bims-mireme 2021-08-08 papers

bims-mireme

Biomed News

on Mitochondria in regenerative medicine

Issue of 2021–08–08
eight papers selected by
Brian Spurlock, The University of North Carolina at Chapel Hill

Functional Diversity of Mitochondrial Peptidyl-tRNA Hydrolase ICT1 in Human Cells.
Mitochondria Can Cross Cell Boundaries: An Overview of the Biological Relevance, Pathophysiological Implications and Therapeutic Perspectives of Intercellular Mitochondrial Transfer.
Oxidative-Signaling in Neural Stem Cell-Mediated Plasticity: Implications for Neurodegenerative Diseases.
The Role of Metabolism in Heart Failure and Regeneration.
Oxidative bursts of single mitochondria mediate retrograde signaling toward the ER.
Diverse Functions of Tim50, a Component of the Mitochondrial Inner Membrane Protein Translocase.
Metabolism navigates neural cell fate in development, aging and neurodegeneration.
Co-culture with mouse embryonic fibroblasts improves maintenance of metabolic function of human small hepatocyte progenitor cells.

Front Mol Biosci. 2021 ;8 716885

Functional Diversity of Mitochondrial Peptidyl-tRNA Hydrolase ICT1 in Human Cells.

I V Chicherin, S V Dukhalin, R A Khannanov, M V Baleva, S A Levitskii, M V Patrushev, P V Sergiev, P Kamenski.

  Mitochondria are energy producing organelles of the eukaryotic cell, involved in the synthesis of key metabolites, calcium homeostasis and apoptosis. Protein biosynthesis in these organelles is a relic of its endosymbiotic origin. While mitochondrial translational factors have homologues among prokaryotes, they possess a number of unique traits. Remarkably as many as four mammalian mitochondrial proteins possess a clear similarity with translation termination factors. The review focuses on the ICT1, which combines several functions. It is a non-canonical termination factor for protein biosynthesis, a rescue factor for stalled mitochondrial ribosomes, a structural protein and a regulator of proliferation, cell cycle, and apoptosis. Such a diversity of roles demonstrates the high functionality of mitochondrial translation associated proteins and their relationship with numerous processes occurring in a living cell.

Keywords:  apoptosis; cell cycle; mitochondria; proliferation; regulation; ribosome, signaling; termination; translation

DOI:  https://doi.org/10.3389/fmolb.2021.716885
Int J Mol Sci. 2021 Aug 02. pii: 8312. [Epub ahead of print]22(15):

Mitochondria Can Cross Cell Boundaries: An Overview of the Biological Relevance, Pathophysiological Implications and Therapeutic Perspectives of Intercellular Mitochondrial Transfer.

Daniela Valenti, Rosa Anna Vacca, Loredana Moro, Anna Atlante.

  Mitochondria are complex intracellular organelles traditionally identified as the powerhouses of eukaryotic cells due to their central role in bioenergetic metabolism. In recent decades, the growing interest in mitochondria research has revealed that these multifunctional organelles are more than just the cell powerhouses, playing many other key roles as signaling platforms that regulate cell metabolism, proliferation, death and immunological response. As key regulators, mitochondria, when dysfunctional, are involved in the pathogenesis of a wide range of metabolic, neurodegenerative, immune and neoplastic disorders. Far more recently, mitochondria attracted renewed attention from the scientific community for their ability of intercellular translocation that can involve whole mitochondria, mitochondrial genome or other mitochondrial components. The intercellular transport of mitochondria, defined as horizontal mitochondrial transfer, can occur in mammalian cells both in vitro and in vivo, and in physiological and pathological conditions. Mitochondrial transfer can provide an exogenous mitochondrial source, replenishing dysfunctional mitochondria, thereby improving mitochondrial faults or, as in in the case of tumor cells, changing their functional skills and response to chemotherapy. In this review, we will provide an overview of the state of the art of the up-to-date knowledge on intercellular trafficking of mitochondria by discussing its biological relevance, mode and mechanisms underlying the process and its involvement in different pathophysiological contexts, highlighting its therapeutic potential for diseases with mitochondrial dysfunction primarily involved in their pathogenesis.

Keywords:  bioenergetics; cancer; ccf-mtDNA; extracellular mitochondria; extracellular mitovesicles; immune-metabolic regulation; intercellular mitochondria trafficking; mitochondria; mitochondrial transplantation; neurodegenerative diseases; neurodevelopmental disorders; oxidative phosphorylation; tunneling nanotubes

DOI:  https://doi.org/10.3390/ijms22158312
Antioxidants (Basel). 2021 Jul 06. pii: 1088. [Epub ahead of print]10(7):

Oxidative-Signaling in Neural Stem Cell-Mediated Plasticity: Implications for Neurodegenerative Diseases.

Mafalda Ferreira Dos Santos, Catarina Roxo, Susana Solá.

