bims-imseme Biomed News
on Immunosenescence and T cell metabolism
Issue of 2021‒11‒28
twenty-one papers selected by
Pierpaolo Ginefra
Ludwig Institute for Cancer Research
  1. LSD1 inhibition sustains T cell invigoration with a durable response to PD-1 blockade.
  2. Mitochondrial aspartate regulates TNF biogenesis and autoimmune tissue inflammation.
  3. Enhancing CAR T Function with the Engineered Secretion of C. Perfringens Neuraminidase.
  4. Targeting Mitochondrial Metabolism as a Strategy to Treat Senescence.
  5. Immune ageing at single-cell resolution.
  6. High-throughput and high-dimensional single-cell analysis of antigen-specific CD8+ T cells.
  7. How Immunosenescence and Inflammaging May Contribute to Hyperinflammatory Syndrome in COVID-19.
  8. The Role of Immune Cells in Oxi-Inflamm-Aging.
  9. TCR-independent Activation in Presence of a Src-family Kinase Inhibitor Improves CAR-T Cell Product Attributes.
  10. Hematopoiesis under telomere attrition at the single-cell resolution.
  11. Metabolic Regulation of Inflammation and Its Resolution: Current Status, Clinical Needs, Challenges, and Opportunities.
  12. Single-Cell Transcriptomic Analysis Reveals a Tumor-Reactive T Cell Signature Associated With Clinical Outcome and Immunotherapy Response In Melanoma.
  13. Sirtuins as Metabolic Regulators of Immune Cells Phenotype and Function.
  14. Association between senescence of T cells and disease activity in patients with systemic lupus erythematosus.
  15. An Asp to Strike Out Cancer? Therapeutic Possibilities Arising from Aspartate's Emerging Roles in Cell Proliferation and Survival.
  16. Microtubule-Based Mitochondrial Dynamics as a Valuable Therapeutic Target in Cancer.
  17. miR-99a regulates CD4+ T cell differentiation and attenuates experimental autoimmune encephalomyelitis by mTOR-mediated glycolysis.
  18. Micro but mighty-Micronutrients in the epigenetic regulation of adaptive immune responses.
  19. Mitochondrial signals regulate ER size and TNF production in rheumatoid arthritis.
  20. Quantitative high-confidence human mitochondrial proteome and its dynamics in cellular context.
  21. LARP7 ameliorates cellular senescence and aging by allosterically enhancing SIRT1 deacetylase activity.
  1. Nat Commun. 2021 Nov 24. 12(1): 6831
    LSD1 inhibition sustains T cell invigoration with a durable response to PD-1 blockade.
    Yi Liu, Brian Debo, Mingfeng Li, Zhennan Shi, Wanqiang Sheng, Yang Shi.
      Exhausted CD8+ T cells are key targets of immune checkpoint blockade therapy and their ineffective reinvigoration limits the durable benefit in some cancer patients. Here, we demonstrate that histone demethylase LSD1 acts to enforce an epigenetic program in progenitor exhausted CD8+ T cells to antagonize the TCF1-mediated progenitor maintenance and to promote terminal differentiation. Consequently, genetic perturbation or small molecules targeting LSD1 increases the persistence of the progenitor exhausted CD8+ T cells, which provide a sustained source for the proliferative conversion to numerically larger terminally exhausted T cells with tumor-killing cytotoxicity, thereby leading to effective and durable responses to anti-PD1 therapy. Collectively, our findings provide important insights into epigenetic mechanisms that regulate T cell exhaustion and have important implications for durable immunotherapy.
    DOI:  https://doi.org/10.1038/s41467-021-27179-7
  2. Nat Immunol. 2021 Nov 22.
    Mitochondrial aspartate regulates TNF biogenesis and autoimmune tissue inflammation.
    Bowen Wu, Tuantuan V Zhao, Ke Jin, Zhaolan Hu, Matthew P Abdel, Ken J Warrington, Jörg J Goronzy, Cornelia M Weyand.
      Misdirected immunity gives rise to the autoimmune tissue inflammation of rheumatoid arthritis, in which excess production of the cytokine tumor necrosis factor (TNF) is a central pathogenic event. Mechanisms underlying the breakdown of self-tolerance are unclear, but T cells in the arthritic joint have a distinctive metabolic signature of ATPlo acetyl-CoAhi proinflammatory effector cells. Here we show that a deficiency in the production of mitochondrial aspartate is an important abnormality in these autoimmune T cells. Shortage of mitochondrial aspartate disrupted the regeneration of the metabolic cofactor nicotinamide adenine dinucleotide, causing ADP deribosylation of the endoplasmic reticulum (ER) sensor GRP78/BiP. As a result, ribosome-rich ER membranes expanded, promoting co-translational translocation and enhanced biogenesis of transmembrane TNF. ERrich T cells were the predominant TNF producers in the arthritic joint. Transfer of intact mitochondria into T cells, as well as supplementation of exogenous aspartate, rescued the mitochondria-instructed expansion of ER membranes and suppressed TNF release and rheumatoid tissue inflammation.
