bims-mireme Biomed News
on Mitochondria in regenerative medicine
Issue of 2021–08–29
nine papers selected by
Brian Spurlock, The University of North Carolina at Chapel Hill
  1. Autophagy and Metabolism in Normal and Malignant Hematopoiesis.
  2. Aspartate availability limits hematopoietic stem cell function during hematopoietic regeneration.
  3. High Glycolytic Activity Enhances Stem Cell Reprogramming of Fahd1-KO Mouse Embryonic Fibroblasts.
  4. Metabolic plasticity drives development during mammalian embryogenesis.
  5. Physiological Signaling Functions of Reactive Oxygen Species in Stem Cells: From Flies to Man.
  6. Requirements for successful mitochondrial transplantation.
  7. Cell cycle induction in human cardiomyocytes is dependent on biosynthetic pathway activation.
  8. Decreased PGC1β expression results in disrupted human erythroid differentiation, impaired hemoglobinization and cell cycle exit.
  9. QuinoMit Q10-Fluid attenuates hydrogen peroxide-induced irregular beating in mouse pluripotent stem cell-derived cardiomyocytes.
  1. Int J Mol Sci. 2021 Aug 09. pii: 8540. [Epub ahead of print]22(16):
    Autophagy and Metabolism in Normal and Malignant Hematopoiesis.
    Ioanna E Stergiou, Efstathia K Kapsogeorgou.
      The hematopoietic system relies on regulation of both metabolism and autophagy to maintain its homeostasis, ensuring the self-renewal and multipotent differentiation potential of hematopoietic stem cells (HSCs). HSCs display a distinct metabolic profile from that of their differentiated progeny, while metabolic rewiring from glycolysis to oxidative phosphorylation (OXPHOS) has been shown to be crucial for effective hematopoietic differentiation. Autophagy-mediated regulation of metabolism modulates the distinct characteristics of quiescent and differentiating hematopoietic cells. In particular, mitophagy determines the cellular mitochondrial content, thus modifying the level of OXPHOS at the different differentiation stages of hematopoietic cells, while, at the same time, it ensures the building blocks and energy for differentiation. Aberrations in both the metabolic status and regulation of the autophagic machinery are implicated in the development of hematologic malignancies, especially in leukemogenesis. In this review, we aim to investigate the role of metabolism and autophagy, as well as their interconnections, in normal and malignant hematopoiesis.
    Keywords:  autophagy; hematopoiesis; hematopoietic stem cells; leukemia; metabolism; mitophagy
    DOI:  https://doi.org/10.3390/ijms22168540
  2. Cell Stem Cell. 2021 Aug 21. pii: S1934-5909(21)00296-4. [Epub ahead of print]
    Aspartate availability limits hematopoietic stem cell function during hematopoietic regeneration.
    Le Qi, Misty S Martin-Sandoval, Salma Merchant, Wen Gu, Matthias Eckhardt, Thomas P Mathews, Zhiyu Zhao, Michalis Agathocleous, Sean J Morrison.
      The electron transport chain promotes aspartate synthesis, which is required for cancer cell proliferation. However, it is unclear whether aspartate is limiting in normal stem cells. We found that mouse hematopoietic stem cells (HSCs) depend entirely on cell-autonomous aspartate synthesis, which increases upon HSC activation. Overexpression of the glutamate/aspartate transporter, Glast, or deletion of glutamic-oxaloacetic transaminase 1 (Got1) each increased aspartate levels in HSCs/progenitor cells and increased the function of HSCs but not colony-forming progenitors. Conversely, deletion of Got2 reduced aspartate levels and the function of HSCs but not colony-forming progenitors. Deletion of Got1 and Got2 eliminated HSCs. Isotope tracing showed aspartate was used to synthesize asparagine and purines. Both contributed to increased HSC function as deletion of asparagine synthetase or treatment with 6-mercaptopurine attenuated the increased function of GLAST-overexpressing HSCs. HSC function is thus limited by aspartate, purine, and asparagine availability during hematopoietic regeneration.
