bims-imseme Biomed News
on Immunosenescence and T cell metabolism
Issue of 2023‒06‒11
seventeen papers selected by
Pierpaolo Ginefra
Ludwig Institute for Cancer Research
  1. Fumarate disarms CD8+ T cells against cancer.
  2. Uptake of long-chain fatty acids from the bone marrow suppresses CD8+ T-cell metabolism and function in multiple myeloma.
  3. Effects of T cell leptin signaling on systemic glucose tolerance and T cell responses in obesity.
  4. Age-related differences in T cell subsets and markers of subclinical inflammation in aging are independently associated with type 2 diabetes in the Health and Retirement Study.
  5. Quantitating CD8+ T cell memory development.
  6. Picking up speed: cell cycle regulation during effector CD8+ T cell differentiation.
  7. Bacterial induction of B cell senescence drives gut microbiota aging.
  8. Reshaping immunometabolism in the tumour microenvironment to improve cancer immunotherapy.
  9. Cancer immunosurveillance by gut T cells.
  10. IL-36/IL-36R Signaling Promotes CD4+ T Cell-Dependent Colitis via Pro-Inflammatory Cytokine Production.
  11. Lysophosphatidic acid modulates CD8 T cell immunosurveillance and metabolism to impair anti-tumor immunity.
  12. Crosstalk between arginine, glutamine, and the branched chain amino acid metabolism in the tumor microenvironment.
  13. Aging and chronic inflammation: highlights from a multidisciplinary workshop.
  14. Taurine deficiency as a driver of aging.
  15. Oxidative phosphorylation in bone cells.
  16. ROS signaling-induced mitochondrial Sgk1 expression regulates epithelial cell renewal.
  17. Mitochondrial citrate carrier SLC25A1 is a dosage-dependent regulator of metabolic reprogramming and morphogenesis in the developing heart.
  1. Cell Metab. 2023 Jun 06. pii: S1550-4131(23)00182-1. [Epub ahead of print]35(6): 907-909
    Fumarate disarms CD8+ T cells against cancer.
    Luigi Nezi, Teresa Manzo.
      The composition of nutrients in the tumor microenvironment is a key determinant of anti-tumor CD8+ T cell response. In this issue of Cell Metabolism, Jiang and colleagues unveil that tumor-derived fumarate dampens TCR signaling in CD8+ T cells, resulting in defective activation, loss of effector functions, and associated failure of tumor control.
    DOI:  https://doi.org/10.1016/j.cmet.2023.05.005
  2. Blood Adv. 2023 Jun 05. pii: bloodadvances.2023009890. [Epub ahead of print]
    Uptake of long-chain fatty acids from the bone marrow suppresses CD8+ T-cell metabolism and function in multiple myeloma.
    Nancy Gudgeon, Hannah Victoria Giles, Emma Louise Bishop, Taylor Fulton-Ward, Cristina Escribano-Gonzalez, Haydn Munford, Anna James-Bott, Kane Foster, Farheen Karim, Dedunu Abeysekara Jayawardana, Ansar Mahmood, Adam Cribbs, Daniel A Tennant, Supratik Basu, Guy Pratt, Sarah Dimeloe.
      T cells demonstrate impaired function in Multiple Myeloma (MM), but suppressive mechanisms in the bone marrow microenvironment remain poorly defined. We observe that bone marrow CD8+ T-cell function is decreased in MM patients compared to controls, and also is consistently lower within bone marrow samples than matched peripheral blood. These changes are accompanied by decreased mitochondrial mass and markedly elevated long-chain fatty acid uptake. In vitro modelling confirmed that uptake of bone marrow lipids suppresses CD8+ T function, which is impaired in autologous bone marrow plasma, but rescued by lipid removal. Analysis of single-cell RNA-sequencing data identified expression of fatty acid transport protein 1 (FATP1) in bone marrow CD8+ T cells in MM, and FATP1 blockade also rescued CD8+ T-cell function, thereby identifying this as a novel target to augment T cell activity in MM. Finally, analysis of samples from treated patient cohorts identified that CD8+ T cell metabolic dysfunction resolves in treatment-responsive but not relapsed MM patients and is associated with substantial T cell functional restoration.
