bims-mireme Biomed News
on Mitochondria in regenerative medicine
Issue of 2021‒08‒01
eight papers selected by
Brian Spurlock
The University of North Carolina at Chapel Hill
  1. Asymmetric organelle inheritance predicts human blood stem cell fate.
  2. The relevance of mitochondrial DNA variants fluctuation during reprogramming and neuronal differentiation of human iPSCs.
  3. Move it to lose it: Mitocytosis expels damaged mitochondria.
  4. Loss of mitochondrial transcription factor A in neural stem cells leads to immature brain development and triggers the activation of the integral stress response in vivo.
  5. Cardiac-specific β-catenin deletion dysregulates energetic metabolism and mitochondrial function in perinatal cardiomyocytes.
  6. Unravelling the impact of intrauterine growth restriction on heart development: insights into mitochondria and sexual dimorphism from a non-hominoid primate.
  7. Roles of Phase Separation for Cellular Redox Maintenance.
  8. University of Alabama at Birmingham Nathan Shock Center: comparative energetics of aging.
  1. Blood. 2021 Jul 27. pii: blood.2020009778. [Epub ahead of print]
    Asymmetric organelle inheritance predicts human blood stem cell fate.
    Dirk Loeffler, Florin Schneiter, Weijia Wang, Arne Wehling, Tobias Kull, Claudia Lengerke, Markus G Manz, Timm Schroeder.
      Understanding human hematopoietic stem cell fate control is important for their improved therapeutic manipulation. Asymmetric cell division, the asymmetric inheritance of factors during division instructing future daughter cell fates, was recently described in mouse blood stem cells. In human blood stem cells, the possible existence of asymmetric cell division remained unclear due to technical challenges in its direct observation. Here, we use long-term quantitative single-cell imaging to show that lysosomes and active mitochondria are asymmetrically inherited in human blood stem cells and that their inheritance is a coordinated, non-random process. Furthermore, multiple additional organelles, including autophagosomes, mitophagosomes, autolysosomes and recycling endosomes show preferential asymmetric co-segregation with lysosomes. Importantly, asymmetric lysosomal inheritance predicts future asymmetric daughter cell cycle length, differentiation and stem cell marker expression, while asymmetric inheritance of active mitochondria correlates with daughter metabolic activity. Hence, human hematopoietic stem cell fates are regulated by asymmetric cell division, with both mechanistic evolutionary conservation and differences to the mouse system.
    DOI:  https://doi.org/10.1182/blood.2020009778
  2. Stem Cell Reports. 2021 Jul 15. pii: S2213-6711(21)00324-6. [Epub ahead of print]
    The relevance of mitochondrial DNA variants fluctuation during reprogramming and neuronal differentiation of human iPSCs.
    Flavia Palombo, Camille Peron, Leonardo Caporali, Angelo Iannielli, Alessandra Maresca, Ivano Di Meo, Claudio Fiorini, Alice Segnali, Francesca L Sciacca, Ambra Rizzo, Sonia Levi, Anu Suomalainen, Alessandro Prigione, Vania Broccoli, Valerio Carelli, Valeria Tiranti.
      The generation of inducible pluripotent stem cells (iPSCs) is a revolutionary technique allowing production of pluripotent patient-specific cell lines used for disease modeling, drug screening, and cell therapy. Integrity of nuclear DNA (nDNA) is mandatory to allow iPSCs utilization, while quality control of mitochondrial DNA (mtDNA) is rarely included in the iPSCs validation process. In this study, we performed mtDNA deep sequencing during the transition from parental fibroblasts to reprogrammed iPSC and to differentiated neuronal precursor cells (NPCs) obtained from controls and patients affected by mitochondrial disorders. At each step, mtDNA variants, including those potentially pathogenic, fluctuate between emerging and disappearing, and some having functional implications. We strongly recommend including mtDNA analysis as an unavoidable assay to obtain fully certified usable iPSCs and NPCs.
    Keywords:  human iPSCs; iPSCs quality control; mtDNA deep sequencing; neuronal precursor cells
    DOI:  https://doi.org/10.1016/j.stemcr.2021.06.016
  3. Dev Cell. 2021 Jul 26. pii: S1534-5807(21)00546-3. [Epub ahead of print]56(14): 2014-2015
    Move it to lose it: Mitocytosis expels damaged mitochondria.
    Chahat Mehra, Lena Pernas.
