Copper deficiency-induced anemia is caused by a mitochondrial metabolic reprograming in erythropoietic cells

Erik L. Jensen, Alvaro M. Gonzalez-Ibanez, Pierina Mendoza, Lina M. Ruiz, Claudia A. Riedel, Felipe Simon, Jan J. Schuringa, Alvaro A. Elorza

Resultado de la investigación: Article

1 Cita (Scopus)

Resumen

The lack of copper has been associated with anemia, myelodysplastic syndromes and leukemia as well as with a loss in complex IV activity and an enlarged mitochondrial morphology. Mitochondria play a key role during the differentiation of hematopoietic stem cells by regulating the passage from a glycolytic to oxidative metabolism. The former is associated with cell proliferation and the latter with cell differentiation. Oxidative metabolism, which occurs inside mitochondria, is sustained by the respiratory chain, where complex IV is copper-dependent. We have hypothesized that a copper deficiency induces a mitochondrial metabolic reprogramming, favoring cell expansion over cell differentiation in erythropoiesis. Erythroid progression analysis of the bone marrow of mice fed with a copper deficient diet and of the in vitro erythropoiesis of human CD34+ cells treated with a bathocuproine-a copper chelator-showed a major expansion of progenitor cells and a decreased differentiation. Under copper deficiency, mitochondria switched to a higher membrane potential, lower oxygen consumption rate and lower ROS levels as compared with control cells. In addition, mitochondrial biomass was increased and an up-regulation of the mitochondrial fusion protein mitofusin 2 was observed. Most copper-deficient phenotypes were mimicked by the pharmacological inhibition of complex IV with azide. We concluded that copper deficiency induced a mitochondrial metabolic reprogramming, making hematopoietic stem cells favor progenitor cell expansion over cell differentiation.

Idioma originalEnglish
Páginas (desde-hasta)282-290
Número de páginas9
PublicaciónMetallomics
Volumen11
N.º2
DOI
EstadoPublished - 1 feb 2019

Huella dactilar

Anemia
Copper
Mitochondria
Cell Differentiation
Erythropoiesis
Hematopoietic Stem Cells
Stem cells
Metabolism
Stem Cells
Mitochondrial Dynamics
Azides
Mitochondrial Proteins
Myelodysplastic Syndromes
Cell proliferation
Nutrition
Chelating Agents
Electron Transport
Oxygen Consumption
Membrane Potentials
Biomass

ASJC Scopus subject areas

  • Chemistry (miscellaneous)
  • Biophysics
  • Biomaterials
  • Biochemistry
  • Metals and Alloys

Citar esto

Jensen, Erik L. ; Gonzalez-Ibanez, Alvaro M. ; Mendoza, Pierina ; Ruiz, Lina M. ; Riedel, Claudia A. ; Simon, Felipe ; Schuringa, Jan J. ; Elorza, Alvaro A. / Copper deficiency-induced anemia is caused by a mitochondrial metabolic reprograming in erythropoietic cells. En: Metallomics. 2019 ; Vol. 11, N.º 2. pp. 282-290.
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abstract = "The lack of copper has been associated with anemia, myelodysplastic syndromes and leukemia as well as with a loss in complex IV activity and an enlarged mitochondrial morphology. Mitochondria play a key role during the differentiation of hematopoietic stem cells by regulating the passage from a glycolytic to oxidative metabolism. The former is associated with cell proliferation and the latter with cell differentiation. Oxidative metabolism, which occurs inside mitochondria, is sustained by the respiratory chain, where complex IV is copper-dependent. We have hypothesized that a copper deficiency induces a mitochondrial metabolic reprogramming, favoring cell expansion over cell differentiation in erythropoiesis. Erythroid progression analysis of the bone marrow of mice fed with a copper deficient diet and of the in vitro erythropoiesis of human CD34+ cells treated with a bathocuproine-a copper chelator-showed a major expansion of progenitor cells and a decreased differentiation. Under copper deficiency, mitochondria switched to a higher membrane potential, lower oxygen consumption rate and lower ROS levels as compared with control cells. In addition, mitochondrial biomass was increased and an up-regulation of the mitochondrial fusion protein mitofusin 2 was observed. Most copper-deficient phenotypes were mimicked by the pharmacological inhibition of complex IV with azide. We concluded that copper deficiency induced a mitochondrial metabolic reprogramming, making hematopoietic stem cells favor progenitor cell expansion over cell differentiation.",
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Jensen, EL, Gonzalez-Ibanez, AM, Mendoza, P, Ruiz, LM, Riedel, CA, Simon, F, Schuringa, JJ & Elorza, AA 2019, 'Copper deficiency-induced anemia is caused by a mitochondrial metabolic reprograming in erythropoietic cells', Metallomics, vol. 11, n.º 2, pp. 282-290. https://doi.org/10.1039/c8mt00224j