    DOI:  https://doi.org/10.1038/s41590-021-01065-2
  3. Mol Ther. 2021 Nov 20. pii: S1525-0016(21)00585-2. [Epub ahead of print]
    Enhancing CAR T Function with the Engineered Secretion of C. Perfringens Neuraminidase.
    Joseph S Durgin, Radhika Thokala, Lexus Johnson, Edward Song, John Leferovich, Vijay Bhoj, Saba Ghassemi, Michael Milone, Zev Binder, Donald M O'Rourke, Roddy S O'Connor.
      Prior to adoptive transfer, CAR T cells are activated, lentivirally infected with CAR transgenes, and expanded over 9-11 days. An unintended consequence of this process is the progressive differentiation of CAR T cells over time in culture. Differentiated T cells engraft poorly which limits their ability to persist and provide sustained tumor control in hematologic as well as solid tumors. Solid tumors include other barriers to CAR T cell therapies including immune and metabolic checkpoints that suppress effector function and durability. Sialic acids are ubiquitous surface molecules with known immune checkpoint functions. The enzyme C. Perfringens neuraminidase (CpNA) removes sialic acid residues from target cells, with good activity at physiologic conditions. In combination with galactose oxidase (GO), NA has been found to stimulate T cell mitogenesis and cytotoxicity in vitro. Here we determine if CpNA, alone, and in combination with GO, promotes CAR-T cell anti-tumor efficacy. We show that CpNA restrains CAR T cell differentiation during ex-vivo culture, giving rise to progeny with enhanced therapeutic potential. CAR T-cells expressing CpNA have superior effector function and cytotoxicity in vitro. In a Nalm-6 xenograft model of leukemia, CAR T-cells expressing CpNA show enhanced anti-tumor efficacy. Arming CAR T cells with CpNA also enhanced tumor control in xenograft models of glioblastoma as well as syngeneic model of melanoma. Given our findings, we hypothesize that charge repulsion via surface glycans is a regulatory parameter influencing differentiation. As T cells engage target cells within tumors, and undergo constitutive activation through their CARs, critical thresholds of negative charge may impede cell-cell interactions underlying synapse formation and cytolysis. Removing the dense pool of negative cell-surface charge with CpNA is an effective approach to limit CAR T cell differentiation and enhance overall persistence and efficacy.
    DOI:  https://doi.org/10.1016/j.ymthe.2021.11.014
  4. Cells. 2021 Nov 03. pii: 3003. [Epub ahead of print]10(11):
    Targeting Mitochondrial Metabolism as a Strategy to Treat Senescence.
    Yun Haeng Lee, Ji Yun Park, Haneur Lee, Eun Seon Song, Myeong Uk Kuk, Junghyun Joo, Sekyung Oh, Hyung Wook Kwon, Joon Tae Park, Sang Chul Park.
      Mitochondria are one of organelles that undergo significant changes associated with senescence. An increase in mitochondrial size is observed in senescent cells, and this increase is ascribed to the accumulation of dysfunctional mitochondria that generate excessive reactive oxygen species (ROS). Such dysfunctional mitochondria are prime targets for ROS-induced damage, which leads to the deterioration of oxidative phosphorylation and increased dependence on glycolysis as an energy source. Based on findings indicating that senescent cells exhibit mitochondrial metabolic alterations, a strategy to induce mitochondrial metabolic reprogramming has been proposed to treat aging and age-related diseases. In this review, we discuss senescence-related mitochondrial changes and consequent mitochondrial metabolic alterations. We assess the significance of mitochondrial metabolic reprogramming for senescence regulation and propose the appropriate control of mitochondrial metabolism to ameliorate senescence. Learning how to regulate mitochondrial metabolism will provide knowledge for the control of aging and age-related pathologies. Further research focusing on mitochondrial metabolic reprogramming will be an important guide for the development of anti-aging therapies, and will provide novel strategies for anti-aging interventions.
    Keywords:  ROS; mitochondria; mitochondrial metabolic reprogramming; senescence amelioration
    DOI:  https://doi.org/10.3390/cells10113003
  5. Nat Rev Immunol. 2021 Nov 23.
    Immune ageing at single-cell resolution.
