 transcriptional regulators, 28 target genes and 12 exercise-induced phenotypes. Using this network, we formulated a logic-based ordinary differential equation model predicting time-dependent molecular and phenotypic alterations following acute endurance and resistance exercises. Compared with nine independent studies, the model accurately predicted 18/21 (85%) acute responses to resistance exercise and 12/16 (75%) acute responses to endurance exercise. Detailed sensitivity analysis of differential phenotypic responses to resistance and endurance training showed that, in the model, exercise regulates cell growth and protein synthesis primarily by signalling via mechanistic target of rapamycin, which is activated by Akt and inhibited in endurance exercise by AMP-activated protein kinase. Endurance exercise preferentially activates inflammation via reactive oxygen species and nuclear factor κB signalling. Furthermore, the expected preferential activation of mitochondrial biogenesis by endurance exercise was counterbalanced in the model by protein kinase C in response to resistance training. This model provides a new tool for investigating cross-talk between skeletal muscle signalling pathways activated by endurance and resistance exercise, and the mechanisms of interactions such as the interference effects of endurance training on resistance exercise outcomes.
    Keywords:  computational model; endurance exercise; exercise; resistance exercise; signalling network; skeletal muscle
    DOI:  https://doi.org/10.1113/EP091712
  4. Biol Direct. 2024 Apr 23. 19(1): 29
    Loss of AMPK activity induces organelle dysfunction and oxidative stress during oocyte aging.
    Lin-Lin Hu, Mei-Hua Liao, Ya-Xi Liu, Chun-Hua Xing, Lan-Lan Nong, Feng-Lian Yang, Shao-Chen Sun.
       BACKGROUND: Oocyte quality is critical for the mammalian reproduction due to its necessity on fertilization and early development. During aging, the declined oocytes showing with organelle dysfunction and oxidative stress lead to infertility. AMP-activated protein kinase (AMPK) is a serine/threonine protein kinase which is important for energy homeostasis for metabolism. Little is known about the potential relationship between AMPK with oocyte aging.
    RESULTS: In present study we reported that AMPK was related with low quality of oocytes under post ovulatory aging and the potential mechanism. We showed the altered AMPK level during aging and inhibition of AMPK activity induced mouse oocyte maturation defect. Further analysis indicated that similar with its upstream regulator PKD1, AMPK could reduce ROS level to avoid oxidative stress in oocytes, and this might be due to its regulation on mitochondria function, since loss of AMPK activity induced abnormal distribution, reduced ATP production and mtDNA copy number of mitochondria. Besides, we also found that the ER and Golgi apparatus distribution was aberrant after AMPK inhibition, and enhanced lysosome function was also observed.
    CONCLUSIONS: Taken together, these data indicated that AMPK is important for the organelle function to reduce oxidative stress during oocyte meiotic maturation.
    Keywords:  AMPK; Meiosis; Mitochondria; Oocyte; Oxidative stress
    DOI:  https://doi.org/10.1186/s13062-024-00471-4
  5. Cells. 2024 Apr 09. pii: 659. [Epub ahead of print]13(8):
    Cell Senescence-Independent Changes of Human Skin Fibroblasts with Age.
    Nicola Fullard, James Wordsworth, Ciaran Welsh, Victoria Maltman, Charlie Bascom, Ryan Tasseff, Robert Isfort, Lydia Costello, Rebekah-Louise Scanlan, Stefan Przyborski, Daryl Shanley.
      Skin ageing is defined, in part, by collagen depletion and fragmentation that leads to a loss of mechanical tension. This is currently believed to reflect, in part, the accumulation of senescent cells. We compared the expression of genes and proteins for components of the extracellular matrix (ECM) as well as their regulators and found that in vitro senescent cells produced more matrix metalloproteinases (MMPs) than proliferating cells from adult and neonatal donors. This was consistent with previous reports of senescent cells contributing to increased matrix degradation with age; however, cells from adult donors proved significantly less capable of producing new collagen than neonatal or senescent cells, and they showed significantly lower myofibroblast activation as determined by the marker α-SMA. Functionally, adult cells also showed slower migration than neonatal cells. We concluded that the increased collagen degradation of aged fibroblasts might reflect senescence, the reduced collagen production likely reflects senescence-independent processes.