    Keywords:  asparagine; aspartate; electron transport chain; hematopoietic stem cell; metabolism; mitochondria; purine; regeneration
    DOI:  https://doi.org/10.1016/j.stem.2021.07.011
  3. Cells. 2021 Aug 10. pii: 2040. [Epub ahead of print]10(8):
    High Glycolytic Activity Enhances Stem Cell Reprogramming of Fahd1-KO Mouse Embryonic Fibroblasts.
    Ahmad Salti, Solmaz Etemad, Marta Suarez Cubero, Eva Albertini, Beata Kovacs-Szalka, Max Holzknecht, Elia Cappuccio, Maria Cavinato, Frank Edenhofer, Pidder Jansen Dürr.
      Mitochondria play a key role in metabolic transitions involved in the reprogramming of somatic cells into induced pluripotent stem cells (iPSCs), but the underlying molecular mechanisms remain largely unexplored. To obtain new insight into the mechanisms of cellular reprogramming, we studied the role of FAH domain-containing protein 1 (FAHD1) in the reprogramming of murine embryonic fibroblasts (MEFs) into iPSCs and their subsequent differentiation into neuronal cells. MEFs from wild type (WT) and Fahd1-knock-out (KO) mice were reprogrammed into iPSCs and characterized for alterations in metabolic parameters and the expression of marker genes indicating mitochondrial biogenesis. Fahd1-KO MEFs showed a higher reprogramming efficiency accompanied by a significant increase in glycolytic activity as compared to WT. We also observed a strong increase of mitochondrial DNA copy number and expression of biogenesis marker genes in Fahd1-KO iPSCs relative to WT. Neuronal differentiation of iPSCs was accompanied by increased expression of mitochondrial biogenesis genes in both WT and Fahd1-KO neurons with higher expression in Fahd1-KO neurons. Together these observations establish a role of FAHD1 as a potential negative regulator of reprogramming and add additional insight into mechanisms by which FAHD1 modulates mitochondrial functions.
    Keywords:  FAHD1; glycolytic activity; iPSCs; mitochondria; neuronal differentiation; oxidative phosphorylation; reprogramming
    DOI:  https://doi.org/10.3390/cells10082040
  4. Dev Cell. 2021 Aug 23. pii: S1534-5807(21)00603-1. [Epub ahead of print]56(16): 2329-2347.e6
    Metabolic plasticity drives development during mammalian embryogenesis.
    Mark S Sharpley, Fangtao Chi, Johanna Ten Hoeve, Utpal Banerjee.
      Mammalian preimplantation embryos follow a stereotypic pattern of development from zygotes to blastocysts. Here, we use labeled nutrient isotopologue analysis of small numbers of embryos to track downstream metabolites. Combined with transcriptomic analysis, we assess the capacity of the embryo to reprogram its metabolism through development. Early embryonic metabolism is rigid in its nutrient requirements, sensitive to reductive stress and has a marked disequilibrium between two halves of the TCA cycle. Later, loss of maternal LDHB and transcription of zygotic products favors increased activity of bioenergetic shuttles, fatty-acid oxidation and equilibration of the TCA cycle. As metabolic plasticity peaks, blastocysts can develop without external nutrients. Normal developmental metabolism of the early embryo is distinct from cancer metabolism. However, similarities emerge upon reductive stress. Increased metabolic plasticity with maturation is due to changes in redox control mechanisms and to transcriptional reprogramming of later-stage embryos during homeostasis or upon adaptation to environmental changes.
    Keywords:  MYC; NAD+/NADH; developmental metabolism; embryo; metabolic plasticity; metabolic reprogramming; preimplantation; redox; reductive stress; zygotic genome activation
    DOI:  https://doi.org/10.1016/j.devcel.2021.07.020
  5. Front Cell Dev Biol. 2021 ;9 714370
    Physiological Signaling Functions of Reactive Oxygen Species in Stem Cells: From Flies to Man.
    Sergey A Sinenko, Tatiana Yu Starkova, Andrey A Kuzmin, Alexey N Tomilin.