    Denis A Mogilenko, Irina Shchukina, Maxim N Artyomov.
      Ageing leads to profound alterations in the immune system and increases susceptibility to some chronic, infectious and autoimmune diseases. In recent years, widespread application of single-cell techniques has enabled substantial progress in our understanding of the ageing immune system. These comprehensive approaches have expanded and detailed the current views of ageing and immunity. Here we review a body of recent studies that explored how the immune system ages using unbiased profiling techniques at single-cell resolution. Specifically, we discuss an emergent understanding of age-related alterations in innate and adaptive immune cell populations, antigen receptor repertoires and immune cell-supporting microenvironments of the peripheral tissues. Focusing on the results obtained in mice and humans, we describe the multidimensional data that align with established concepts of immune ageing as well as novel insights emerging from these studies. We further discuss outstanding questions in the field and highlight techniques that will advance our understanding of immune ageing in the future.
    DOI:  https://doi.org/10.1038/s41577-021-00646-4
  6. Nat Immunol. 2021 Nov 22.
    High-throughput and high-dimensional single-cell analysis of antigen-specific CD8+ T cells.
    Ke-Yue Ma, Alexandra A Schonnesen, Chenfeng He, Amanda Y Xia, Eric Sun, Eunise Chen, Katherine R Sebastian, Yu-Wan Guo, Robert Balderas, Mrinalini Kulkarni-Date, Ning Jiang.
      Although critical to T cell function, antigen specificity is often omitted in high-throughput multiomics-based T cell profiling due to technical challenges. We describe a high-dimensional, tetramer-associated T cell antigen receptor (TCR) sequencing (TetTCR-SeqHD) method to simultaneously profile cognate antigen specificities, TCR sequences, targeted gene expression and surface-protein expression from tens of thousands of single cells. Using human polyclonal CD8+ T cells with known antigen specificity and TCR sequences, we demonstrate over 98% precision for detecting the correct antigen specificity. We also evaluate gene expression and phenotypic differences among antigen-specific CD8+ T cells and characterize phenotype signatures of influenza- and Epstein-Barr virus-specific CD8+ T cells that are unique to their pathogen targets. Moreover, with the high-throughput capacity of profiling hundreds of antigens simultaneously, we apply TetTCR-SeqHD to identify antigens that preferentially enrich cognate CD8+ T cells in patients with type 1 diabetes compared to healthy controls and discover a TCR that cross-reacts with diabetes-related and microbiome antigens. TetTCR-SeqHD is a powerful approach for profiling T cell responses in humans and mice.
    DOI:  https://doi.org/10.1038/s41590-021-01073-2
  7. Int J Mol Sci. 2021 Nov 21. pii: 12539. [Epub ahead of print]22(22):
    How Immunosenescence and Inflammaging May Contribute to Hyperinflammatory Syndrome in COVID-19.
    Ludmila Müller, Svetlana Di Benedetto.
      Aging is characterized by the dynamic remodeling of the immune system designated "immunosenescence," and is associated with altered hematopoiesis, thymic involution, and lifelong immune stimulation by multitudinous chronic stressors, including the cytomegalovirus (CMV). Such alterations may contribute to a lowered proportion of naïve T-cells and to reduced diversity of the T-cell repertoire. In the peripheral circulation, a shift occurs towards accumulations of T and B-cell populations with memory phenotypes, and to accumulation of putatively senescent and exhausted immune cells. The aging-related accumulations of functionally exhausted memory T lymphocytes, commonly secreting pro-inflammatory cytokines, together with mediators and factors of the innate immune system, are considered to contribute to the low-grade inflammation (inflammaging) often observed in elderly people. These senescent immune cells not only secrete inflammatory mediators, but are also able to negatively modulate their environments. In this review, we give a short summary of the ways that immunosenescence, inflammaging, and CMV infection may cause insufficient immune responses, contribute to the establishment of the hyperinflammatory syndrome and impact the severity of the coronavirus disease 2019 (COVID-19) in elderly people.
    Keywords:  CMV; COVID-19; aging; cytokine storm; hyperinflammatory syndrome; immunosenescence; inflammaging; senescence-associated secretory phenotype (SASP)
    DOI:  https://doi.org/10.3390/ijms222212539
  8. Cells. 2021 Nov 01. pii: 2974. [Epub ahead of print]10(11):
    The Role of Immune Cells in Oxi-Inflamm-Aging.
    Irene Martínez de Toda, Noemi Ceprián, Estefanía Díaz-Del Cerro, Mónica De la Fuente.