    Keywords:  TGF; ageing; collagen; extracellular matrix; fibroblast; fibrosis; metalloproteinase; myofibroblast; senescence; skin
    DOI:  https://doi.org/10.3390/cells13080659
  6. bioRxiv. 2024 Apr 10. pii: 2024.04.10.588794. [Epub ahead of print]
    Profiling microRNA expression during senescence and aging: mining for a diagnostic tool of senescent-cell burden.
    Moritz Weigl, Teresa L Krammer, Marianne Pultar, Matthias Wieser, Selim Chaib, Masayoshi Suda, Andreas Diendorfer, Kseniya Khamina-Kotisch, Nino Giorgadze, Tamar Pirtskhalava, Kurt O Johnson, Christina L Inman, Ailing Xue, Ingo Lämmermann, Barbara Meixner, Lichao Wang, Ming Xu, Regina Grillari, Mikolaj Ogrodnik, Tamar Tchkonia, Matthias Hackl, James L Kirkland, Johannes Grillari.
      In the last decade cellular senescence, a hallmark of aging, has come into focus for pharmacologically targeting aging processes. Senolytics are one of these interventive strategies that have advanced into clinical trials, creating an unmet need for minimally invasive biomarkers of senescent cell load to identify patients at need for senotherapy. We created a landscape of miRNA and mRNA expression in five human cell types induced to senescence in-vitro and provide proof-of-principle evidence that miRNA expression can track senescence burden dynamically in-vivo using transgenic p21 high senescent cell clearance in HFD fed mice. Finally, we profiled miRNA expression in seven different tissues, total plasma, and plasma derived EVs of young and 25 months old mice. In a systematic analysis, we identified 22 candidate senomiRs with potential to serve as circulating biomarkers of senescence not only in rodents, but also in upcoming human clinical senolytic trials.
    DOI:  https://doi.org/10.1101/2024.04.10.588794
  7. Biomolecules. 2024 Apr 18. pii: 493. [Epub ahead of print]14(4):
    Mitochondrial Transplantation's Role in Rodent Skeletal Muscle Bioenergetics: Recharging the Engine of Aging.
    Tasnim Arroum, Gerald A Hish, Kyle J Burghardt, James D McCully, Maik Hüttemann, Moh H Malek.
       BACKGROUND: Mitochondria are the 'powerhouses of cells' and progressive mitochondrial dysfunction is a hallmark of aging in skeletal muscle. Although different forms of exercise modality appear to be beneficial to attenuate aging-induced mitochondrial dysfunction, it presupposes that the individual has a requisite level of mobility. Moreover, non-exercise alternatives (i.e., nutraceuticals or pharmacological agents) to improve skeletal muscle bioenergetics require time to be effective in the target tissue and have another limitation in that they act systemically and not locally where needed. Mitochondrial transplantation represents a novel directed therapy designed to enhance energy production of tissues impacted by defective mitochondria. To date, no studies have used mitochondrial transplantation as an intervention to attenuate aging-induced skeletal muscle mitochondrial dysfunction. The purpose of this investigation, therefore, was to determine whether mitochondrial transplantation can enhance skeletal muscle bioenergetics in an aging rodent model. We hypothesized that mitochondrial transplantation would result in sustained skeletal muscle bioenergetics leading to improved functional capacity.
    METHODS: Fifteen female mice (24 months old) were randomized into two groups (placebo or mitochondrial transplantation). Isolated mitochondria from a donor mouse of the same sex and age were transplanted into the hindlimb muscles of recipient mice (quadriceps femoris, tibialis anterior, and gastrocnemius complex).
    RESULTS: The results indicated significant increases (ranging between ~36% and ~65%) in basal cytochrome c oxidase and citrate synthase activity as well as ATP levels in mice receiving mitochondrial transplantation relative to the placebo. Moreover, there were significant increases (approx. two-fold) in protein expression of mitochondrial markers in both glycolytic and oxidative muscles. These enhancements in the muscle translated to significant improvements in exercise tolerance.
