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Erythroid Differentiation and Heme Biosynthesis Are Dependent on a Shift in the Balance of Mitochondrial Fusion and Fission Dynamics
Erythropoiesis is the most robust cellular differentiation and proliferation system, with a production of ∼2 × 10(11) cells per day. In this fine-tuned process, the hematopoietic stem cells (HSCs) generate erythroid progenitors, which proliferate and mature into erythrocytes. During erythropoiesis,...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Frontiers Media S.A.
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7719720/ https://www.ncbi.nlm.nih.gov/pubmed/33330472 http://dx.doi.org/10.3389/fcell.2020.592035 |
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author | Gonzalez-Ibanez, Alvaro M. Ruiz, Lina M. Jensen, Erik Echeverria, Cesar A. Romero, Valentina Stiles, Linsey Shirihai, Orian S. Elorza, Alvaro A. |
author_facet | Gonzalez-Ibanez, Alvaro M. Ruiz, Lina M. Jensen, Erik Echeverria, Cesar A. Romero, Valentina Stiles, Linsey Shirihai, Orian S. Elorza, Alvaro A. |
author_sort | Gonzalez-Ibanez, Alvaro M. |
collection | PubMed |
description | Erythropoiesis is the most robust cellular differentiation and proliferation system, with a production of ∼2 × 10(11) cells per day. In this fine-tuned process, the hematopoietic stem cells (HSCs) generate erythroid progenitors, which proliferate and mature into erythrocytes. During erythropoiesis, mitochondria are reprogrammed to drive the differentiation process before finally being eliminated by mitophagy. In erythropoiesis, mitochondrial dynamics (MtDy) are expected to be a key regulatory point that has not been described previously. We described that a specific MtDy pattern occurs in human erythropoiesis from EPO-induced human CD34(+) cells, characterized predominantly by mitochondrial fusion at early stages followed by fission at late stages. The fusion protein MFN1 and the fission protein FIS1 are shown to play a key role in the progression of erythropoiesis. Fragmentation of the mitochondrial web by the overexpression of FIS1 (gain of fission) resulted in both the inhibition of hemoglobin biosynthesis and the arrest of erythroid differentiation, keeping cells in immature differentiation stages. These cells showed specific mitochondrial features as compared with control cells, such as an increase in round and large mitochondrial morphology, low mitochondrial membrane potential, a drop in the expression of the respiratory complexes II and IV and increased ROS. Interestingly, treatment with the mitochondrial permeability transition pore (mPTP) inhibitor, cyclosporin A, rescued mitochondrial morphology, hemoglobin biosynthesis and erythropoiesis. Studies presented in this work reveal MtDy as a hot spot in the control of erythroid differentiation, which might signal downstream for metabolic reprogramming through regulation of the mPTP. |
format | Online Article Text |
id | pubmed-7719720 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-77197202020-12-15 Erythroid Differentiation and Heme Biosynthesis Are Dependent on a Shift in the Balance of Mitochondrial Fusion and Fission Dynamics Gonzalez-Ibanez, Alvaro M. Ruiz, Lina M. Jensen, Erik Echeverria, Cesar A. Romero, Valentina Stiles, Linsey Shirihai, Orian S. Elorza, Alvaro A. Front Cell Dev Biol Cell and Developmental Biology Erythropoiesis is the most robust cellular differentiation and proliferation system, with a production of ∼2 × 10(11) cells per day. In this fine-tuned process, the hematopoietic stem cells (HSCs) generate erythroid progenitors, which proliferate and mature into erythrocytes. During erythropoiesis, mitochondria are reprogrammed to drive the differentiation process before finally being eliminated by mitophagy. In erythropoiesis, mitochondrial dynamics (MtDy) are expected to be a key regulatory point that has not been described previously. We described that a specific MtDy pattern occurs in human erythropoiesis from EPO-induced human CD34(+) cells, characterized predominantly by mitochondrial fusion at early stages followed by fission at late stages. The fusion protein MFN1 and the fission protein FIS1 are shown to play a key role in the progression of erythropoiesis. Fragmentation of the mitochondrial web by the overexpression of FIS1 (gain of fission) resulted in both the inhibition of hemoglobin biosynthesis and the arrest of erythroid differentiation, keeping cells in immature differentiation stages. These cells showed specific mitochondrial features as compared with control cells, such as an increase in round and large mitochondrial morphology, low mitochondrial membrane potential, a drop in the expression of the respiratory complexes II and IV and increased ROS. Interestingly, treatment with the mitochondrial permeability transition pore (mPTP) inhibitor, cyclosporin A, rescued mitochondrial morphology, hemoglobin biosynthesis and erythropoiesis. Studies presented in this work reveal MtDy as a hot spot in the control of erythroid differentiation, which might signal downstream for metabolic reprogramming through regulation of the mPTP. Frontiers Media S.A. 2020-11-23 /pmc/articles/PMC7719720/ /pubmed/33330472 http://dx.doi.org/10.3389/fcell.2020.592035 Text en Copyright © 2020 Gonzalez-Ibanez, Ruiz, Jensen, Echeverria, Romero, Stiles, Shirihai and Elorza. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Cell and Developmental Biology Gonzalez-Ibanez, Alvaro M. Ruiz, Lina M. Jensen, Erik Echeverria, Cesar A. Romero, Valentina Stiles, Linsey Shirihai, Orian S. Elorza, Alvaro A. Erythroid Differentiation and Heme Biosynthesis Are Dependent on a Shift in the Balance of Mitochondrial Fusion and Fission Dynamics |
title | Erythroid Differentiation and Heme Biosynthesis Are Dependent on a Shift in the Balance of Mitochondrial Fusion and Fission Dynamics |
title_full | Erythroid Differentiation and Heme Biosynthesis Are Dependent on a Shift in the Balance of Mitochondrial Fusion and Fission Dynamics |
title_fullStr | Erythroid Differentiation and Heme Biosynthesis Are Dependent on a Shift in the Balance of Mitochondrial Fusion and Fission Dynamics |
title_full_unstemmed | Erythroid Differentiation and Heme Biosynthesis Are Dependent on a Shift in the Balance of Mitochondrial Fusion and Fission Dynamics |
title_short | Erythroid Differentiation and Heme Biosynthesis Are Dependent on a Shift in the Balance of Mitochondrial Fusion and Fission Dynamics |
title_sort | erythroid differentiation and heme biosynthesis are dependent on a shift in the balance of mitochondrial fusion and fission dynamics |
topic | Cell and Developmental Biology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7719720/ https://www.ncbi.nlm.nih.gov/pubmed/33330472 http://dx.doi.org/10.3389/fcell.2020.592035 |
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