      Aging is the result of the deterioration of the homeostatic systems (nervous, endocrine, and immune systems), which preserve the organism's health. We propose that the age-related impairment of these systems is due to the establishment of a chronic oxidative stress situation that leads to low-grade chronic inflammation throughout the immune system's activity. It is known that the immune system weakens with age, which increases morbidity and mortality. In this context, we describe how the function of immune cells can be used as an indicator of the rate of aging of an individual. In addition to this passive role as a marker, we describe how the immune system can work as a driver of aging by amplifying the oxidative-inflammatory stress associated with aging (oxi-inflamm-aging) and inducing senescence in far tissue cells. Further supporting our theory, we discuss how certain lifestyle conditions (such as social environment, nutrition, or exercise) can have an impact on longevity by affecting the oxidative and inflammatory state of immune cells, regulating immunosenescence and its contribution to oxi-inflamm-aging.
    Keywords:  aging; biological age; immune cells; inflammatory stress; oxidative stress
    DOI:  https://doi.org/10.3390/cells10112974
  9. J Immunother. 2021 Nov 22.
    TCR-independent Activation in Presence of a Src-family Kinase Inhibitor Improves CAR-T Cell Product Attributes.
    Gauri Lamture, Alan Baer, Joseph W Fischer, Winston Colon-Moran, Nirjal Bhattarai.
      Chimeric antigen receptor expressing T cells (CAR-T cells) have shown remarkable efficacy against some blood cancers and have potential to treat many other human diseases. During CAR-T cell manufacturing, T cells are activated via engagement of the T-cell receptor (TCR); however, persistent TCR engagement can induce unchecked activation, differentiation, and exhaustion, which can negatively affect CAR-T cell product quality and in vivo potency. In addition, T cells may not uniformly respond to TCR-dependent activation (TCRD) contributing to lot-to-lot variability, poor expansion, and manufacturing failures. TCRD also presents challenges during manufacturing of allogeneic CAR-T cells when endogenous TCR is deleted to prevent graft-versus-host disease. Thus, novel strategies to activate T cells may help improve CAR-T cell product attributes and reduce manufacturing failures. In this study, we compared the effect of TCRD and TCR-independent activation (TCRI) on CAR-T cell product attributes. We found that TCRI in presence of a Src-kinase inhibitor significantly improved CAR-T cell expansion and yield without affecting viability and CD4/CD8 ratio. Markers of T-cell activation, exhaustion and differentiation were also reduced in these CAR-T cells compared with CAR-T cells manufactured by TCRD. TCRI did not affect CAR-T cell in vitro potency; however, following co-culture with target cells, CAR-T cells manufactured by TCRI released significantly less inflammatory cytokines compared with CAR-T cells manufactured by TCRD. Together, these data suggest that manufacturing CAR-T cells by TCRI activation in the presence of a Src-kinase inhibitor improves product quality attributes and may help reduce manufacturing failures and improve CAR-T cell safety and efficacy in vivo.
    DOI:  https://doi.org/10.1097/CJI.0000000000000402
  10. Nat Commun. 2021 Nov 25. 12(1): 6850
    Hematopoiesis under telomere attrition at the single-cell resolution.
    Natthakan Thongon, Feiyang Ma, Andrea Santoni, Matteo Marchesini, Elena Fiorini, Ashley Rose, Vera Adema, Irene Ganan-Gomez, Emma M Groarke, Fernanda Gutierrez-Rodrigues, Shuaitong Chen, Pamela Lockyer, Sarah Schneider, Carlos Bueso-Ramos, Guillermo Montalban-Bravo, Caleb A Class, Kelly A Soltysiak, Matteo Pellegrini, Ergun Sahin, Alison A Bertuch, Courtney D DiNardo, Guillermo Garcia-Manero, Neal S Young, Karen Dwyer, Simona Colla.
      The molecular mechanisms that drive hematopoietic stem cell functional decline under conditions of telomere shortening are not completely understood. In light of recent advances in single-cell technologies, we sought to redefine the transcriptional and epigenetic landscape of mouse and human hematopoietic stem cells under telomere attrition, as induced by pathogenic germline variants in telomerase complex genes. Here, we show that telomere attrition maintains hematopoietic stem cells under persistent metabolic activation and differentiation towards the megakaryocytic lineage through the cell-intrinsic upregulation of the innate immune signaling response, which directly compromises hematopoietic stem cells' self-renewal capabilities and eventually leads to their exhaustion. Mechanistically, we demonstrate that targeting members of the Ifi20x/IFI16 family of cytosolic DNA sensors using the oligodeoxynucleotide A151, which comprises four repeats of the TTAGGG motif of the telomeric DNA, overcomes interferon signaling activation in telomere-dysfunctional hematopoietic stem cells and these cells' skewed differentiation towards the megakaryocytic lineage. This study challenges the historical hypothesis that telomere attrition limits the proliferative potential of hematopoietic stem cells by inducing apoptosis, autophagy, or senescence, and suggests that targeting IFI16 signaling axis might prevent hematopoietic stem cell functional decline in conditions affecting telomere maintenance.