    CONCLUSIONS: This study provides initial evidence showing how mitochondrial transplantation can promote skeletal muscle bioenergetics in an aging rodent model.
    Keywords:  endurance; energy production; exercise physiology
    DOI:  https://doi.org/10.3390/biom14040493
  8. Nurs Older People. 2024 Apr 24.
    Wound care in older people: overcoming the challenges of assessment and management.
    Joanna Swan, Jane Mogford, Katie Leek.
      Age-related skin changes lead to increased susceptibility to skin damage and delayed wound healing, which is exacerbated by comorbidities such as cardiovascular disease and diabetes mellitus. In some cases, wound healing is not achievable or realistic and this needs to be reflected in the wound management plan. To improve outcomes and experience in older people presenting with wounds it is important to select wound management products that protect the wound bed and surrounding skin, minimise trauma, reduce symptoms and/or promote healing. This article explores how conducting holistic wound assessments, setting realistic treatment aims, and using wound management strategies tailored to each person's needs and wishes can have a positive effect on older people's quality of life.
    Keywords:  care homes; clinical; leg ulcers; nursing homes; older people; pressure ulcers; skin; skin assessment; wound assessment; wound care; wound management
    DOI:  https://doi.org/10.7748/nop.2024.e1471
  9. J Clin Invest. 2024 Apr 23. pii: e167371. [Epub ahead of print]
    Sedentary behavior in mice induces metabolic inflexibility by suppressing skeletal muscle pyruvate metabolism.
    Piyarat Siripoksup, Guoshen Cao, Ahmad A Cluntun, J Alan Maschek, Quentinn Pearce, Marisa J Lang, Mi-Young Jeong, Hiroaki Eshima, Patrick J Ferrara, Precious C Opurum, Ziad S Mahmassani, Alek D Peterlin, Shinya Watanabe, Maureen A Walsh, Eric B Taylor, James E Cox, Micah J Drummond, Jared Rutter, Katsuhiko Funai.
      Carbohydrates and lipids provide the majority of substrates to fuel mitochondrial oxidative phosphorylation (OXPHOS). Metabolic inflexibility, defined as an impaired ability to switch between these fuels, is implicated in a number of metabolic diseases. Here we explore the mechanism by which physical inactivity promotes metabolic inflexibility in skeletal muscle. We developed a mouse model of sedentariness, small mouse cage (SMC) that, unlike other classic models of disuse in mice, faithfully recapitulated metabolic responses that occur in humans. Bioenergetic phenotyping of skeletal muscle mitochondria displayed metabolic inflexibility induced by physical inactivity, demonstrated by a reduction in pyruvate-stimulated respiration (JO2) in absence of a change in palmitate-stimulated JO2. Pyruvate resistance in these mitochondria was likely driven by a decrease in phosphatidylethanolamine (PE) abundance in the mitochondrial membrane. Reduction in mitochondrial PE by heterozygous deletion of phosphatidylserine decarboxylase (PSD) was sufficient to induce metabolic inflexibility measured at the whole-body level, as well as at the level of skeletal muscle mitochondria. Low mitochondrial PE in C2C12 myotubes was sufficient to increase glucose flux towards lactate. We further implicate that resistance to pyruvate metabolism is due to attenuated mitochondrial entry via mitochondrial pyruvate carrier (MPC). These findings suggest a mechanism by which mitochondrial PE directly regulates MPC activity to modulate metabolic flexibility in mice.
    Keywords:  Metabolism; Mitochondria; Skeletal muscle
    DOI:  https://doi.org/10.1172/JCI167371
  10. Cancer Res Commun. 2024 Apr 23.
    Mutant RAS-driven secretome causes skeletal muscle defects in breast cancer.
    Ruizhong Wang, Aditi S Khatpe, Brijesh Kumar, Henry Elmer Mang, Katie Batic, Adedeji K Adebayo, Harikrishna Nakshatri.