    DOI:  https://doi.org/10.1182/bloodadvances.2023009890
  3. PLoS One. 2023 ;18(6): e0286470
    Effects of T cell leptin signaling on systemic glucose tolerance and T cell responses in obesity.
    Kaitlin Kiernan, Amanda G Nichols, Yazan Alwarawrah, Nancie J MacIver.
      BACKGROUND/OBJECTIVES: Leptin is an adipokine secreted in proportion to adipocyte mass and is therefore increased in obesity. Leptin signaling has been shown to directly promote inflammatory T helper 1 (Th1) and T helper 17 (Th17) cell number and function. Since T cells have a critical role in driving inflammation and systemic glucose intolerance in obesity, we sought to determine the role of leptin signaling in this context.METHODS: Male and female T cell-specific leptin receptor knockout mice and littermate controls were placed on low-fat diet or high-fat diet to induce obesity for 18 weeks. Weight gain, serum glucose levels, systemic glucose tolerance, T cell metabolism, and T cell differentiation and cytokine production were examined.
    RESULTS: In both male and female mice, T cell-specific leptin receptor deficiency did not reverse impaired glucose tolerance in obesity, although it did prevent impaired fasting glucose levels in obese mice compared to littermate controls, in a sex dependent manner. Despite these minimal effects on systemic metabolism, T cell-specific leptin signaling was required for changes in T cell metabolism, differentiation, and cytokine production observed in mice fed high-fat diet compared to low-fat diet. Specifically, we observed increased T cell oxidative metabolism, increased CD4+ T cell IFN-γ expression, and increased proportion of T regulatory (Treg) cells in control mice fed high-fat diet compared to low-fat diet, which were not observed in the leptin receptor conditional knockout mice, suggesting that leptin receptor signaling is required for some of the inflammatory changes observed in T cells in obesity.
    CONCLUSIONS: T cell-specific deficiency of leptin signaling alters T cell metabolism and function in obesity but has minimal effects on obesity-associated systemic metabolism. These results suggest a redundancy in cytokine receptor signaling pathways in response to inflammatory signals in obesity.
    DOI:  https://doi.org/10.1371/journal.pone.0286470
  4. Can J Diabetes. 2023 Jun 01. pii: S1499-2671(23)00136-3. [Epub ahead of print]
    Age-related differences in T cell subsets and markers of subclinical inflammation in aging are independently associated with type 2 diabetes in the Health and Retirement Study.
    Sithara Vivek, Eileen M Crimmins, Anna E Prizment, Helen C S Meier, Ramya Ramasubramanian, Helene Barcelo, Jessica Faul, Bharat Thyagarajan.
      AIMS: Age-related changes in adaptive immunity and subclinical inflammation are both important risk factors for diabetes in older adults. We evaluated the independent association between T cell subsets, subclinical inflammation, and diabetes risk in the Health and Retirement Study (HRS).METHODS: We measured 11 T cell subsets, five pro-inflammatory markers, and two anti-inflammatory markers from the 2016 wave of HRS (baseline). Diabetes/prediabetes status was estimated at the 2016, 2018, and 2020 waves of HRS based on levels of blood glucose/HbA1C in plasma or self-reported status. We used survey generalized logit models to evaluate the cross-sectional associations and Cox proportional hazard models to evaluate longitudinal associations.
