AK2 deficiency compromises the mitochondrial energy metabolism required for differentiation of human neutrophil and lymphoid lineages.
Reticular dysgenesis is a human severe combined immunodeficiency that is primarily characterized by profound neutropenia and lymphopenia. The condition is caused by mutations in the adenylate kinase 2 (AK2) gene, resulting in the loss of mitochondrial AK2 protein expression. AK2 regulates the homeostasis of mitochondrial adenine nucleotides (ADP, ATP and AMP) by catalyzing the transfer of high-energy phosphate. Our present results demonstrate that AK2-knocked-down progenitor cells have poor proliferative and survival capacities and are blocked in their differentiation toward lymphoid and granulocyte lineages. We also observed that AK2 deficiency impaired mitochondrial function in general and oxidative phosphorylation in particular - showing that AK2 is critical in the control of energy metabolism. Loss of AK2 disrupts this regulation and leads to a profound block in lymphoid and myeloid cell differentiation.
1] Laboratory of Human Lymphohematopoiesis, INSERM UMR 1163, Paris, France [2] Paris Descartes-Sorbonne Paris Cité University, Imagine Institute, Paris, France.
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Six
1] Laboratory of Human Lymphohematopoiesis, INSERM UMR 1163, Paris, France [2] Paris Descartes-Sorbonne Paris Cité University, Imagine Institute, Paris, France.
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Lagresle-Peyrou
1] Laboratory of Human Lymphohematopoiesis, INSERM UMR 1163, Paris, France [2] Paris Descartes-Sorbonne Paris Cité University, Imagine Institute, Paris, France.
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Susini
1] Laboratory of Human Lymphohematopoiesis, INSERM UMR 1163, Paris, France [2] Paris Descartes-Sorbonne Paris Cité University, Imagine Institute, Paris, France.
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De Chappedelaine
1] Laboratory of Human Lymphohematopoiesis, INSERM UMR 1163, Paris, France [2] Paris Descartes-Sorbonne Paris Cité University, Imagine Institute, Paris, France.
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Sigrist
1] Laboratory of Human Lymphohematopoiesis, INSERM UMR 1163, Paris, France [2] Paris Descartes-Sorbonne Paris Cité University, Imagine Institute, Paris, France.
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Sadek
1] Laboratory of Human Lymphohematopoiesis, INSERM UMR 1163, Paris, France [2] Paris Descartes-Sorbonne Paris Cité University, Imagine Institute, Paris, France.
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Chouteau
SFR Necker, Plateforme de bioinformatique, Paris Descartes-Sorbonne Paris Cité University, Paris, France.
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Cagnard
Department of Immunology and Hematology, Cochin Institute, INSERM U1016, Paris, France.
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Fontenay
1] Paris Descartes-Sorbonne Paris Cité University, Imagine Institute, Paris, France [2] Department of Adult Hematology, Necker Children's Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France.
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Hermine
1] Service de Biologie Cellulaire, Hopital Saint-Louis, Assistance Publique-Hôpitaux de Paris, Paris, France [2] INSERM UMRS 940, Diderot - Sorbonne Paris Cité University, Paris, France.
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Chomienne
UMR CNRS6214, INSERM 1083, Département de Biochimie et Génétique, Centre Hospitalier Universitaire, Angers, France.
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Reynier
1] Paris Descartes-Sorbonne Paris Cité University, Imagine Institute, Paris, France [2] Pediatric Immunology-Hematology and Rhumatology Department, Necker Children's Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France [3] Collège de France, Paris, France.
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Fischer
1] Laboratory of Human Lymphohematopoiesis, INSERM UMR 1163, Paris, France [2] Paris Descartes-Sorbonne Paris Cité University, Imagine Institute, Paris, France.
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André-Schmutz
UMR CNRS6214, INSERM 1083, Département de Biochimie et Génétique, Centre Hospitalier Universitaire, Angers, France.
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Gueguen
1] Laboratory of Human Lymphohematopoiesis, INSERM UMR 1163, Paris, France [2] Paris Descartes-Sorbonne Paris Cité University, Imagine Institute, Paris, France [3] Biotherapy Department, Necker Children's Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France [4] Biotherapy Clinical Investigation Center, Groupe Hospitalier Universitaire Ouest, Assistance Publique-Hôpitaux de Paris, INSERM, Paris, France.
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Cavazzana
D000227:Adenine Nucleotides / Q000378:metabolism; D000263:Adenylate Kinase / Q000172:deficiency / Q000235:genetics*; D018952:Antigens, CD34 / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D055785:Gene Knockdown Techniques; D018922:HL-60 Cells; D006801:Humans; D007970:Leukopenia / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D008214:Lymphocytes / Q000201:enzymology* / Q000473:pathology; D008928:Mitochondria / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D009154:Mutation; D009504:Neutrophils / Q000201:enzymology* / Q000473:pathology; D010085:Oxidative Phosphorylation; D061251:Primary Cell Culture; D016511:Severe Combined Immunodeficiency / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D013234:Stem Cells / Q000201:enzymology* / Q000473:pathology
D000227:Adenine Nucleotides; D018952:Antigens, CD34; D000263:Adenylate Kinase; C110938:adenylate kinase 2