      Cancer-induced skeletal muscle defects differ in severity between individuals with the same cancer type. Cancer subtype-specific genomic aberrations are suggested to mediate these differences, but experimental validation studies are very limited. We utilized three different breast cancer patient-derived xenograft (PDX) models to correlate cancer subtype with skeletal muscle defects. PDXs were derived from brain metastasis of triple negative breast cancer (TNBC), Estrogen Receptor-positive/Progesterone Receptor-positive (ER+/PR+) primary breast cancer from a BRCA2-mutation carrier, and pleural effusion from an ER+/PR- breast cancer. While impaired skeletal muscle function as measured through rotarod performance and reduced levels of circulating and/or skeletal muscle miR-486 were common across all three PDXs, only TNBC-derived PDX activated phospho-p38 in skeletal muscle. To further extend these results, we generated transformed variants of human primary breast epithelial cells from healthy donors using HRASG12V or PIK3CAH1047R mutant oncogenes. Mutations in RAS oncogene or its modulators are found in ~37% of metastatic breast cancers, which is often associated with skeletal muscle defects. Although cells transformed with both oncogenes generated adenocarcinomas in NSG mice, only HRASG12V-derived tumors caused skeletal muscle defects affecting rotarod performance, skeletal muscle contraction force, and miR-486, Pax7, pAKT, and p53 levels in skeletal muscle. Circulating levels of the chemokine CXCL1 were elevated only in animals with tumors containing HRASG12V mutation. Since RAS pathway aberrations are found in 19% of cancers, evaluating skeletal muscle defects in the context of genomic aberrations in cancers, particularly RAS pathway mutations, may accelerate development of therapeutic modalities to overcome cancer-induced systemic effects.
    DOI:  https://doi.org/10.1158/2767-9764.CRC-24-0045
  11. J Cell Biol. 2024 Jun 03. pii: e202306150. [Epub ahead of print]223(6):
    Transcription factor Nrf1 regulates proteotoxic stress-induced autophagy.
    Madison A Ward, Janakiram R Vangala, Hatem Elif Kamber Kaya, Holly A Byers, Nayyerehalsadat Hosseini, Antonio Diaz, Ana Maria Cuervo, Susmita Kaushik, Senthil K Radhakrishnan.
      Cells exposed to proteotoxic stress invoke adaptive responses aimed at restoring proteostasis. Our previous studies have established a firm role for the transcription factor Nuclear factor-erythroid derived-2-related factor-1 (Nrf1) in responding to proteotoxic stress elicited by inhibition of cellular proteasome. Following proteasome inhibition, Nrf1 mediates new proteasome synthesis, thus enabling the cells to mitigate the proteotoxic stress. Here, we report that under similar circumstances, multiple components of the autophagy-lysosomal pathway (ALP) were transcriptionally upregulated in an Nrf1-dependent fashion, thus providing the cells with an additional route to cope with proteasome insufficiency. In response to proteasome inhibitors, Nrf1-deficient cells displayed profound defects in invoking autophagy and clearance of aggresomes. This phenomenon was also recapitulated in NGLY1 knockout cells, where Nrf1 is known to be non-functional. Conversely, overexpression of Nrf1 induced ALP genes and endowed the cells with an increased capacity to clear aggresomes. Overall, our results significantly expand the role of Nrf1 in shaping the cellular response to proteotoxic stress.
    DOI:  https://doi.org/10.1083/jcb.202306150
  12. Nat Commun. 2024 Apr 24. 15(1): 3445
    Wild-type IDH2 is a therapeutic target for triple-negative breast cancer.
    Jiang-Jiang Li, Tiantian Yu, Peiting Zeng, Jingyu Tian, Panpan Liu, Shuang Qiao, Shijun Wen, Yumin Hu, Qiao Liu, Wenhua Lu, Hui Zhang, Peng Huang.