    RESULTS: Among 8540 participants (age 56-107), 27.6% had prevalent type 2 diabetes and 31.1% had prediabetes in the 2016 survey. After adjusting for age, sex, race/ethnicity, education, obesity, smoking, comorbidity index and cytomegalovirus (CMV) seropositivity, individuals with type 2 diabetes had lower naïve T cells and higher memory and terminal effector T cells as compared to normoglycemic individuals. Among 3230 normoglycemic participants at the 2016 survey, the incidence of diabetes was 1.8% over four years of follow up. The baseline percentage of CD4+ effector memory T cells was associated with a lower risk of incident diabetes (HR=0.63; 95% CI [0.49, 0.80], p=0.0003) after adjustment for covariates. Baseline levels of Interleukin-6 (IL-6) was associated with risk of incident diabetes (HR=1.52; 95% CI [1.18, 1.97], p=0.002). The associations between age-related changes in CD4+ effector memory T cells and risk of incident diabetes remained unchanged after adjustment for subclinical inflammation, though adjusting for CD4+ effector memory T cells nullified the association between IL-6 and incident diabetes.
    CONCLUSIONS: This study showed that the baseline percentage of CD4+ effector memory T cells was inversely associated with incident diabetes independent of subclinical inflammation, though CD4+ effector memory T cell subsets affected the relationship between IL-6 and incident diabetes. Further studies are needed to confirm and investigate mechanisms by which T cell immunity affects diabetes risk.
    Keywords:  Age-related immune phenotype; CMV Seropositivity; Diabetes; Inflammation; Memory T cells; Naïve T cells
    DOI:  https://doi.org/10.1016/j.jcjd.2023.05.010
  5. Trends Immunol. 2023 Jun 03. pii: S1471-4906(23)00085-6. [Epub ahead of print]
    Quantitating CD8+ T cell memory development.
    Tamar Nizharadze, Nils B Becker, Thomas Höfer.
      In acute immune responses to infection, memory T cells develop that can spawn recall responses. This process has not been observable directly in vivo. Here we highlight the utility of mathematical inference to derive quantitatively testable models of mammalian CD8+ T cell memory development from complex experimental data. Previous inference studies suggested that precursors of memory T cells arise early during the immune response. Recent work has both validated a crucial prediction of this T cell diversification model and refined the model. While multiple developmental routes to distinct memory subsets might exist, a branch point occurs early in proliferating T cell blasts, from which separate differentiation pathways emerge for slowly dividing precursors of re-expandable memory cells and rapidly dividing effectors.
    Keywords:  T cell diversification; branching model; inference; mathematical modeling; progenitor-effector hierarchy; statistical learning
    DOI:  https://doi.org/10.1016/j.it.2023.05.004
  6. Med Microbiol Immunol. 2023 Jun 06.
    Picking up speed: cell cycle regulation during effector CD8+ T cell differentiation.
    Lorenz Kretschmer, Noémie Fuchs, Dirk H Busch, Veit R Buchholz.
      Clonal expansion and development of immunological memory are two hallmarks of adaptive immune responses. Resolving the intricate pathways that regulate cell cycle activity and lead to the generation of diverse effector and memory T cell subsets is essential for improving our understanding of protective T cell immunity. A deeper knowledge of cell cycle regulation in T cells also has translational implications for adoptive cell therapies and vaccinations against infectious diseases. Here, we summarize recent evidence for an early diversification of effector and memory CD8+ T cell fates and discuss how this process is coupled to discrete changes in division speed. We further review technical advances in lineage tracing and cell cycle analysis and outline how these techniques have shed new light on the population dynamics of CD8+ T cell responses, thereby refining our current understanding of the developmental organization of the memory T cell pool.
    Keywords:  CD8+ T cells; Cell cycle; Clonal expansion; Immunological memory; Single cell fate mapping; T cell memory
    DOI:  https://doi.org/10.1007/s00430-023-00768-7
  7. Nat Aging. 2023 Jun 08.
    Bacterial induction of B cell senescence drives gut microbiota aging.
    Hannah Walters.
      
    DOI:  https://doi.org/10.1038/s43587-023-00444-8
  8. Biomed Pharmacother. 2023 Jun 01. pii: S0753-3322(23)00753-9. [Epub ahead of print]164 114963
    Reshaping immunometabolism in the tumour microenvironment to improve cancer immunotherapy.
    Shuchen Chen, He Duan, Gongping Sun.
