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Journal ArticleDOI: 10.1016/J.STEM.2021.02.011

Mitochondria as Signaling Organelles Control Mammalian Stem Cell Fate.

04 Mar 2021-Cell Stem Cell (Cell Press)-Vol. 28, Iss: 3, pp 394-408
Abstract: Recent evidence supports the notion that mitochondrial metabolism is necessary for the determination of stem cell fate. Historically, mitochondrial metabolism is linked to the production of ATP and tricarboxylic acid (TCA) cycle metabolites to support stem cell survival and growth, respectively. However, it is now clear that beyond these canonical roles, mitochondria as signaling organelles dictate stem cell fate and function. In this review, we focus on key conceptual ideas on how mitochondria control mammalian stem cell fate and function through reactive oxygen species (ROS) generation, TCA cycle metabolite production, NAD+/NADH ratio regulation, pyruvate metabolism, and mitochondrial dynamics.

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Topics: Mitochondrion (56%), Stem cell (54%), Citric acid cycle (52%)

14 results found

Open accessJournal ArticleDOI: 10.3389/FCELL.2021.720490
Abstract: Mitochondria are master regulators of metabolism and have emerged as key signalling organelles of the innate immune system. Each mitochondrion harbours potent agonists of inflammation, including mitochondrial DNA (mtDNA), which are normally shielded from the rest of the cell and extracellular environment and therefore do not elicit detrimental inflammatory cascades. Mitochondrial damage and dysfunction can lead to the cytosolic and extracellular exposure of mtDNA, which triggers inflammation in a number of diseases including autoimmune neurodegenerative disorders. However, recent research has revealed that the extra-mitochondrial exposure of mtDNA is not solely a negative consequence of mitochondrial damage and pointed to an active role of mitochondria in innate immunity. Metabolic cues including nucleotide imbalance can stimulate the release of mtDNA from mitochondria in order to drive a type I interferon response. Moreover, important effectors of the innate immune response to pathogen infection, such as the mitochondrial antiviral signalling protein (MAVS), are located at the mitochondrial surface and modulated by the cellular metabolic status and mitochondrial dynamics. In this review, we explore how and why metabolism and innate immunity converge at the mitochondria and describe how mitochondria orchestrate innate immune signalling pathways in different metabolic scenarios. Understanding how cellular metabolism and metabolic programming of mitochondria are translated into innate immune responses bears relevance to a broad range of human diseases including cancer.

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Topics: Innate immune system (56%), Mitochondrion (53%), Mitochondrial DNA (52%)

4 Citations

Open accessJournal ArticleDOI: 10.1016/J.REDOX.2021.101953
27 Mar 2021-Redox biology
Abstract: Controlling reactive oxygen species (ROS) at sustainable levels can drive multiple facets of tumor biology, including within the cancer stem cell (CSC) population Tight regulation of ROS is one key component in CSCs that drives disease recurrence, cell signaling, and therapeutic resistance While ROS are well-appreciated to need oxygen and are a product of oxidative phosphorylation, there are also important roles for ROS under hypoxia As hypoxia promotes and sustains major stemness pathways, further consideration of ROS impacts on CSCs in the tumor microenvironment is important Furthermore, glycolytic shifts that occur in cancer and may be promoted by hypoxia are associated with multiple mechanisms to mitigate oxidative stress This altered metabolism provides survival advantages that sustain malignant features, such as proliferation and self-renewal, while producing the necessary antioxidants that reduce damage from oxidative stress Finally, disease recurrence is believed to be attributed to therapy resistant CSCs which can be quiescent and have changes in redox status Effective DNA damage response pathways and/or a slow-cycling state can protect CSCs from the genomic catastrophe induced by irradiation and genotoxic agents This review will explore the delicate, yet complex, relationship between ROS and its pleiotropic role in modulating the CSC

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Topics: Cancer stem cell (56%), Oxidative stress (55%), Population (52%) ... read more

3 Citations

Open accessJournal ArticleDOI: 10.3389/FCELL.2021.672545
Abstract: In multicellular organisms, tissue generation, maintenance, and homeostasis depend on stem cells. Cellular metabolic status is an essential component of different differentiated states, from stem to fully differentiated cells. Threonine (Thr) metabolism has emerged as a critical factor required to maintain pluripotent/multipotent stem cells in both plants and animals. Thus, both kingdoms conserved or converged upon this fundamental feature of stem cell function. Here, we examine similarities and differences in Thr metabolism-dependent mechanisms supporting stem cell maintenance in these two kingdoms. We then consider common features of Thr metabolism in stem cell maintenance and predict and speculate that some knowledge about Thr metabolism and its role in stem cell function in one kingdom may apply to the other. Finally, we outline future research directions to explore these hypotheses.