    DOI:  https://doi.org/10.1038/s41467-021-27206-7
  11. J Immunol. 2021 12 01. 207(11): 2625-2630
    Metabolic Regulation of Inflammation and Its Resolution: Current Status, Clinical Needs, Challenges, and Opportunities.
    Pushpa Tandon, Natalie D Abrams, Danielle M Carrick, Preethi Chander, Johanna Dwyer, Rebecca Fuldner, Gallya Gannot, Maren Laughlin, George McKie, Mercy PrabhuDas, Anju Singh, Shang-Yi Anne Tsai, Merriline M Vedamony, Chiayeng Wang, Christina H Liu.
      Metabolism and inflammation have been viewed as two separate processes with distinct but critical functions for our survival: metabolism regulates the utilization of nutrients, and inflammation is responsible for defense and repair. Both respond to an organism's stressors to restore homeostasis. The interplay between metabolic status and immune response (immunometabolism) plays an important role in maintaining health or promoting disease development. Understanding these interactions is critical in developing tools for facilitating novel preventative and therapeutic approaches for diseases, including cancer. This trans-National Institutes of Health workshop brought together basic scientists, technology developers, and clinicians to discuss state-of-the-art, innovative approaches, challenges, and opportunities to understand and harness immunometabolism in modulating inflammation and its resolution.
    DOI:  https://doi.org/10.4049/jimmunol.2100829
  12. Front Immunol. 2021 ;12 758288
    Single-Cell Transcriptomic Analysis Reveals a Tumor-Reactive T Cell Signature Associated With Clinical Outcome and Immunotherapy Response In Melanoma.
    Min Yan, Jing Hu, Yanyan Ping, Liwen Xu, Gaoming Liao, Zedong Jiang, Bo Pang, Shangqin Sun, Yunpeng Zhang, Yun Xiao, Xia Li.
      The infiltration of tumor-reactive T cells in the tumor site is associated with better survival and immunotherapy response. However, tumor-reactive T cells were often represented by the infiltration of total CD8+ T cells, which was confounded by the presence of bystander T cells. To identify tumor-reactive T cells at the cancer lesion, we performed integration analyses of three scRNA-seq data sets of T cells in melanoma. Extensive heterogeneous functional states of T cells were revealed in the tumor microenvironment. Among these states, we identified a subset of tumor-reactive T cells which specifically expressed tumor-reactive markers and T cell activation signature, and were strongly enriched for larger T cell receptor (TCR) clones. We further identified and validated a tumor-reactive T cell signature (TRS) to evaluate the tumor reactivity of T cells in tumor patients. Patients with high TRS scores have strong immune activity and high mutation burden in the TCGA-SKCM cohort. We also demonstrated a significant association of the TRS with the clinical outcomes of melanoma patients, with higher TRS scores representing better survival, which was validated in four external independent cohorts. Furthermore, the TRS scores exhibited greater performance on prognosis prediction than infiltration levels of CD8+ T cells and previously published prognosis-related signatures. Finally, we observed the capability of TRS to predict immunotherapy response in melanoma. Together, based on integrated analysis of single-cell RNA-sequencing, we developed and validated a tumor-reactive-related signature that demonstrated significant association with clinical outcomes and response to immunotherapy.
    Keywords:  exhausted T cells; immunotherapy; melanoma; tumor reactivity; tumor-infiltrating T cells
    DOI:  https://doi.org/10.3389/fimmu.2021.758288
  13. Genes (Basel). 2021 Oct 26. pii: 1698. [Epub ahead of print]12(11):
    Sirtuins as Metabolic Regulators of Immune Cells Phenotype and Function.
    Lídia Fortuny, Carlos Sebastián.
      Beyond its role on the conversion of nutrients into energy and biomass, cellular metabolism is actively involved in the control of many physiological processes. Among these, it is becoming increasingly evident that specific metabolic pathways are associated with the phenotype of several immune cell types and, importantly, are crucial in controlling their differentiation, proliferation, and effector functions, thus shaping the immune response against pathogens and tumors. In this context, data generated over the last decade have uncovered mammalian sirtuins as important regulators of cellular metabolism, immune cell function, and cancer. Here, we summarize our current knowledge on the roles of this family of protein deacylases on the metabolic control of immune cells and their implications on immune-related diseases and cancer.