  The adult mammalian brain is capable of generating new neurons from existing neural stem cells (NSCs) in a process called adult neurogenesis. This process, which is critical for sustaining cognition and mental health in the mature brain, can be severely hampered with ageing and different neurological disorders. Recently, it is believed that the beneficial effects of NSCs in the injured brain relies not only on their potential to differentiate and integrate into the preexisting network, but also on their secreted molecules. In fact, further insight into adult NSC function is being gained, pointing to these cells as powerful endogenous "factories" that produce and secrete a large range of bioactive molecules with therapeutic properties. Beyond anti-inflammatory, neurogenic and neurotrophic effects, NSC-derived secretome has antioxidant proprieties that prevent mitochondrial dysfunction and rescue recipient cells from oxidative damage. This is particularly important in neurodegenerative contexts, where oxidative stress and mitochondrial dysfunction play a significant role. In this review, we discuss the current knowledge and the therapeutic opportunities of NSC secretome for neurodegenerative diseases with a particular focus on mitochondria and its oxidative state.

Keywords:  antioxidant; degenerative diseases; mitochondrial dysfunction; neural stem cells; oxidative stress; regeneration; secretome

DOI:  https://doi.org/10.3390/antiox10071088
Front Cardiovasc Med. 2021 ;8 702920

The Role of Metabolism in Heart Failure and Regeneration.

Jiyoung Bae, Wyatt G Paltzer, Ahmed I Mahmoud.

  Heart failure is the leading cause of death worldwide. The inability of the adult mammalian heart to regenerate following injury results in the development of systolic heart failure. Thus, identifying novel approaches toward regenerating the adult heart has enormous therapeutic potential for adult heart failure. Mitochondrial metabolism is an essential homeostatic process for maintaining growth and survival. The emerging role of mitochondrial metabolism in controlling cell fate and function is beginning to be appreciated. Recent evidence suggests that metabolism controls biological processes including cell proliferation and differentiation, which has profound implications during development and regeneration. The regenerative potential of the mammalian heart is lost by the first week of postnatal development when cardiomyocytes exit the cell cycle and become terminally differentiated. This inability to regenerate following injury is correlated with the metabolic shift from glycolysis to fatty acid oxidation that occurs during heart maturation in the postnatal heart. Thus, understanding the mechanisms that regulate cardiac metabolism is key to unlocking metabolic interventions during development, disease, and regeneration. In this review, we will focus on the emerging role of metabolism in cardiac development and regeneration and discuss the potential of targeting metabolism for treatment of heart failure.

Keywords:  cell cycle; development; heart failure; heart regeneration; metabolism

DOI:  https://doi.org/10.3389/fcvm.2021.702920
Mol Cell. 2021 Jul 27. pii: S1097-2765(21)00583-9. [Epub ahead of print]

Oxidative bursts of single mitochondria mediate retrograde signaling toward the ER.

David M Booth, Péter Várnai, Suresh K Joseph, György Hajnóczky.

  The emerging role of mitochondria as signaling organelles raises the question of whether individual mitochondria can initiate heterotypic communication with neighboring organelles. Using fluorescent probes targeted to the endoplasmic-reticulum-mitochondrial interface, we demonstrate that single mitochondria generate oxidative bursts, rapid redox oscillations, confined to the nanoscale environment of the interorganellar contact sites. Using probes fused to inositol 1,4,5-trisphosphate receptors (IP3Rs), we show that Ca2+ channels directly sense oxidative bursts and respond with Ca2+ transients adjacent to active mitochondria. Application of specific mitochondrial stressors or apoptotic stimuli dramatically increases the frequency and amplitude of the oxidative bursts by enhancing transient permeability transition pore openings. Conversely, blocking interface Ca2+ transport via elimination of IP3Rs or mitochondrial calcium uniporter channels suppresses ER-mitochondrial Ca2+ feedback and cell death. Thus, single mitochondria initiate local retrograde signaling by miniature oxidative bursts and, upon metabolic or apoptotic stress, may also amplify signals to the rest of the cell.

Keywords:  Ca2+ microdomain; Inositol-1,4,5-trisphosphate receptor; Mitochondrial retrograde signaling; Organelle contacts; Redox nanodomain

DOI:  https://doi.org/10.1016/j.molcel.2021.07.014
Int J Mol Sci. 2021 Jul 21. pii: 7779. [Epub ahead of print]22(15):

Diverse Functions of Tim50, a Component of the Mitochondrial Inner Membrane Protein Translocase.

Minu Chaudhuri, Anuj Tripathi, Fidel Soto Gonzalez.