      The evolving understanding of cellular metabolism has revealed a the promise of strategies aiming to modulate anticancer immunity by targeting metabolism. The combination of metabolic inhibitors with immune checkpoint blockade (ICB), chemotherapy and radiotherapy may offer new approaches to cancer treatment. However, it remains unclear how these strategies can be better utilized despite the complex tumour microenvironment (TME). Oncogene-driven metabolic changes in tumour cells can affect the TME, limiting the immune response and creating many barriers to cancer immunotherapy. These changes also reveal opportunities to reshape the TME to restore immunity by targeting metabolic pathways. Further exploration is required to determine how to make better use of these mechanistic targets. Here, we review the mechanisms by which tumour cells reshape the TME and cause immune cells to transition into an abnormal state by secreting multiple factors, with the ultimate goal of proposing targets and optimizing the use of metabolic inhibitors. Deepening our understanding of changes in metabolism and immune function in the TME will help advance this promising field and enhance immunotherapy.
    Keywords:  Diet; Immunometabolism; Immunotherapy; Lactate; Tumour microenvironment
    DOI:  https://doi.org/10.1016/j.biopha.2023.114963
  9. Science. 2023 Jun 09. 380(6649): 1011-1012
    Cancer immunosurveillance by gut T cells.
    Brandon M Pratt, J Justin Milner.
      T cells primed in the gut influence immune responses to extraintestinal tumors.
    DOI:  https://doi.org/10.1126/science.adi3357
  10. bioRxiv. 2023 May 24. pii: 2023.05.24.542162. [Epub ahead of print]
    IL-36/IL-36R Signaling Promotes CD4+ T Cell-Dependent Colitis via Pro-Inflammatory Cytokine Production.
    Maya Maarouf, Michal Kuczma, Timothy L Denning.
      Inflammatory bowel disease (IBD) is a multifactorial, chronic disease that affects approximately 1.5 million people in the United States [1]. It presents with inflammation of the intestine with unknown etiology and its two main forms are Crohn's disease (CD) and ulcerative colitis (UC). Several important factors are implicated in the pathogenesis of IBD, one being dysregulation of the immune system resulting in the accumulation and stimulation of innate and adaptive immune cells and subsequent release of soluble factors, including pro-inflammatory cytokines. One of these cytokines is a member of the IL-36 cytokine family, IL-36γ, which is overexpressed in human IBD and experimental mouse models of colitis. In this study, we explored the role of IL-36γ in promoting CD4 + T cell activation and cytokine secretion. We found that IL-36γ stimulation of naïve CD4 + T cells significantly induced IFNγ expression in vitro and was associated with augmented intestinal inflammation in vivo using naive CD4 + cell transfer model of colitis. Using IFNγ-/- CD4 + cells, we observed a dramatic decrease in the ability of TNFα production and delayed colitis. This data not only suggests that IL-36γ is a master regulator of a pro-inflammatory cytokine network involving IFNγ and TNFα, but also highlights the importance of targeting IL-36γ and IFNγ as therapeutic approaches. Our studies have broad implications in relation to targeting specific cytokines in human IBD.
    DOI:  https://doi.org/10.1101/2023.05.24.542162
  11. Nat Commun. 2023 Jun 03. 14(1): 3214
    Lysophosphatidic acid modulates CD8 T cell immunosurveillance and metabolism to impair anti-tumor immunity.
    Jacqueline A Turner, Malia A Fredrickson, Marc D'Antonio, Elizabeth Katsnelson, Morgan MacBeth, Robert Van Gulick, Tugs-Saikhan Chimed, Martin McCarter, Angelo D'Alessandro, William A Robinson, Kasey L Couts, Roberta Pelanda, Jared Klarquist, Richard P Tobin, Raul M Torres.
