bims-mireme Biomed News
on Mitochondria in regenerative medicine
Issue of 2021–04–25
nine papers selected by
Brian Spurlock, University of Alabama at Birmingham
  1. Mitochondrial Sirtuins in Stem cells and Cancer.
  2. The FOXO signaling axis displays conjoined functions in redox homeostasis and stemness.
  3. The role of SQSTM1 (p62) in mitochondrial function and clearance in human cortical neurons.
  4. Stir it up: The role of actin in mitochondrial mixing during mitosis.
  5. Unraveling the Big Sleep: Molecular Aspects of Stem Cell Dormancy and Hibernation.
  6. SPATA33 functions as a mitophagy receptor in mammalian germline.
  7. Mechanistic connections between mitochondrial biology and regulated cell death.
  8. Fitness selection in human pluripotent stem cells and interspecies chimeras: Implications for human development and regenerative medicine.
  9. Human Huntington's disease pluripotent stem cell-derived microglia develop normally but are abnormally hyper-reactive and release elevated levels of reactive oxygen species.
  1. FEBS J. 2021 Apr 18.
    Mitochondrial Sirtuins in Stem cells and Cancer.
    Amit Jaiswal, Zhu Xudong, Ju Zhenyu, Gabriele Saretzki.
      The mammalian sirtuin family consists of seven proteins, three of which (SIRT3, SIRT4, and SIRT5) localise specifically within mitochondria and preserve mitochondrial function and homeostasis. Mitochondrial sirtuins are involved in diverse functions such as deacetylation, ADP-ribosylation, demalonylation and desuccinylation, thus affecting various aspect of cell fate. Intriguingly, mitochondrial sirtuins are able to manage these delicate processes with accuracy mediated by cross-talk between the nucleus and mitochondria. Previous studies have provided ample information about their substrates and targets, whereas less is known about their role in cancer and stem cells. Here, we review and discuss recent advances in our understanding of the structural and functional properties of mitochondrial sirtuins, including their targets in cancer and stem cells. These advances could help to improve the understanding of their interplay with signalling cascades and pathways, leading to new avenues for developing novel drugs for sirtuin-related disease treatments. We also highlight the complex network of mitochondrial sirtuins in cancer and stem cells, which may be important in deciphering the molecular mechanism for their activation and inhibition.
    Keywords:   SIRT3 ; SIRT4 ; SIRT5 ; Cancer; Mitochondria; Sirtuins; Stem cells
    DOI:  https://doi.org/10.1111/febs.15879
  2. Free Radic Biol Med. 2021 Apr 17. pii: S0891-5849(21)00229-X. [Epub ahead of print]
    The FOXO signaling axis displays conjoined functions in redox homeostasis and stemness.
    Ruthia Soh, Ariana Hardy, Nicole I Zur Nieden.
      Previous views of reactive oxygen species (ROS) depicted them as harmful byproducts of metabolism as uncontrolled levels of ROS can lead to DNA damage and cell death. However, recent studies have shed light into the key role of ROS in the self-renewal or differentiation of the stem cell. The interplay between ROS levels, metabolism, and the downstream redox signaling pathways influence stem cell fate. In this review we will define ROS, explain how they are generated, and how ROS signaling can influence transcription factors, first and foremost forkhead box-O transcription factors, that shape not only the cellular redox state, but also stem cell fate. Now that studies have illustrated the importance of redox homeostasis and the role of redox signaling, understanding the mechanisms behind this interplay will further shed light into stem cell biology.
    Keywords:  Pluripotent stem cell; adult stem cell; forkhead box O; oxidative stress; reactive oxygen species; stemness
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2021.04.022
  3. Stem Cell Reports. 2021 Apr 13. pii: S2213-6711(21)00161-2. [Epub ahead of print]
    The role of SQSTM1 (p62) in mitochondrial function and clearance in human cortical neurons.
    Anna Poon, Harpreet Saini, Siddharth Sethi, Gregory A O'Sullivan, Hélène Plun-Favreau, Selina Wray, Lee A Dawson, James M McCarthy.
      Sequestosome-1 (SQSTM1/p62) is involved in cellular processes such as autophagy and metabolic reprogramming. Mutations resulting in the loss of function of SQSTM1 lead to neurodegenerative diseases including frontotemporal dementia. The pathogenic mechanism that contributes to SQSTM1-related neurodegeneration has been linked to its role as an autophagy adaptor, but this is poorly understood, and its precise role in mitochondrial function and clearance remains to be clarified. Here, we assessed the importance of SQSTM1 in human induced pluripotent stem cell (iPSC)-derived cortical neurons through the knockout of SQSTM1. We show that SQSTM1 depletion causes altered mitochondrial gene expression and functionality, as well as autophagy flux, in iPSC-derived neurons. However, SQSTM1 is not essential for mitophagy despite having a significant impact on early PINK1-dependent mitophagy processes including PINK1 recruitment and phosphorylation of ubiquitin on depolarized mitochondria. These findings suggest that SQSTM1 is important for mitochondrial function rather than clearance.