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Topics: Stem cell (62%), Multipotent Stem Cell (61%), Embryonic stem cell (58%) ... read more

2 Citations

Open accessJournal ArticleDOI: 10.1016/J.CONB.2021.05.003
Ryohei Iwata1, Pierre Vanderhaeghen1Institutions (1)
Abstract: Neural stem cells (NSCs) undergo massive molecular and cellular changes during neuronal differentiation. These include mitochondria and metabolism remodelling, which were thought to be mostly permissive cues, but recent work indicates that they are causally linked to neurogenesis. Striking remodelling of mitochondria occurs right after mitosis of NSCs, which influences the postmitotic daughter cells towards self-renewal or differentiation. The transitioning to neuronal fate requires metabolic rewiring including increased oxidative phosphorylation activity, which drives transcriptional and epigenetic effects to influence cell fate. Mitochondria metabolic pathways also contribute in an essential way to the regulation of NSC proliferation and self-renewal. The influence of mitochondria and metabolism on neurogenesis is conserved from fly to human systems, but also displays striking differences linked to cell context or species. These new findings have important implications for our understanding of neurodevelopmental diseases and possibly human brain evolution.

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Topics: Neurogenesis (59%), Neural stem cell (53%), Cell fate determination (52%)

2 Citations

Open accessJournal ArticleDOI: 10.1111/FEBS.16164
30 Aug 2021-FEBS Journal
Abstract: Coenzyme Q (CoQ, ubiquinone) is the electron-carrying lipid in the mitochondrial electron transport system (ETS). In mammals, it serves as the electron acceptor for nine mitochondrial inner membrane dehydrogenases. These include the NADH dehydrogenase (complex I, CI) and succinate dehydrogenase (complex II, CII) but also several others that are often omitted in the context of respiratory enzymes: dihydroorotate dehydrogenase, choline dehydrogenase, electron-transferring flavoprotein dehydrogenase, mitochondrial glycerol-3-phosphate dehydrogenase, proline dehydrogenases 1 and 2, and sulfide:quinone oxidoreductase. The metabolic pathways these enzymes are involved in range from amino acid and fatty acid oxidation to nucleotide biosynthesis, methylation, and hydrogen sulfide detoxification, among many others. The CoQ-linked metabolism depends on CoQ reoxidation by the mitochondrial complex III (cytochrome bc1 complex, CIII). However, the literature is surprisingly limited as for the role of the CoQ-linked metabolism in the pathogenesis of human diseases of oxidative phosphorylation (OXPHOS), in which the CoQ homeostasis is directly or indirectly affected. In this review, we give an introduction to CIII function, and an overview of the pathological consequences of CIII dysfunction in humans and mice and of the CoQ-dependent metabolic processes potentially affected in these pathological states. Finally, we discuss some experimental tools to dissect the various aspects of compromised CoQ oxidation.

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2 Citations


141 results found

Open accessJournal ArticleDOI: 10.1042/BJ20081386
Abstract: The production of ROS (reactive oxygen species) by mammalian mitochondria is important because it underlies oxidative damage in many pathologies and contributes to retrograde redox signalling from the organelle to the cytosol and nucleus. Superoxide (O2•−) is the proximal mitochondrial ROS, and in the present review I outline the principles that govern O2•− production within the matrix of mammalian mitochondria. The flux of O2•− is related to the concentration of potential electron donors, the local concentration of O2 and the second-order rate constants for the reactions between them. Two modes of operation by isolated mitochondria result in significant O2•− production, predominantly from complex I: (i) when the mitochondria are not making ATP and consequently have a high Δp (protonmotive force) and a reduced CoQ (coenzyme Q) pool; and (ii) when there is a high NADH/NAD+ ratio in the mitochondrial matrix. For mitochondria that are actively making ATP, and consequently have a lower Δp and NADH/NAD+ ratio, the extent of O2•− production is far lower. The generation of O2•− within the mitochondrial matrix depends critically on Δp, the NADH/NAD+ and CoQH2/CoQ ratios and the local O2 concentration, which are all highly variable and difficult to measure in vivo. Consequently, it is not possible to estimate O2•− generation by mitochondria in vivo from O2•−-production rates by isolated mitochondria, and such extrapolations in the literature are misleading. Even so, the description outlined here facilitates the understanding of factors that favour mitochondrial ROS production. There is a clear need to develop better methods to measure mitochondrial O2•− and H2O2 formation in vivo, as uncertainty about these values hampers studies on the role of mitochondrial ROS in pathological oxidative damage and redox signalling.