      Lysophosphatidic acid (LPA) is a bioactive lipid which increases in concentration locally and systemically across different cancer types. Yet, the exact mechanism(s) of how LPA affects CD8 T cell immunosurveillance during tumor progression remain unknown. We show LPA receptor (LPAR) signaling by CD8 T cells promotes tolerogenic states via metabolic reprogramming and potentiating exhaustive-like differentiation to modulate anti-tumor immunity. We found LPA levels predict response to immunotherapy and Lpar5 signaling promotes cellular states associated with exhausted phenotypes on CD8 T cells. Importantly, we show that Lpar5 regulates CD8 T cell respiration, proton leak, and reactive oxygen species. Together, our findings reveal that LPA serves as a lipid-regulated immune checkpoint by modulating metabolic efficiency through LPAR5 signaling on CD8 T cells. Our study offers key insights into the mechanisms governing adaptive anti-tumor immunity and demonstrates LPA could be exploited as a T cell directed therapy to improve dysfunctional anti-tumor immunity.
    DOI:  https://doi.org/10.1038/s41467-023-38933-4
  12. Front Oncol. 2023 ;13 1186539
    Crosstalk between arginine, glutamine, and the branched chain amino acid metabolism in the tumor microenvironment.
    Tanner J Wetzel, Sheila C Erfan, Lucas D Figueroa, Leighton M Wheeler, Elitsa A Ananieva.
      Arginine, glutamine, and the branched chain amino acids (BCAAs) are a focus of increased interest in the field of oncology due to their importance in the metabolic reprogramming of cancer cells. In the tumor microenvironment (TME), these amino acids serve to support the elevated biosynthetic and energy demands of cancer cells, while simultaneously maintaining the growth, homeostasis, and effector function of tumor-infiltrating immune cells. To escape immune destruction, cancer cells utilize a variety of mechanisms to suppress the cytotoxic activity of effector T cells, facilitating T cell exhaustion. One such mechanism is the ability of cancer cells to overexpress metabolic enzymes specializing in the catabolism of arginine, glutamine, and the BCAAs in the TME. The action of such enzymes supplies cancer cells with metabolic intermediates that feed into the TCA cycle, supporting energy generation, or providing precursors for purine, pyrimidine, and polyamine biosynthesis. Armed with substantial metabolic flexibility, cancer cells redirect amino acids from the TME for their own advantage and growth, while leaving the local infiltrating effector T cells deprived of essential nutrients. This review addresses the metabolic pressure that cancer cells exert over immune cells in the TME by up-regulating amino acid metabolism, while discussing opportunities for targeting amino acid metabolism for therapeutic intervention. Special emphasis is given to the crosstalk between arginine, glutamine, and BCAA metabolism in affording cancer cells with metabolic dominance in the TME.
    Keywords:  TME; arginine; glutamine; isoleucine; leucine; metabolism; valine
    DOI:  https://doi.org/10.3389/fonc.2023.1186539
  13. Immun Ageing. 2023 Jun 08. 20(1): 25
    Aging and chronic inflammation: highlights from a multidisciplinary workshop.
    Danay Saavedra, Ana Laura Añé-Kourí, Nir Barzilai, Calogero Caruso, Kyung-Hyun Cho, Luigi Fontana, Claudio Franceschi, Daniela Frasca, Nuris Ledón, Laura J Niedernhofer, Karla Pereira, Paul D Robbins, Alexa Silva, Gisela M Suarez, Wim Vanden Berghe, Thomas von Zglinicki, Graham Pawelec, Agustín Lage.
      Aging is a gradual, continuous series of natural changes in biological, physiological, immunological, environmental, psychological, behavioral, and social processes. Aging entails changes in the immune system characterized by a decrease in thymic output of naïve lymphocytes, an accumulated chronic antigenic stress notably caused by chronic infections such as cytomegalovirus (CMV), and immune cell senescence with acquisition of an inflammatory senescence-associated secretory phenotype (SASP). For this reason, and due to the SASP originating from other tissues, aging is commonly accompanied by low-grade chronic inflammation, termed "inflammaging". After decades of accumulating evidence regarding age-related processes and chronic inflammation, the domain now appears mature enough to allow an integrative reinterpretation of old data. Here, we provide an overview of the topics discussed in a recent workshop "Aging and Chronic Inflammation" to which many of the major players in the field contributed. We highlight advances in systematic measurement and interpretation of biological markers of aging, as well as their implications for human health and longevity and the interventions that can be envisaged to maintain or improve immune function in older people.
