bims-mireme Biomed News
on Mitochondria in regenerative medicine
Issue of 2021‒05‒30
six papers selected by
Brian Spurlock
University of Alabama at Birmingham

  1. Elife. 2021 May 24. pii: e59791. [Epub ahead of print]10
      The Wnt-pathway is part of a signalling network that regulates many aspects of cell biology. Recently we discovered crosstalk between AMPA/Kainate-type ionotropic glutamate receptors (iGluRs) and the Wnt-pathway during the initial Wnt3a-interaction at the cytonemes of mouse embryonic stem cells (ESCs). Here, we demonstrate that this crosstalk persists throughout the Wnt3a-response in ESCs. Both AMPA- and Kainate-receptors regulate early Wnt3a-recruitment, dynamics on the cell membrane, and orientation of the spindle towards a Wnt3a-source at mitosis. AMPA-receptors specifically are required for segregating cell fate components during Wnt3a-mediated asymmetric cell division (ACD). Using Wnt-pathway component knockout lines, we determine that Wnt co-receptor Lrp6 has particular functionality over Lrp5 in cytoneme formation, and in facilitating ACD. Both Lrp5 and 6, alongside pathway effector β-catenin act in concert to mediate the positioning of the dynamic interaction with, and spindle orientation to, a localized Wnt3a-source. Wnt-iGluR crosstalk may prove pervasive throughout embryonic and adult stem cell signalling.
    Keywords:  cell biology; mouse; regenerative medicine; stem cells
  2. Development. 2021 May 15. pii: dev191924. [Epub ahead of print]148(10):
      Cellular metabolism has recently emerged as a key regulator of stem cell behavior. Various studies have suggested that metabolic regulatory mechanisms are conserved in different stem cell niches, suggesting a common level of stem cell regulation across tissues. Although the balance between glycolysis and oxidative phosphorylation has been shown to be distinct in stem cells and their differentiated progeny, much less is known about lipid metabolism in stem cell regulation. In this Review, we focus on how stem cells are affected by two major lipid metabolic pathways: the build-up of lipids, called de novo lipogenesis, and the breakdown of lipids, called fatty acid beta-oxidation. We cover the recent literature on hematopoietic stem cells, intestinal stem cells, neural stem/progenitor cells and cancer stem cells, where these two lipid pathways have been studied in more depth.
    Keywords:   De novo lipogenesis; Cancer stem cells; Fatty acid beta-oxidation; Hematopoietic stem cells; Intestinal stem cells; Lipid metabolism; Neural stem/progenitor cells
  3. Anal Chem. 2021 May 26.
      Peroxynitrite (ONOO-) and glutathione (GSH), two unique reactive species, play an essential regulating role in the oxidation and antioxidation in the living body and are closely associated with various physiological and pathological processes, like cancer, cardiovascular disorders, diabetes, inflammation, Alzheimer's disease, and hepatotoxicity. Thus, it is crucial to study mitochondria ONOO-/GSH redox cycles by an effective molecular tool. In this work, a mitochondria-targeting and redox-reversible near-infrared (NIR) phosphorescent iridium complex, Ir-diol, has been synthesized and used for the detection and imaging of a cellular redox state by visualizing endogenous ONOO-/GSH content. Ir-diol shows excellent photophysical properties, including NIR emission (the maximum emissive wavelength for 704 nm, approximately) and high phosphorescent quantum yield (Φ = 0.136) and exhibits high sensitivity and selectivity toward ONOO-/GSH redox cycles in aqueous solution and living cells. Therefore, these features, combined with low cytotoxicity and excellent cell permeability, enable probe Ir-diol to monitor the changes of the intracellular ONOO-/GSH level induced by drug both in vitro and in vivo.
  4. Br J Haematol. 2021 May 25.
      Adult erythropoiesis entails a series of well-coordinated events that produce mature red blood cells. One of such events is the mitochondria clearance that occurs cell-autonomously via autophagy-dependent mechanisms. Interestingly, recent studies have shown mitochondria transfer activities between various cell types. In the context of erythropoiesis, macrophages are known to interact closely with the early stages of erythroblasts to provide a specialized niche, termed erythroblastic islands (EBI). However, whether mitochondria transfer can occur in the EBI niche has not been explored. Here, we report that mitochondria transfer in the EBI niche occurs in vivo. We observed mitochondria transfer activities from the early stages of erythroblasts to macrophages in the reconstituted in vitro murine EBI via different modes, including tunnelling nanotubes (TNT). Moreover, we demonstrated that Wiskott-Aldrich syndrome protein (WASp) in macrophages mediates TNT formation and mitochondria transfer via the modulation of F-actin filamentation, thus promoting mitochondria clearance from erythroid cells, to potentially enhance their differentiation. Taken together, our findings provide novel insight into the mitochondria clearance machineries that mediate erythroid maturation.
    Keywords:  F-actin filamentation; erythroblastic island; erythropoiesis; mitochondria transfer; tunnelling nanotubes
  5. Sci Rep. 2021 May 25. 11(1): 10897
      Mitochondrial diseases currently have no cure regardless of whether the cause is a nuclear or mitochondrial genome mutation. Mitochondrial dysfunction notably affects a wide range of disorders in aged individuals, including neurodegenerative diseases, cancers, and even senescence. Here, we present a procedure to generate mitochondrial DNA-replaced somatic cells with a combination of a temporal reduction in endogenous mitochondrial DNA and coincubation with exogeneous isolated mitochondria. Heteroplasmy in mitochondrial disease patient-derived fibroblasts in which the mutant genotype was dominant over the wild-type genotype was reversed. Mitochondrial disease patient-derived fibroblasts regained respiratory function and showed lifespan extension. Mitochondrial membranous components were utilized as a vehicle to deliver the genetic materials into endogenous mitochondria-like horizontal genetic transfer in prokaryotes. Mitochondrial DNA-replaced cells could be a resource for transplantation to treat maternal inherited mitochondrial diseases.
  6. Front Oncol. 2021 ;11 672781
      Mitochondria are vital organelles in cells, regulating energy metabolism and apoptosis. Mitochondrial transcellular transfer plays a crucial role during physiological and pathological conditions, such as rescuing recipient cells from bioenergetic deficit and tumorigenesis. Studies have shown several structures that conduct transcellular transfer of mitochondria, including tunneling nanotubes (TNTs), extracellular vesicles (EVs), and Cx43 gap junctions (GJs). The intra- and intercellular transfer of mitochondria is driven by a transport complex. Mitochondrial Rho small GTPase (MIRO) may be the adaptor that connects the transport complex with mitochondria, and myosin XIX is the motor protein of the transport complex, which participates in the transcellular transport of mitochondria through TNTs. In this review, the roles of TNTs, EVs, GJs, and related transport complexes in mitochondrial transcellular transfer are discussed in detail, as well as the formation mechanisms of TNTs and EVs. This review provides the basis for the development of potential clinical therapies targeting the structures of mitochondrial transcellular transfer.
    Keywords:  Cx43 gap junction; Miro; extracellular vesicles; mitochondria; myosin XIX; transcellular transport; tunneling nanotubes