    Keywords:  immune cells; immune-related diseases; metabolism; sirtuins
    DOI:  https://doi.org/10.3390/genes12111698
  14. Reumatologia. 2021 ;59(5): 292-301
    Association between senescence of T cells and disease activity in patients with systemic lupus erythematosus.
    Handono Kalim, Cesarius Singgih Wahono, Bunga Petriana Oktarini Permana, Mirza Zaka Pratama, Kusworini Handono.
      Objectives: Systemic lupus erythematosus (SLE) patients are predisposed to chronic immune activation, leading to accelerated immunosenescence. The aging of the immune system causes the T cells to express several senescence markers such as CD57 and KLRG1, which produce pro-inflammatory cytokine interferon γ (IFN-γ). Immunosenescence was associated with high morbidity and mortality in other diseases. This research was conducted to prove the association between senescent T cells and SLE disease activity.Material and methods: This research was an observational cross-sectional study on 53 women aged 16-45 years diagnosed with SLE based on SLICC 2012 criteria. All subjects were recorded for demographic and clinical data, and their SLE disease activity index (SLEDAI) score was measured to evaluate disease activity. Active disease was defined as SLEDAI score ≥ 3. The CD57 antigen and KLRG1 expression on CD4+ and CD8+ T cells were calculated from peripheral blood mononuclear cells (PBMC) by flow cytometry. Interferon γ was measured from serum using ELISA. The comparison was done using the Mann-Whitney U test, and correlation was tested using the Spearman test. Associations between variables were calculated using linear regression models.
    Results: Systemic lupus erythematosus patients with active disease had markedly higher CD4+KLRG1+ (3.1 [1.3-5.5]% vs. 0.3 [0.1-0.5]%), CD8+CD57+ (11.6 ±7.1% vs. 2.4 ±2.0%, p = 0.000), and CD8+KLRG1+ T cell percentages (13.7 ±7.5% vs. 0.3 ±0.1%, p = 0.000), and IFN- γ levels (208.9 [148.3-233.8] vs. 146.7 [130.2-210.8] pg/ml, p = 0.048), compared to the inactive patients. Positive correlation and association was found between the CD8+CD57+ and CD8+KLRG1+ percentages with the SLEDAI score (p = 0.007 and p = 0.007, for the linear regression analysis, respectively).
    Conclusions: Systemic lupus erythematosus patients showed significantly higher senescence T cell markers compared to controls, and the increase of T cell senescence, especially in the CD8 compartment, has some association with increased disease activity in patients with SLE.
    Keywords:  T cell senescence; immunosenescence; systemic lupus erythematosus; systemic lupus erythematosus disease activity index
    DOI:  https://doi.org/10.5114/reum.2021.110318
  15. Biomolecules. 2021 Nov 10. pii: 1666. [Epub ahead of print]11(11):
    An Asp to Strike Out Cancer? Therapeutic Possibilities Arising from Aspartate's Emerging Roles in Cell Proliferation and Survival.
    Iiro Taneli Helenius, Hanumantha Rao Madala, Jing-Ruey Joanna Yeh.
      A better understanding of the metabolic constraints of a tumor may lead to more effective anticancer treatments. Evidence has emerged in recent years shedding light on a crucial aspartate dependency of many tumor types. As a precursor for nucleotide synthesis, aspartate is indispensable for cell proliferation. Moreover, the malate-aspartate shuttle plays a key role in redox balance, and a deficit in aspartate can lead to oxidative stress. It is now recognized that aspartate biosynthesis is largely governed by mitochondrial metabolism, including respiration and glutaminolysis in cancer cells. Therefore, under conditions that suppress mitochondrial metabolism, including mutations, hypoxia, or chemical inhibitors, aspartate can become a limiting factor for tumor growth and cancer cell survival. Notably, aspartate availability has been associated with sensitivity or resistance to various therapeutics that are presently in the clinic or in clinical trials, arguing for a critical need for more effective aspartate-targeting approaches. In this review, we present current knowledge of the metabolic roles of aspartate in cancer cells and describe how cancer cells maintain aspartate levels under different metabolic states. We also highlight several promising aspartate level-modulating agents that are currently under investigation.
    Keywords:  GOT1; alpha-ketoglutarate; asparagine; aspartate; cancer metabolism; glutaminase; hypoxia; mitochondrial DNA mutation; mitochondrial respiration; oxidative phosphorylation
    DOI:  https://doi.org/10.3390/biom11111666
  16. Cancers (Basel). 2021 Nov 19. pii: 5812. [Epub ahead of print]13(22):
    Microtubule-Based Mitochondrial Dynamics as a Valuable Therapeutic Target in Cancer.