    Keywords:  Aging; Biomodulina T; Cell senescence; Chronic inflammation; Immunosenescence; Inflammaging; Metformin; SASP; Senolytic
    DOI:  https://doi.org/10.1186/s12979-023-00352-w
  14. Science. 2023 Jun 09. 380(6649): eabn9257
    Taurine deficiency as a driver of aging.
    Parminder Singh, Kishore Gollapalli, Stefano Mangiola, Daniela Schranner, Mohd Aslam Yusuf, Manish Chamoli, Sting L Shi, Bruno Lopes Bastos, Tripti Nair, Annett Riermeier, Elena M Vayndorf, Judy Z Wu, Aishwarya Nilakhe, Christina Q Nguyen, Michael Muir, Michael G Kiflezghi, Anna Foulger, Alex Junker, Jack Devine, Kunal Sharan, Shankar J Chinta, Swati Rajput, Anand Rane, Philipp Baumert, Martin Schönfelder, Francescopaolo Iavarone, Giorgia di Lorenzo, Swati Kumari, Alka Gupta, Rajesh Sarkar, Costerwell Khyriem, Amanpreet S Chawla, Ankur Sharma, Nazan Sarper, Naibedya Chattopadhyay, Bichitra K Biswal, Carmine Settembre, Perumal Nagarajan, Kimara L Targoff, Martin Picard, Sarika Gupta, Vidya Velagapudi, Anthony T Papenfuss, Alaattin Kaya, Miguel Godinho Ferreira, Brian K Kennedy, Julie K Andersen, Gordon J Lithgow, Abdullah Mahmood Ali, Arnab Mukhopadhyay, Aarno Palotie, Gabi Kastenmüller, Matt Kaeberlein, Henning Wackerhage, Bhupinder Pal, Vijay K Yadav.
      Aging is associated with changes in circulating levels of various molecules, some of which remain undefined. We find that concentrations of circulating taurine decline with aging in mice, monkeys, and humans. A reversal of this decline through taurine supplementation increased the health span (the period of healthy living) and life span in mice and health span in monkeys. Mechanistically, taurine reduced cellular senescence, protected against telomerase deficiency, suppressed mitochondrial dysfunction, decreased DNA damage, and attenuated inflammaging. In humans, lower taurine concentrations correlated with several age-related diseases and taurine concentrations increased after acute endurance exercise. Thus, taurine deficiency may be a driver of aging because its reversal increases health span in worms, rodents, and primates and life span in worms and rodents. Clinical trials in humans seem warranted to test whether taurine deficiency might drive aging in humans.
    DOI:  https://doi.org/10.1126/science.abn9257
  15. Bone Rep. 2023 Jun;18 101688
    Oxidative phosphorylation in bone cells.
    Elena Sabini, Lorenzo Arboit, Mohd Parvez Khan, Giulia Lanzolla, Ernestina Schipani.
      The role of energy metabolism in bone cells is an active field of investigation. Bone cells are metabolically very active and require high levels of energy in the form of adenosine triphosphate (ATP) to support their function. ATP is generated in the cytosol via glycolysis coupled with lactic acid fermentation and in the mitochondria via oxidative phosphorylation (OXPHOS). OXPHOS is the final convergent metabolic pathway for all oxidative steps of dietary nutrients catabolism. The formation of ATP is driven by an electrochemical gradient that forms across the mitochondrial inner membrane through to the activity of the electron transport chain (ETC) complexes and requires the presence of oxygen as the final electron acceptor. The current literature supports a model in which glycolysis is the main source of energy in undifferentiated mesenchymal progenitors and terminally differentiated osteoblasts, whereas OXPHOS appears relevant in an intermediate stage of differentiation of those cells. Conversely, osteoclasts progressively increase OXPHOS during differentiation until they become multinucleated and mitochondrial-rich terminal differentiated cells. Despite the abundance of mitochondria, mature osteoclasts are considered ATP-depleted, and the availability of ATP is a critical factor that regulates the low survival capacity of these cells, which rapidly undergo death by apoptosis. In addition to ATP, bioenergetic metabolism generates reactive oxygen species (ROS) and intermediate metabolites that regulate a variety of cellular functions, including epigenetics changes of genomic DNA and histones. This review will briefly discuss the role of OXPHOS and the cross-talks OXPHOS-glycolysis in the differentiation process of bone cells.