      Mutations in isocitrate dehydrogenases (IDH) are oncogenic events due to the generation of oncogenic metabolite 2-hydroxyglutarate. However, the role of wild-type IDH in cancer development remains elusive. Here we show that wild-type IDH2 is highly expressed in triple negative breast cancer (TNBC) cells and promotes their proliferation in vitro and tumor growth in vivo. Genetic silencing or pharmacological inhibition of wt-IDH2 causes a significant increase in α-ketoglutarate (α-KG), indicating a suppression of reductive tricarboxylic acid (TCA) cycle. The aberrant accumulation of α-KG due to IDH2 abrogation inhibits mitochondrial ATP synthesis and promotes HIF-1α degradation, leading to suppression of glycolysis. Such metabolic double-hit results in ATP depletion and suppression of tumor growth, and renders TNBC cells more sensitive to doxorubicin treatment. Our study reveals a metabolic property of TNBC cells with active utilization of glutamine via reductive TCA metabolism, and suggests that wild-type IDH2 plays an important role in this metabolic process and could be a potential therapeutic target for TNBC.
    DOI:  https://doi.org/10.1038/s41467-024-47536-6
  13. Biomedicines. 2024 Mar 27. pii: 743. [Epub ahead of print]12(4):
    The Role and Prospects of Mesenchymal Stem Cells in Skin Repair and Regeneration.
    Si Wu, Shengbo Sun, Wentao Fu, Zhengyang Yang, Hongwei Yao, Zhongtao Zhang.
      Mesenchymal stem cells (MSCs) have been recognized as a cell therapy with the potential to promote skin healing. MSCs, with their multipotent differentiation ability, can generate various cells related to wound healing, such as dermal fibroblasts (DFs), endothelial cells, and keratinocytes. In addition, MSCs promote neovascularization, cellular regeneration, and tissue healing through mechanisms including paracrine and autocrine signaling. Due to these characteristics, MSCs have been extensively studied in the context of burn healing and chronic wound repair. Furthermore, during the investigation of MSCs, their unique roles in skin aging and scarless healing have also been discovered. In this review, we summarize the mechanisms by which MSCs promote wound healing and discuss the recent findings from preclinical and clinical studies. We also explore strategies to enhance the therapeutic effects of MSCs. Moreover, we discuss the emerging trend of combining MSCs with tissue engineering techniques, leveraging the advantages of MSCs and tissue engineering materials, such as biodegradable scaffolds and hydrogels, to enhance the skin repair capacity of MSCs. Additionally, we highlight the potential of using paracrine and autocrine characteristics of MSCs to explore cell-free therapies as a future direction in stem cell-based treatments, further demonstrating the clinical and regenerative aesthetic applications of MSCs in skin repair and regeneration.
    Keywords:  mesenchymal stem cells; skin regeneration; skin rejuvenation; wound healing
    DOI:  https://doi.org/10.3390/biomedicines12040743
  14. Mol Biol Rep. 2024 Apr 24. 51(1): 567
    Beta hydroxybutyrate induces lung cancer cell death, mitochondrial impairment and oxidative stress in a long term glucose-restricted condition.
    Farzad Izak Shirian, Milad Karimi, Maryam Alipour, Siamak Salami, Mitra Nourbakhsh, Samira Nekufar, Nahid Safari-Alighiarloo, Masoumeh Tavakoli-Yaraki.
       BACKGROUND: Metabolic plasticity gives cancer cells the ability to shift between signaling pathways to facilitate their growth and survival. This study investigates the role of glucose deprivation in the presence and absence of beta-hydroxybutyrate (BHB) in growth, death, oxidative stress and the stemness features of lung cancer cells.
    METHODS AND RESULTS: A549 cells were exposed to various glucose conditions, both with and without beta-hydroxybutyrate (BHB), to evaluate their effects on apoptosis, mitochondrial membrane potential, reactive oxygen species (ROS) levels using flow cytometry, and the expression of CD133, CD44, SOX-9, and β-Catenin through Quantitative PCR. The activity of superoxide dismutase, glutathione peroxidase, and malondialdehyde was assessed using colorimetric assays. Treatment with therapeutic doses of BHB triggered apoptosis in A549 cells, particularly in cells adapted to glucose deprivation. The elevated ROS levels, combined with reduced levels of SOD and GPx, indicate that oxidative stress contributes to the cell arrest induced by BHB. Notably, BHB treatment under glucose-restricted conditions notably decreased CD133 expression, suggesting a potential inhibition of cell survival through the downregulation of CD133 levels. Additionally, the simultaneous decrease in mitochondrial membrane potential and increase in ROS levels indicate the potential for creating oxidative stress conditions to impede tumor cell growth in such environmental settings.