    Rosa Vona, Anna Maria Mileo, Paola Matarrese.
      Mitochondria constitute an ever-reorganizing dynamic network that plays a key role in several fundamental cellular functions, including the regulation of metabolism, energy production, calcium homeostasis, production of reactive oxygen species, and programmed cell death. Each of these activities can be found to be impaired in cancer cells. It has been reported that mitochondrial dynamics are actively involved in both tumorigenesis and metabolic plasticity, allowing cancer cells to adapt to unfavorable environmental conditions and, thus, contributing to tumor progression. The mitochondrial dynamics include fusion, fragmentation, intracellular trafficking responsible for redistributing the organelle within the cell, biogenesis, and mitophagy. Although the mitochondrial dynamics are driven by the cytoskeleton-particularly by the microtubules and the microtubule-associated motor proteins dynein and kinesin-the molecular mechanisms regulating these complex processes are not yet fully understood. More recently, an exchange of mitochondria between stromal and cancer cells has also been described. The advantage of mitochondrial transfer in tumor cells results in benefits to cell survival, proliferation, and spreading. Therefore, understanding the molecular mechanisms that regulate mitochondrial trafficking can potentially be important for identifying new molecular targets in cancer therapy to interfere specifically with tumor dissemination processes.
    Keywords:  cancer bioenergetics; microtubules; mitochondria dynamics; mitophagy; tunneling nanotubes
    DOI:  https://doi.org/10.3390/cancers13225812
  17. Mol Ther Nucleic Acids. 2021 Dec 03. 26 1173-1185
    miR-99a regulates CD4+ T cell differentiation and attenuates experimental autoimmune encephalomyelitis by mTOR-mediated glycolysis.
    Yuting Gu, Hong Zhou, Hongshuang Yu, Wanlin Yang, Bei Wang, Fengtao Qian, Yiji Cheng, Shan He, Xiaonan Zhao, Linqiao Zhu, Yanyun Zhang, Min Jin, Eryi Lu.
      Multiple microRNAs exhibit diverse functions to regulate inflammatory and autoimmune diseases. MicroRNA-99a (miR-99a) has been shown to be involved in adipose tissue inflammation and to be downregulated in the inflammatory lesions of autoimmune diseases rheumatoid arthritis and systemic lupus erythematosus. In this study, we found that miR-99a was downregulated in CD4+ T cells from experimental autoimmune encephalomyelitis (EAE) mice, an animal model of multiple sclerosis. Overexpression of miR-99a alleviated EAE development by promoting regulator T cells and inhibiting T helper type 1 (Th1) cell differentiation. Bioinformatics and functional analyses further revealed that the anti-inflammatory effects of miR-99a was attributable to its role in negatively regulating glycolysis reprogramming of CD4+ T cells by targeting the mTOR pathway. Additionally, miR-99a expression was induced by transforming growth factor β (TGF-β) to regulate CD4+ T cell glycolysis and differentiation. Taken together, our results characterize a pivotal role of miR-99a in regulating CD4+ T cell differentiation and glycolysis reprogramming during EAE development, which may indicate that miR-99a is a promising therapeutic target for the amelioration of multiple sclerosis and possibly other autoimmune diseases.
    Keywords:  EAE; T-cell differentiation; TGF-β; glycolysis; mTOR; miR-99a
    DOI:  https://doi.org/10.1016/j.omtn.2021.07.010
  18. Immunol Rev. 2021 Nov 24.
    Micro but mighty-Micronutrients in the epigenetic regulation of adaptive immune responses.
    Heng-Yi Chen, Michael Hsu, Chan-Wang Jerry Lio.
      Micronutrients are essential small molecules required by organisms in minute quantity for survival. For instance, vitamins and minerals, the two major categories of micronutrients, are central for biological processes such as metabolism, cell replication, differentiation, and immune response. Studies estimated that around two billion humans worldwide suffer from micronutrient deficiencies, also known as "hidden hunger," linked to weakened immune responses. While micronutrients affect the immune system at multiple levels, recent studies showed that micronutrients potentially impact the differentiation and function of immune cells as cofactors for epigenetic enzymes, including the 2-oxoglutarate-dependent dioxygenase (2OGDD) family involved in histone and DNA demethylation. Here, we will first provide an overview of the role of DNA methylation in T cells and B cells, followed by the micronutrients ascorbate (vitamin C) and iron, two critical cofactors for 2OGDD. We will discuss the emerging evidence of these micronutrients could regulate adaptive immune response by influencing epigenetic remodeling.