    Keywords:  FTD; SQSTM1; iPSC disease modeling; mitochondria
    DOI:  https://doi.org/10.1016/j.stemcr.2021.03.030
  4. Dev Cell. 2021 Apr 19. pii: S1534-5807(21)00268-9. [Epub ahead of print]56(8): 1080-1082
    Stir it up: The role of actin in mitochondrial mixing during mitosis.
    Sarah E Yde, Rachel S Kadzik, David R Kovar.
      During symmetric cell division, it is important that daughter cells receive not only equal genetic information, but also equal allocations of organelles. Recently, in Nature,Moore et al. (2021) identify three complementary F-actin networks that help ensure proper mixing and distribution of functionally equivalent mitochondria to daughter cells.
    DOI:  https://doi.org/10.1016/j.devcel.2021.03.028
  5. Front Physiol. 2021 ;12 624950
    Unraveling the Big Sleep: Molecular Aspects of Stem Cell Dormancy and Hibernation.
    Itamar B Dias, Hjalmar R Bouma, Robert H Henning.
      Tissue-resident stem cells may enter a dormant state, also known as quiescence, which allows them to withstand metabolic stress and unfavorable conditions. Similarly, hibernating mammals can also enter a state of dormancy used to evade hostile circumstances, such as food shortage and low ambient temperatures. In hibernation, the dormant state of the individual and its cells is commonly known as torpor, and is characterized by metabolic suppression in individual cells. Given that both conditions represent cell survival strategies, we here compare the molecular aspects of cellular quiescence, particularly of well-studied hematopoietic stem cells, and torpor at the cellular level. Critical processes of dormancy are reviewed, including the suppression of the cell cycle, changes in metabolic characteristics, and cellular mechanisms of dealing with damage. Key factors shared by hematopoietic stem cell quiescence and torpor include a reversible activation of factors inhibiting the cell cycle, a shift in metabolism from glucose to fatty acid oxidation, downregulation of mitochondrial activity, key changes in hypoxia-inducible factor one alpha (HIF-1α), mTOR, reversible protein phosphorylation and autophagy, and increased radiation resistance. This similarity is remarkable in view of the difference in cell populations, as stem cell quiescence regards proliferating cells, while torpor mainly involves terminally differentiated cells. A future perspective is provided how to advance our understanding of the crucial pathways that allow stem cells and hibernating animals to engage in their 'great slumbers.'
    Keywords:  cell cycle; cell dormancy; hibernation; metabolism; quiescence; torpor
    DOI:  https://doi.org/10.3389/fphys.2021.624950
  6. Autophagy. 2021 Apr 05. 1-3
    SPATA33 functions as a mitophagy receptor in mammalian germline.
    Xu Xu, Ying Zhang, Hanhua Cheng, Rongjia Zhou.
      Mitophagy is an essential mechanism in maintaining cellular homeostasis, in which damaged and superfluous mitochondria are selectively degraded by the autophagy-lysosome pathway. Our recent study revealed that SPATA33 functions as a novel receptor for mitophagy in the priming of mitochondria for degradation in male germline cells. SPATA33 directly mediates the interaction of the outer mitochondrial membrane protein VDAC2 with the autophagy machinery component ATG16L1 during mitophagy. Upon starvation induction, SPATA33 can promote mitophagy as an autophagy receptor. Thus, SPATA33 confers cargo selectivity during mitophagy in germline cells. These findings provide new insights into selective autophagy and mitochondrial homeostasis.
    Keywords:  Autophagy; SPATA33; mammals; mitochondria; spermatogenesis
    DOI:  https://doi.org/10.1080/15548627.2021.1909836
  7. Dev Cell. 2021 Apr 16. pii: S1534-5807(21)00308-7. [Epub ahead of print]
    Mechanistic connections between mitochondrial biology and regulated cell death.
    Jerry Edward Chipuk, Jarvier N Mohammed, Jesse D Gelles, Yiyang Chen.
      The ancient, dynamic, and multifaceted functions of the mitochondrial network are essential for organismal homeostasis and contribute to numerous human diseases. As central hubs for metabolism, ion transport, and multiple macromolecular synthesis pathways, mitochondria establish and control extensive signaling networks to ensure cellular survival. In this review, we explore how these same mitochondrial functions also participate in the control of regulated cell death (RCD). We discuss the complementary essential mitochondrial functions as compartments that participate in the production and presentation of key molecules and platforms that actively enable, initiate, and execute RCD.