Copper deficiency-induced anemia is caused by a mitochondrial metabolic reprograming in erythropoietic cells. / Jensen, Erik L.; Gonzalez-Ibanez, Alvaro M.; Mendoza, Pierina; Ruiz, Lina M.; Riedel, Claudia A.; Simon, Felipe; Schuringa, Jan J.; Elorza, Alvaro A.

En: Metallomics, Vol. 11, N.º 2, 01.02.2019, p. 282-290.

Resultado de la investigación: Article

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T1 - Copper deficiency-induced anemia is caused by a mitochondrial metabolic reprograming in erythropoietic cells

AU - Jensen, Erik L.

AU - Gonzalez-Ibanez, Alvaro M.

AU - Mendoza, Pierina

AU - Ruiz, Lina M.

AU - Riedel, Claudia A.

AU - Simon, Felipe

AU - Schuringa, Jan J.

AU - Elorza, Alvaro A.

PY - 2019/2/1

Y1 - 2019/2/1

N2 - The lack of copper has been associated with anemia, myelodysplastic syndromes and leukemia as well as with a loss in complex IV activity and an enlarged mitochondrial morphology. Mitochondria play a key role during the differentiation of hematopoietic stem cells by regulating the passage from a glycolytic to oxidative metabolism. The former is associated with cell proliferation and the latter with cell differentiation. Oxidative metabolism, which occurs inside mitochondria, is sustained by the respiratory chain, where complex IV is copper-dependent. We have hypothesized that a copper deficiency induces a mitochondrial metabolic reprogramming, favoring cell expansion over cell differentiation in erythropoiesis. Erythroid progression analysis of the bone marrow of mice fed with a copper deficient diet and of the in vitro erythropoiesis of human CD34+ cells treated with a bathocuproine-a copper chelator-showed a major expansion of progenitor cells and a decreased differentiation. Under copper deficiency, mitochondria switched to a higher membrane potential, lower oxygen consumption rate and lower ROS levels as compared with control cells. In addition, mitochondrial biomass was increased and an up-regulation of the mitochondrial fusion protein mitofusin 2 was observed. Most copper-deficient phenotypes were mimicked by the pharmacological inhibition of complex IV with azide. We concluded that copper deficiency induced a mitochondrial metabolic reprogramming, making hematopoietic stem cells favor progenitor cell expansion over cell differentiation.

AB - The lack of copper has been associated with anemia, myelodysplastic syndromes and leukemia as well as with a loss in complex IV activity and an enlarged mitochondrial morphology. Mitochondria play a key role during the differentiation of hematopoietic stem cells by regulating the passage from a glycolytic to oxidative metabolism. The former is associated with cell proliferation and the latter with cell differentiation. Oxidative metabolism, which occurs inside mitochondria, is sustained by the respiratory chain, where complex IV is copper-dependent. We have hypothesized that a copper deficiency induces a mitochondrial metabolic reprogramming, favoring cell expansion over cell differentiation in erythropoiesis. Erythroid progression analysis of the bone marrow of mice fed with a copper deficient diet and of the in vitro erythropoiesis of human CD34+ cells treated with a bathocuproine-a copper chelator-showed a major expansion of progenitor cells and a decreased differentiation. Under copper deficiency, mitochondria switched to a higher membrane potential, lower oxygen consumption rate and lower ROS levels as compared with control cells. In addition, mitochondrial biomass was increased and an up-regulation of the mitochondrial fusion protein mitofusin 2 was observed. Most copper-deficient phenotypes were mimicked by the pharmacological inhibition of complex IV with azide. We concluded that copper deficiency induced a mitochondrial metabolic reprogramming, making hematopoietic stem cells favor progenitor cell expansion over cell differentiation.

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DO - 10.1039/c8mt00224j

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JO - Metallomics

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