      Mechanisms by which cells remove damaged mitochondria extracellularly are unclear. Recent work by Jiao and colleagues in Cell shows that migrating cells expel dysfunctional mitochondria in membrane-bound structures called migrasomes to maintain mitochondrial homeostasis.
    DOI:  https://doi.org/10.1016/j.devcel.2021.07.001
  4. PLoS One. 2021 ;16(7): e0255355
    Loss of mitochondrial transcription factor A in neural stem cells leads to immature brain development and triggers the activation of the integral stress response in vivo.
    Rintaro Kuroda, Kaoru Tominaga, Katsumi Kasashima, Kenji Kuroiwa, Eiji Sakashita, Hiroko Hayakawa, Tom Kouki, Nobuhiko Ohno, Kensuke Kawai, Hitoshi Endo.
      Mitochondrial dysfunction is significantly associated with neurological deficits and age-related neurological diseases. While mitochondria are dynamically regulated and properly maintained during neurogenesis, the manner in which mitochondrial activities are controlled and contribute to these processes is not fully understood. Mitochondrial transcription factor A (TFAM) contributes to mitochondrial function by maintaining mitochondrial DNA (mtDNA). To clarify how mitochondrial dysfunction affects neurogenesis, we induced mitochondrial dysfunction specifically in murine neural stem cells (NSCs) by inactivating Tfam. Tfam inactivation in NSCs resulted in mitochondrial dysfunction by reducing respiratory chain activities and causing a severe deficit in neural differentiation and maturation both in vivo and in vitro. Brain tissue from Tfam-deficient mice exhibited neuronal cell death primarily at layer V and microglia were activated prior to cell death. Cultured Tfam-deficient NSCs showed a reduction in reactive oxygen species produced by the mitochondria. Tfam inactivation during neurogenesis resulted in the accumulation of ATF4 and activation of target gene expression. Therefore, we propose that the integrated stress response (ISR) induced by mitochondrial dysfunction in neurogenesis is activated to protect the progression of neurodegenerative diseases.
    DOI:  https://doi.org/10.1371/journal.pone.0255355
  5. Mitochondrion. 2021 Jul 21. pii: S1567-7249(21)00098-2. [Epub ahead of print]
    Cardiac-specific β-catenin deletion dysregulates energetic metabolism and mitochondrial function in perinatal cardiomyocytes.
    Volodymyr V Balatskyi, Vasyl O Vaskivskyi, Anna Myronova, Diana Avramets, Karim Abu Nahia, Larysa L Macewicz, Tetiana P Ruban, Dar'ya Yu Kucherenko, Oleksandr O Soldatkin, Iryna V Lushnikova, Galyna G Skibo, Cecilia L Winata, Pawel Dobrzyn, Oksana O Piven.
      β-Catenin signaling pathway regulates cardiomyocytes proliferation and differentiation, though its involvement in metabolic regulation of cardiomyocytes remains unknown. We used one-day-old mice with cardiac-specific knockout of β-catenin and neonatal rat ventricular myocytes treated with β-catenin inhibitor, to investigate the role of β-catenin metabolism regulation in perinatal cardiomyocytes. Transcriptomics of perinatal β-catenin-ablated hearts revealed a dramatic shift in the expression of genes involved in metabolic processes. Further analysis indicated an inhibition of lipolysis and glycolysis in both in vitro and in vivo models. Finally, we showed that β-catenin deficiency leads to mitochondria dysfunction via the downregulation of Sirt1/ PGC-1α pathway. We conclude that cardiac-specific β-catenin ablation disrupts the energy substrate shift that is essential for postnatal heart maturation, leading to perinatal lethality of homozygous β-catenin knockout mice.
    Keywords:  glycolysis; heart; lipolysis; oxidative phosphorylation; transcriptome; β-catenin
    DOI:  https://doi.org/10.1016/j.mito.2021.07.005
  6. Clin Sci (Lond). 2021 Jul 30. 135(14): 1767-1772
    Unravelling the impact of intrauterine growth restriction on heart development: insights into mitochondria and sexual dimorphism from a non-hominoid primate.
    George W Booz, Gaelle P Massoud, Raffaele Altara, Fouad A Zouein.