    Keywords:  cell biology; mitochondrial function; programed cell death; regulated cell death; signal transduction; stress signaling
    DOI:  https://doi.org/10.1016/j.devcel.2021.03.033
  8. Dev Biol. 2021 Apr 20. pii: S0012-1606(21)00093-2. [Epub ahead of print]
    Fitness selection in human pluripotent stem cells and interspecies chimeras: Implications for human development and regenerative medicine.
    Jun Wu, Ivana Barbaric.
      A small number of pluripotent cells within early embryo gives rise to all cells in the adult body, including germ cells. Hence, any mutations occurring in the pluripotent cell population are at risk of being propagated to their daughter cells and could lead to congenital defects or embryonic lethality and pose a risk of being transmitted to future generations. The observation that genetic errors are relatively common in preimplantation embryos, but their levels reduce as development progresses, suggests the existence of mechanisms for clearance of aberrant, unfit or damaged cells. Although early human embryogenesis is largely experimentally inaccessible, pluripotent stem cell (PSC) lines can be derived either from the inner cell mass (ICM) of a blastocyst or by reprogramming somatic cells into an embryonic stem cell-like state. PSCs retain the ability to differentiate into any cell type in vitro and, hence, they represent a unique and powerful tool for studying otherwise intractable stages of human development. The advent of PSCs has also opened up a possibility of developing regenerative medicine therapies, either through PSC differentiation in vitro or by creating interspecies chimeras for organ replacement. Here, we discuss the emerging evidence of cell selection in human PSC populations in vivo and in vitro and we highlight the implications of understanding this phenomenon for human development and regenerative medicine.
    Keywords:  Cell competition; Human pluripotent stem cells; Interspecies chimeras
    DOI:  https://doi.org/10.1016/j.ydbio.2021.03.025
  9. J Neuroinflammation. 2021 Apr 19. 18(1): 94
    Human Huntington's disease pluripotent stem cell-derived microglia develop normally but are abnormally hyper-reactive and release elevated levels of reactive oxygen species.
    Grace C O'Regan, Sahar H Farag, Caroline S Casey, Alison Wood-Kaczmar, Jennifer M Pocock, Sarah J Tabrizi, Ralph Andre.
       BACKGROUND: Neuroinflammation may contribute to the pathogenesis of Huntington's disease, given evidence of activated microglia and elevated levels of inflammatory molecules in disease gene carriers, even those many years from symptom onset. We have shown previously that monocytes from Huntington's disease patients are hyper-reactive to stimulation in a manner dependent on their autonomous expression of the disease-causing mutant HTT protein. To date, however, whether human microglia are similarly hyper-responsive in a cell-autonomous manner has not been determined.
    METHODS: Microglial-like cells were derived from human pluripotent stem cells (PSCs) expressing mutant HTT containing varying polyglutamine lengths. These included lines that are otherwise isogenic, such that any observed differences can be attributed with certainty to the disease mutation itself. Analyses by quantitative PCR and immunofluorescence microscopy respectively of key genes and protein markers were undertaken to determine whether Huntington's disease PSCs differentiated normally to a microglial fate. The resultant cultures and their supernatants were then assessed by various biochemical assays and multiplex ELISAs for viability and responses to stimulation, including the release of pro-inflammatory cytokines and reactive oxygen species. Conditioned media were applied to PSC-derived striatal neurons, and vice versa, to determine the effects that the secretomes of each cell type might have on the other.
    RESULTS: Human PSCs generated microglia successfully irrespective of the expression of mutant HTT. These cells, however, were hyper-reactive to stimulation in the production of pro-inflammatory cytokines such as IL-6 and TNFα. They also released elevated levels of reactive oxygen species that have neurotoxic potential. Accompanying such phenotypes, human Huntington's disease PSC-derived microglia showed increased levels of apoptosis and were more susceptible to exogenous stress. Such stress appeared to be induced by supernatants from human PSC-derived striatal neurons expressing mutant HTT with a long polyglutamine tract.
    CONCLUSIONS: These studies show, for the first time, that human Huntington's disease PSC-derived microglia are hyper-reactive due to their autonomous expression of mutant HTT. This provides a cellular basis for the contribution that neuroinflammation might make to Huntington's disease pathogenesis.
    Keywords:  Cytokines; Huntington’s disease; Microglia; Neurodegeneration; Pluripotent stem cells; Reactive oxygen species; Striatal neurons
    DOI:  https://doi.org/10.1186/s12974-021-02147-6
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