      Reactive oxygen species (ROS), superoxide anion and hydrogen peroxide, are generated as byproducts of oxidative phosphorylation in the mitochondria or via cell signaling-induced NADPH oxidases in the cytosol. In the recent two decades, a plethora of studies established that elevated ROS levels generated by oxidative eustress are crucial physiological mediators of many cellular and developmental processes. In this review, we discuss the mechanisms of ROS generation and regulation, current understanding of ROS functions in the maintenance of adult and embryonic stem cells, as well as in the process of cell reprogramming to a pluripotent state. Recently discovered cell-non-autonomous ROS functions mediated by growth factors are crucial for controlling cell differentiation and cellular immune response in Drosophila. Importantly, many physiological functions of ROS discovered in Drosophila may allow for deciphering and understanding analogous processes in human, which could potentially lead to the development of novel therapeutic approaches in ROS-associated diseases treatment.
    Keywords:  HMGB1; drosophila; electron transport chain; embryonic stem cells; hematopoiesis; induced pluripotent stem cells; mitochondria; reactive oxygen species
    DOI:  https://doi.org/10.3389/fcell.2021.714370
  6. J Biochem Mol Toxicol. 2021 Aug 25. e22898
    Requirements for successful mitochondrial transplantation.
    Gokhan Burcin Kubat, Oner Ulger, Senay Akin.
      Maintenance of mitochondrial oxidative phosphorylation capacity and other mitochondrial functions are essential for the prevention of mitochondrial dysfunction-related diseases such as neurodegenerative, cardiovascular, and liver diseases. To date, no well-known treatment modality has been developed to prevent or reduce mitochondrial dysfunction. However, a novel approach that transplants fully functional mitochondria directly into defective cells has recently caught the attention of scientists. In this review, we provide an overview of the cell/tissue source of the mitochondria to prompt cell regeneration or tissue repair in vitro and in vivo applications. The animal and human models entail that effective procedures should be used in the isolation and confirmation of mitochondrial membrane potential and function. We believe that these procedures for mitochondrial transplantation for tissue or cell culture will confirm intact, viable, and free from contamination isolated mitochondria from the appropriate sources.
    Keywords:  mitochondria dysfunction; mitochondrial isolation; mitochondrial transplantation
    DOI:  https://doi.org/10.1002/jbt.22898
  7. Redox Biol. 2021 Aug 05. pii: S2213-2317(21)00253-6. [Epub ahead of print]46 102094
    Cell cycle induction in human cardiomyocytes is dependent on biosynthetic pathway activation.
    Riham R E Abouleisa, Lindsey McNally, Abou Bakr M Salama, Sally K Hammad, Qinghui Ou, Collin Wells, Pawel K Lorkiewicz, Roberto Bolli, Tamer M A Mohamed, Bradford G Hill.
       AIMS: The coordinated gene and metabolic programs that facilitate cardiomyocyte entry and progression in the cell cycle are poorly understood. The purpose of this study was to identify the metabolic changes that influence myocyte proliferation.
    METHODS AND RESULTS: In adult mouse cardiomyocytes and human induced pluripotent stem cell cardiomyocytes (hiPS-CMs), cell cycle initiation by ectopic expression of Cyclin B1, Cyclin D1, CDK1, and CDK4 (termed 4F) downregulated oxidative phosphorylation genes and upregulated genes that regulate ancillary biosynthetic pathways of glucose metabolism. Results from metabolic analyses and stable isotope tracing experiments indicate that 4F-mediated cell cycle induction in hiPS-CMs decreases glucose oxidation and oxidative phosphorylation and augments NAD+, glycogen, hexosamine, phospholipid, and serine biosynthetic pathway activity. Interventions that diminish NAD+ synthesis, serine synthesis, or protein O-GlcNAcylation decreased 4F-mediated cell cycle entry. In a gain of function approach, we overexpressed phosphoenolpyruvate carboxykinase 2 (PCK2), which can drive carbon from the Krebs cycle to the glycolytic intermediate pool, and found that PCK2 augments 4F-mediated cell cycle entry.
    CONCLUSIONS: These findings suggest that a metabolic shift from catabolic to anabolic activity is a critical step for cardiomyocyte cell cycle entry and is required to facilitate proliferation.