    Keywords:  B cells; DNA methylation; T cells; epigenetics; iron; micronutrients; vitamin C
    DOI:  https://doi.org/10.1111/imr.13045
  19. Nat Immunol. 2021 Nov 22.
    Mitochondrial signals regulate ER size and TNF production in rheumatoid arthritis.
      
    DOI:  https://doi.org/10.1038/s41590-021-01070-5
  20. Cell Metab. 2021 Nov 12. pii: S1550-4131(21)00529-5. [Epub ahead of print]
    Quantitative high-confidence human mitochondrial proteome and its dynamics in cellular context.
    Marcel Morgenstern, Christian D Peikert, Philipp Lübbert, Ida Suppanz, Cinzia Klemm, Oliver Alka, Conny Steiert, Nataliia Naumenko, Alexander Schendzielorz, Laura Melchionda, Wignand W D Mühlhäuser, Bettina Knapp, Jakob D Busch, Sebastian B Stiller, Stefan Dannenmaier, Caroline Lindau, Mariya Licheva, Christopher Eickhorst, Riccardo Galbusera, Ralf M Zerbes, Michael T Ryan, Claudine Kraft, Vera Kozjak-Pavlovic, Friedel Drepper, Sven Dennerlein, Silke Oeljeklaus, Nikolaus Pfanner, Nils Wiedemann, Bettina Warscheid.
      Mitochondria are key organelles for cellular energetics, metabolism, signaling, and quality control and have been linked to various diseases. Different views exist on the composition of the human mitochondrial proteome. We classified >8,000 proteins in mitochondrial preparations of human cells and defined a mitochondrial high-confidence proteome of >1,100 proteins (MitoCoP). We identified interactors of translocases, respiratory chain, and ATP synthase assembly factors. The abundance of MitoCoP proteins covers six orders of magnitude and amounts to 7% of the cellular proteome with the chaperones HSP60-HSP10 being the most abundant mitochondrial proteins. MitoCoP dynamics spans three orders of magnitudes, with half-lives from hours to months, and suggests a rapid regulation of biosynthesis and assembly processes. 460 MitoCoP genes are linked to human diseases with a strong prevalence for the central nervous system and metabolism. MitoCoP will provide a high-confidence resource for placing dynamics, functions, and dysfunctions of mitochondria into the cellular context.
    Keywords:  Mitochondria; complexome; copy numbers; disease; half-lives; high-confidence proteome; human cells; protein translocation; respiratory chain; smORFs
    DOI:  https://doi.org/10.1016/j.cmet.2021.11.001
  21. Cell Rep. 2021 Nov 23. pii: S2211-1247(21)01520-5. [Epub ahead of print]37(8): 110038
    LARP7 ameliorates cellular senescence and aging by allosterically enhancing SIRT1 deacetylase activity.
    Pengyi Yan, Zixuan Li, Junhao Xiong, Zilong Geng, Weiting Wei, Yan Zhang, Gengze Wu, Tao Zhuang, Xiaoyu Tian, Zhijie Liu, Junling Liu, Kun Sun, Fengyuan Chen, Yuzhen Zhang, Chunyu Zeng, Yu Huang, Bing Zhang.
      Cellular senescence is associated with pleiotropic physiopathological processes, including aging and age-related diseases. The persistent DNA damage is a major stress leading to senescence, but the underlying molecular link remains elusive. Here, we identify La Ribonucleoprotein 7 (LARP7), a 7SK RNA binding protein, as an aging antagonist. DNA damage-mediated Ataxia Telangiectasia Mutated (ATM) activation triggers the extracellular shuttling and downregulation of LARP7, which dampens SIRT1 deacetylase activity, enhances p53 and NF-κB (p65) transcriptional activity by augmenting their acetylation, and thereby accelerates cellular senescence. Deletion of LARP7 leads to senescent cell accumulation and premature aging in rodent model. Furthermore, we show this ATM-LARP7-SIRT1-p53/p65 senescence axis is active in vascular senescence and atherogenesis, and preventing its activation substantially alleviates senescence and atherogenesis. Together, this study identifies LARP7 as a gatekeeper of senescence, and the altered ATM-LARP7-SIRT1-p53/p65 pathway plays an important role in DNA damage response (DDR)-mediated cellular senescence and atherosclerosis.
    Keywords:  DNA damage; LARP7; aging; atherosclerosis; senescence
    DOI:  https://doi.org/10.1016/j.celrep.2021.110038
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