  Mitochondria are essential in eukaryotes. Besides producing 80% of total cellular ATP, mitochondria are involved in various cellular functions such as apoptosis, inflammation, innate immunity, stress tolerance, and Ca2+ homeostasis. Mitochondria are also the site for many critical metabolic pathways and are integrated into the signaling network to maintain cellular homeostasis under stress. Mitochondria require hundreds of proteins to perform all these functions. Since the mitochondrial genome only encodes a handful of proteins, most mitochondrial proteins are imported from the cytosol via receptor/translocase complexes on the mitochondrial outer and inner membranes known as TOMs and TIMs. Many of the subunits of these protein complexes are essential for cell survival in model yeast and other unicellular eukaryotes. Defects in the mitochondrial import machineries are also associated with various metabolic, developmental, and neurodegenerative disorders in multicellular organisms. In addition to their canonical functions, these protein translocases also help maintain mitochondrial structure and dynamics, lipid metabolism, and stress response. This review focuses on the role of Tim50, the receptor component of one of the TIM complexes, in different cellular functions, with an emphasis on the Tim50 homologue in parasitic protozoan Trypanosoma brucei.

Keywords:  HAD-phosphatase family; TIM; TIMM50; TOM; Tim50; Trypanosoma

DOI:  https://doi.org/10.3390/ijms22157779
Dis Model Mech. 2021 Aug 01. pii: dmm048993. [Epub ahead of print]14(8):

Metabolism navigates neural cell fate in development, aging and neurodegeneration.

Larissa Traxler, Jessica Lagerwall, Sophie Eichhorner, Davide Stefanoni, Angelo D'Alessandro, Jerome Mertens.

  An uninterrupted energy supply is critical for the optimal functioning of all our organs, and in this regard the human brain is particularly energy dependent. The study of energy metabolic pathways is a major focus within neuroscience research, which is supported by genetic defects in the oxidative phosphorylation mechanism often contributing towards neurodevelopmental disorders and changes in glucose metabolism presenting as a hallmark feature in age-dependent neurodegenerative disorders. However, as recent studies have illuminated roles of cellular metabolism that span far beyond mere energetics, it would be valuable to first comprehend the physiological involvement of metabolic pathways in neural cell fate and function, and to subsequently reconstruct their impact on diseases of the brain. In this Review, we first discuss recent evidence that implies metabolism as a master regulator of cell identity during neural development. Additionally, we examine the cell type-dependent metabolic states present in the adult brain. As metabolic states have been studied extensively as crucial regulators of malignant transformation in cancer, we reveal how knowledge gained from the field of cancer has aided our understanding in how metabolism likewise controls neural fate determination and stability by directly wiring into the cellular epigenetic landscape. We further summarize research pertaining to the interplay between metabolic alterations and neurodevelopmental and psychiatric disorders, and expose how an improved understanding of metabolic cell fate control might assist in the development of new concepts to combat age-dependent neurodegenerative diseases, particularly Alzheimer's disease.

Keywords:  Brain aging; Epigenetics; Metabolic state; Neural development; Psychiatric disorder

DOI:  https://doi.org/10.1242/dmm.048993
Curr Res Toxicol. 2020 Jun 10. 1 70-84

Co-culture with mouse embryonic fibroblasts improves maintenance of metabolic function of human small hepatocyte progenitor cells.

Srikumar Sengupta, Brian Johnson, Morten Seirup, Hamisha Ardalani, Bret Duffin, Gregory A Barrett-Wilt, Ron Stewart, James A Thomson.

  Derivation and culture of small hepatocyte progenitor cells (SHPCs) capable of proliferating in vitro has been described in rodents and recently in humans. These cells are capable of engrafting in injured livers, however, they display de-differentiated morphology and reduced xenobiotic metabolism activity in culture over passages. Here we report that SHPCs derived from adult primary human hepatocytes (PHHs) and cultured on mouse embryonic fibroblasts (MEFs) not only display differentiated morphology and exhibit gene expression profiles similar to adult PHHs, but importantly, they retain their phenotype over several passages. Further, unlike previous reports, where extensive manipulations of culture conditions are required to convert SHPCs to metabolically functional hepatocytes, SHPCs in our co-culture system maintain expression of xenobiotic metabolism-associated genes. We show that SHPCs in co-culture are able to perform xenobiotic metabolism at rates equal to their parent PHHs as evidenced by the metabolism of acetaminophen to all of its major metabolites. In summary, we present an improved co-culture system that allows generation of SHPCs from adult PHHs that maintain their differentiated phenotype over multiple passages. Our findings would be useful for expansion of limited PHHs for use in studies of drug metabolism and toxicity testing.

Keywords:  AFP, alpha-fetoprotein; Drug metabolism; FBS, fetal bovine serum; Hepatocyte transplantation; Liver disease modeling; Liver regeneration; MACS, magnetic-activated cell sorting; MEFs, mouse embryonic fibroblasts; PHHs, primary human hepatocytes; SHPCs, small hepatocyte progenitor cells; SULTs, sulfotransferases; Toxicity testing; UGTs, glucuronosyl tranferases; sECs, sinusoidal endothelial cells

DOI:  https://doi.org/10.1016/j.crtox.2020.08.001