    DOI:  https://doi.org/10.1016/j.redox.2021.102094
  8. Sci Rep. 2021 Aug 24. 11(1): 17129
    Decreased PGC1β expression results in disrupted human erythroid differentiation, impaired hemoglobinization and cell cycle exit.
    Taha Sen, Jun Chen, Sofie Singbrant.
      Production of red blood cells relies on proper mitochondrial function, both for their increased energy demands during differentiation and for proper heme and iron homeostasis. Mutations in genes regulating mitochondrial function have been reported in patients with anemia, yet their pathophysiological role often remains unclear. PGC1β is a critical coactivator of mitochondrial biogenesis, with increased expression during terminal erythroid differentiation. The role of PGC1β has however mainly been studied in skeletal muscle, adipose and hepatic tissues, and its function in erythropoiesis remains largely unknown. Here we show that perturbed PGC1β expression in human hematopoietic stem/progenitor cells from both bone marrow and cord blood results in impaired formation of early erythroid progenitors and delayed terminal erythroid differentiation in vitro, with accumulations of polychromatic erythroblasts, similar to MDS-related refractory anemia. Reduced levels of PGC1β resulted in deregulated expression of iron, heme and globin related genes in polychromatic erythroblasts, and reduced hemoglobin content in the more mature bone marrow derived reticulocytes. Furthermore, PGC1β knock-down resulted in disturbed cell cycle exit with accumulation of erythroblasts in S-phase and enhanced expression of G1-S regulating genes, with smaller reticulocytes as a result. Taken together, we demonstrate that PGC1β is directly involved in production of hemoglobin and regulation of G1-S transition and is ultimately required for proper terminal erythroid differentiation.
    DOI:  https://doi.org/10.1038/s41598-021-96585-0
  9. Biomed Pharmacother. 2021 Aug 25. pii: S0753-3322(21)00872-6. [Epub ahead of print]142 112089
    QuinoMit Q10-Fluid attenuates hydrogen peroxide-induced irregular beating in mouse pluripotent stem cell-derived cardiomyocytes.
    Filomain Nguemo, Erastus Nembu Nembo, Michelle Vanessa Kamga Kapchoup, Franz Enzmann, Jürgen Hescheler.
       BACKGROUND: Coenzyme Q10 (CoQ10) is a crucial component of the mitochondrial structure which is involved in producing more than 90% of cellular ATP. This study aimed to investigate the protective effects and underlying mechanisms of QuinoMit Q10-Fluid against hydrogen peroxide (H2O2)-induced arrhythmias on cardiomyocytes (CMs).
    METHODS: Undifferentiated stem cell-derived CMs were cultured in the presence of different concentrations of QuinoMit Q10-Fluid. To investigate if CoQ10 has anti-apoptotic activity, CMs were exposed to H2O2 for up to 100 h with or without CoQ10. The expression levels of cardiac reference genes were determined by RT-PCR. The structural and functional properties of CMs were examined by immunofluorescence and the xCELLigence system. Caspase 3/7 assay was also performed for cell apoptosis study.
    RESULTS: The study showed that QuinoMit Q10-Fluid inhibits the proliferation of pluripotent stem cells at high concentrations and had less effect on cardiomyogenesis. However, the beating rate of clusters containing CMs generated under QuinoMit Q10-Fluid (1:100) was significantly increased. This increase was accompanied by the up-regulated expression level of some important cardiac markers during differentiation. Treatment of CMs with H2O2 notably induced irregular beating and decreased the amplitude of the beating signal of CMs, concomitantly with increased caspase-3/7 activity. However, CMs pretreated with QuinoMit exhibited a protective effect against H2O2-induced arrhythmia.
    CONCLUSION: Our results reveal that QuinoMit Q10-Fluid attenuates H2O2-induced irregular beating in mouse pluripotent stem cell-derived CMs, at least partly by reducing the generation of ROS, suggesting a protective effect against CM dysfunctions.
    Keywords:  Apoptosis; Arrhythmia; Cardiomyocytes; Cell Index; Induced pluripotent stem cells; QuinoMit Q10-Fluid; xCELLigence
    DOI:  https://doi.org/10.1016/j.biopha.2021.112089
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