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Topics: Mitochondrial ROS (65%), MitoQ (61%), Mitochondrion (56%) ... read more

5,363 Citations

Open accessJournal ArticleDOI: 10.1016/S0092-8674(00)80085-9
Xuesong Liu1, Caryn Naekyung Kim1, Jie Yang1, Ronald Jemmerson2  +1 moreInstitutions (2)
12 Jul 1996-Cell
Abstract: A cell-free system based on cytosols of normally growing cells is established that reproduces aspects of the apoptotic program in vitro. The apoptotic program is initiated by addition of dATP. Fractionation of cytosol yielded a 15 kDa protein that is required for in vitro apoptosis. The absorption spectrum and protein sequence revealed that this protein is cytochrome c. Elimination of cytochrome c from cytosol by immunodepletion, or inclusion of sucrose to stabilize mitochondria during cytosol preparation, diminished the apoptotic activity. Adding back cytochrome c to the cytochrome c-depleted extracts restored their apoptotic activity. Cells undergoing apoptosis in vivo showed increased release of cytochrome c to their cytosol, suggesting that mitochondria may function in apoptosis by releasing cytochrome c.

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Topics: Cytochrome c (67%), Apoptosome (66%), Cytochrome c oxidase (63%) ... read more

4,987 Citations

Open accessJournal ArticleDOI: 10.1016/J.CCR.2010.12.014
Wei Xu1, Hui Yang1, Ying Liu1, Ying Yang1  +18 moreInstitutions (3)
18 Jan 2011-Cancer Cell
Abstract: IDH1 and IDH2 mutations occur frequently in gliomas and acute myeloid leukemia, leading to simultaneous loss and gain of activities in the production of α-ketoglutarate (α-KG) and 2-hydroxyglutarate (2-HG), respectively. Here we demonstrate that 2-HG is a competitive inhibitor of multiple α-KG-dependent dioxygenases, including histone demethylases and the TET family of 5-methlycytosine (5mC) hydroxylases. 2-HG occupies the same space as α-KG does in the active site of histone demethylases. Ectopic expression of tumor-derived IDH1 and IDH2 mutants inhibits histone demethylation and 5mC hydroxylation. In glioma, IDH1 mutations are associated with increased histone methylation and decreased 5-hydroxylmethylcytosine (5hmC). Hence, tumor-derived IDH1 and IDH2 mutations reduce α-KG and accumulate an α-KG antagonist, 2-HG, leading to genome-wide histone and DNA methylation alterations.

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Topics: Histone Demethylases (69%), Histone demethylation (67%), Histone methyltransferase (67%) ... read more

2,034 Citations

Open accessJournal ArticleDOI: 10.1126/SCIENCE.1164097
22 May 2009-Science
Abstract: Histone acetylation in single cell eukaryotes relies on acetyl-CoA synthetase enzymes that utilize acetate to produce acetyl-CoA. Metazoans, however, use glucose as their main carbon source and have exposure to only low concentrations of extracellular acetate. We show that histone acetylation in mammalian cells is dependent on ATP-citrate lyase (ACL), the enzyme that converts glucose-derived citrate into acetyl-CoA. We find that ACL is required for increases in histone acetylation in response to growth factor stimulation and during differentiation, and that glucose availability can impact histone acetylation in an ACL-dependent manner. Together, these findings suggest that ACL activity is required to link growth-factor-induced increases in nutrient metabolism to the regulation of histone acetylation and gene expression.

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Topics: SAP30 (67%), Histone H2A (66%), Histone methyltransferase (63%) ... read more

1,458 Citations

Open accessJournal ArticleDOI: 10.1016/J.CELL.2007.01.003
26 Jan 2007-Cell
Abstract: Summary To understand the role of FoxO family members in hematopoiesis, we conditionally deleted FoxO1 , FoxO3 , and FoxO4 in the adult hematopoietic system. FoxO- deficient mice exhibited myeloid lineage expansion, lymphoid developmental abnormalities, and a marked decrease of the lineage-negative Sca-1 + , c-Kit + (LSK) compartment that contains the short- and long-term hematopoietic stem cell (HSC) populations. FoxO -deficient bone marrow had defective long-term repopulating activity that correlated with increased cell cycling and apoptosis of HSC. Notably, there was a marked context-dependent increase in reactive oxygen species (ROS) in FoxO -deficient HSC compared with wild-type HSC that correlated with changes in expression of genes that regulate ROS. Furthermore, in vivo treatment with the antioxidative agent N-acetyl-L-cysteine resulted in reversion of the FoxO -deficient HSC phenotype. Thus, FoxO proteins play essential roles in the response to physiologic oxidative stress and thereby mediate quiescence and enhanced survival in the HSC compartment, a function that is required for its long-term regenerative potential.

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Topics: FOXO Family (67%), Hematopoietic stem cell (53%)

1,420 Citations

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