      Fetal exposure to an unfavorable intrauterine environment programs an individual to have a greater susceptibility later in life to non-communicable diseases, such as coronary heart disease, but the molecular processes are poorly understood. An article in Clinical Science recently reported novel details on the effects of maternal nutrient reduction (MNR) on fetal heart development using a primate model that is about 94% genetically similar to humans and is also mostly monotocous. MNR adversely impacted fetal left ventricular (LV) mitochondria in a sex-dependent fashion with a greater effect on male fetuses, although mitochondrial transcripts increased more so in females. Increased expression for several respiratory chain and adenosine triphosphate (ATP) synthase proteins were observed. However, fetal LV mitochondrial complex I and complex II/III activities were significantly decreased, likely contributing to a 73% decreased LV ATP content and increased LV lipid peroxidation. Moreover, MNR fetal LV mitochondria showed sparse and disarranged cristae. This study indicates that mitochondria are targets of the remodeling and imprinting processes in a sex-dependent manner. Mitochondrial ROS production and inadequate energy production add another layer of complexity. Altogether these observations raise the possibility that dysfunctional mitochondria in the fetus may contribute in turn to epigenetic memory of in utero stress in the adult. The role of mitoepigenetics and involvement of mitochondrial and genomic non-coding RNAs in mitochondrial functions and nuclei-mitochondria crosstalk with in utero stress awaits further investigation.
    Keywords:  epigenetics; intrauterine growth restriction; mitochondrial dysfunction; oxidative stress; sex
    DOI:  https://doi.org/10.1042/CS20210524
  7. Front Genet. 2021 ;12 691946
    Roles of Phase Separation for Cellular Redox Maintenance.
    Yuichi Saito, Wataru Kimura.
      The oxidation reaction greatly alters characteristics of various cellular components. In exchange for efficient energy production, mitochondrial aerobic respiration substantially increases the risk of excess oxidation of cellular biomolecules such as lipids, proteins, nucleic acids, and numerous small molecules. To maintain a physiologically balanced cellular reduction-oxidation (redox) state, cells utilize a variety of molecular machineries including cellular antioxidants and protein degradation complexes such as the ubiquitin-proteasome system or autophagy. In the past decade, biomolecular liquid-liquid phase separation (LLPS) has emerged as a subject of great interest in the biomedical field, as it plays versatile roles in the maintenance of cellular homeostasis. With regard to redox homeostasis, LLPS arose as a major player in both well-characterized and newly emerging redox pathways. LLPS is involved in direct redox imbalance sensing, signal transduction, and transcriptional regulation. Also, LLPS is at play when cells resist redox imbalance through metabolic switching, translational remodeling, activating the DNA damage response, and segregation of vulnerable lipids and proteins. On the other hand, chronic accumulation of phase-separated molecular condensates such as lipid droplets and amyloid causes neurotoxic outcomes. In this review we enumerate recent progress on understanding how cells utilize LLPS to deal with oxidative stress, especially related to cell survival or pathogenesis, and we discuss future research directions for understanding biological phase separation in cellular redox regulation.
    Keywords:  Nrf2; autophagy; hypoxia; liquid-liquid phase separation; oxidative stress; redox biology
    DOI:  https://doi.org/10.3389/fgene.2021.691946
  8. Geroscience. 2021 Jul 25.
    University of Alabama at Birmingham Nathan Shock Center: comparative energetics of aging.
    Steven N Austad, Thomas W Buford, David B Allison, Scott W Ballinger, Andrew W Brown, Christy S Carter, Victor M Darley-Usmar, John L Hartman, Timothy R Nagy, Daniel L Smith, Liou Sun, Jianhua Zhang.
      The UAB Nathan Shock Center focuses on comparative energetics and aging. Energetics, as defined for this purpose, encompasses the causes, mechanisms, and consequences of the acquisition, storage, and use of metabolizable energy. Comparative energetics is the study of metabolic processes at multiple scales and across multiple species as it relates to health and aging. The link between energetics and aging is increasingly understood in terms of dysregulated mitochondrial function, altered metabolic signaling, and aberrant nutrient responsiveness with increasing age. The center offers world-class expertise in comprehensive, integrated energetic assessment and analysis from the level of the organelle to the organism and across species from the size of worms to rats as well as state-of-the-art data analytics. The range of services offered by our three research cores, (1) The Organismal Energetics Core, (2) Mitometabolism Core, and (3) Data Analytics Core, is described herein.
    Keywords:  Aging; Analytics; Bioenergetics; Comparative biology; Energetics; Metabolism; Mitochondria
    DOI:  https://doi.org/10.1007/s11357-021-00414-1
This page is being maintained by Thomas Krichel. It was last updated on 2021‒08‒03 at 19:24:44.