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


The lack of copper has been associated with anemia, myelodysplastic syndromes and leukemia as well as with a loss in complex IV activity and enlarged mitochondrial morphology. Mitochondria play a key role during the differentiation of hematopoietic stem cell 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 from bone marrow of mice fed with a copper deficient diet and from in vitro erythropoiesis of human CD34+ cells treated with a bathocuproine –a copper chelator- showed a major cell 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 mitochondrial fusion protein, mitofusin 2, was observed. Most of copper-deficient phenotype was mimicked by the pharmacological inhibition of complex IV with azide. We concluded that copper deficiency induced a mitochondrial metabolic reprogramming making hematopoietic stem cells to favor progenitor cell expansion over cell differentiation.

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Publication details

The article was received on 03 Aug 2018, accepted on 08 Oct 2018 and first published on 10 Oct 2018

Article type: Paper
DOI: 10.1039/C8MT00224J
Citation: Metallomics, 2018, Accepted Manuscript
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    Copper deficiency-induced anemia is caused by a mitochondrial metabolic reprograming in erythropoietic cells

    E. L. Jensen, A. M. González-Ibáñez, P. Mendoza, L. Ruiz, C. Riedel, F. Simón, J. J. Schuringa and A. A. Elorza, Metallomics, 2018, Accepted Manuscript , DOI: 10.1039/C8MT00224J

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