    Keywords:  Mitochondria; OXPHOS; Osteoblasts; Osteoclasts; Osteocytes
    DOI:  https://doi.org/10.1016/j.bonr.2023.101688
  16. Proc Natl Acad Sci U S A. 2023 Jun 13. 120(24): e2216310120
    ROS signaling-induced mitochondrial Sgk1 expression regulates epithelial cell renewal.
    Yingxiang Li, Chengdong Liu, Luke Rolling, Veronica Sikora, Zhimin Chen, Jack Gurwin, Caroline Barabell, Jiandie Lin, Cunming Duan.
      Many types of differentiated cells can reenter the cell cycle upon injury or stress. The underlying mechanisms are still poorly understood. Here, we investigated how quiescent cells are reactivated using a zebrafish model, in which a population of differentiated epithelial cells are reactivated under a physiological context. A robust and sustained increase in mitochondrial membrane potential was observed in the reactivated cells. Genetic and pharmacological perturbations show that elevated mitochondrial metabolism and ATP synthesis are critical for cell reactivation. Further analyses showed that elevated mitochondrial metabolism increases mitochondrial ROS levels, which induces Sgk1 expression in the mitochondria. Genetic deletion and inhibition of Sgk1 in zebrafish abolished epithelial cell reactivation. Similarly, ROS-dependent mitochondrial expression of SGK1 promotes S phase entry in human breast cancer cells. Mechanistically, SGK1 coordinates mitochondrial activity with ATP synthesis by phosphorylating F1Fo-ATP synthase. These findings suggest a conserved intramitochondrial signaling loop regulating epithelial cell renewal.
    Keywords:  F1Fo-ATP synthase; IGF/insulin signaling; mitochondrial membrane potential; reactive oxygen species; serum- and glucocorticoid-regulated kinase 1
    DOI:  https://doi.org/10.1073/pnas.2216310120
  17. bioRxiv. 2023 May 22. pii: 2023.05.22.541833. [Epub ahead of print]
    Mitochondrial citrate carrier SLC25A1 is a dosage-dependent regulator of metabolic reprogramming and morphogenesis in the developing heart.
    Chiemela Ohanele, Jessica N Peoples, Anja Karlstaedt, Joshua T Geiger, Ashley D Gayle, Nasab Ghazal, Fateemaa Sohani, Milton E Brown, Michael E Davis, George A Porter, Victor Faundez, Jennifer Q Kwong.
      The developing mammalian heart undergoes an important metabolic shift from glycolysis toward mitochondrial oxidation, such that oxidative phosphorylation defects may present with cardiac abnormalities. Here, we describe a new mechanistic link between mitochondria and cardiac morphogenesis, uncovered by studying mice with systemic loss of the mitochondrial citrate carrier SLC25A1. Slc25a1 null embryos displayed impaired growth, cardiac malformations, and aberrant mitochondrial function. Importantly, Slc25a1 haploinsufficient embryos, which are overtly indistinguishable from wild type, exhibited an increased frequency of these defects, suggesting Slc25a1 dose-dependent effects. Supporting clinical relevance, we found a near-significant association between ultrarare human pathogenic SLC25A1 variants and pediatric congenital heart disease. Mechanistically, SLC25A1 may link mitochondria to transcriptional regulation of metabolism through epigenetic control of PPARγ to promote metabolic remodeling in the developing heart. Collectively, this work positions SLC25A1 as a novel mitochondrial regulator of ventricular morphogenesis and cardiac metabolic maturation and suggests a role in congenital heart disease.
    DOI:  https://doi.org/10.1101/2023.05.22.541833
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