    CONCLUSION: The induced cell death, oxidative stress and mitochondria impairment beside attenuated levels of cancer stem cell markers following BHB administration emphasize on the distinctive role of metabolic plasticity of cancer cells and propose possible therapeutic approaches to control cancer cell growth through metabolic fuels.
    Keywords:  A459 cells; Apoptosis; Beta-hydroxybutyrate; Mitochondria membrane potential (ΔΨm); Reactive oxygen species (ROS); Stemness
    DOI:  https://doi.org/10.1007/s11033-024-09501-w
  15. J Cell Biol. 2024 Jun 03. pii: e202305010. [Epub ahead of print]223(6):
    Mitochondrial sites of contact with the nucleus.
    Michelangelo Campanella, Brindha Kannan.
      Membrane contact sites (MCS) between mitochondria and the nucleus have been recently described. Termed nucleus associated mitochondria (NAM), they prime the expression of genes required for cellular resistance to stressors, thus offering a tethering mechanism for homeostatic communication. Here, we discuss the composition of NAM and their physiological and pathological significance.
    DOI:  https://doi.org/10.1083/jcb.202305010
  16. Mol Neurobiol. 2024 Apr 23.
    Neuronal Mitochondrial Calcium Uniporter (MCU) Deficiency Is Neuroprotective in Hyperexcitability by Modulation of Metabolic Pathways and ROS Balance.
    Laura Bierhansl, Lukas Gola, Venu Narayanan, Andre Dik, Sven G Meuth, Heinz Wiendl, Stjepana Kovac.
      Epilepsy is one of the most common neurological disorders in the world. Common epileptic drugs generally affect ion channels or neurotransmitters and prevent the emergence of seizures. However, up to a third of the patients suffer from drug-resistant epilepsy, and there is an urgent need to develop new therapeutic strategies that go beyond acute antiepileptic (antiseizure) therapies towards therapeutics that also might have effects on chronic epilepsy comorbidities such as cognitive decline and depression. The mitochondrial calcium uniporter (MCU) mediates rapid mitochondrial Ca2+ transport through the inner mitochondrial membrane. Ca2+ influx is essential for mitochondrial functions, but longer elevations of intracellular Ca2+ levels are closely associated with seizure-induced neuronal damage, which are underlying mechanisms of cognitive decline and depression. Using neuronal-specific MCU knockout mice (MCU-/-ΔN), we demonstrate that neuronal MCU deficiency reduced hippocampal excitability in vivo. Furthermore, in vitro analyses of hippocampal glioneuronal cells reveal no change in total Ca2+ levels but differences in intracellular Ca2+ handling. MCU-/-ΔN reduces ROS production, declines metabolic fluxes, and consequently prevents glioneuronal cell death. This effect was also observed under pathological conditions, such as the low magnesium culture model of seizure-like activity or excitotoxic glutamate stimulation, whereby MCU-/-ΔN reduces ROS levels and suppresses Ca2+ overload seen in WT cells. This study highlights the importance of MCU at the interface of Ca2+ handling and metabolism as a mediator of stress-related mitochondrial dysfunction, which indicates the modulation of MCU as a potential target for future antiepileptogenic therapy.
    Keywords:  Hyperexcitability; Metabolism; Mitochondrial calcium uniporter (MCU); Neuroprotection; Oxidative stress
    DOI:  https://doi.org/10.1007/s12035-024-04148-x
  17. Nat Commun. 2024 Apr 20. 15(1): 3375
    Inflammation and mitophagy are mitochondrial checkpoints to aging.
    Emma Guilbaud, Kristopher A Sarosiek, Lorenzo Galluzzi.
      
    DOI:  https://doi.org/10.1038/s41467-024-47840-1
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