Human erythroid differentiation requires VDAC1-mediated mitochondrial clearance
Martina Moras,
Claude Hattab,
Pedro Gonzalez-Menendez,
Claudio M. Fader,
Michael Dussiot,
Jerome Larghero,
Caroline Le Van Kim,
Sandrina Kinet,
Naomi Taylor,
Sophie D. Lefevre,
Mariano A. Ostuni
Affiliations
Martina Moras
Université de Paris, UMR_S1134, BIGR, Inserm, F-75015 Paris, France; Institut National de Transfusion Sanguine, F-75015 Paris, France; Laboratoire d’Excellence GR-Ex, F-75015, Paris
Claude Hattab
Université de Paris, UMR_S1134, BIGR, Inserm, F-75015 Paris, France; Institut National de Transfusion Sanguine, F-75015 Paris, France; Laboratoire d’Excellence GR-Ex, F-75015, Paris
Pedro Gonzalez-Menendez
Laboratoire d’Excellence GR-Ex, F-75015, Paris, France; Institut de Génétique Moléculaire de Montpellier, Univ Montpellier, CNRS, Montpellier
Claudio M. Fader
Laboratorio de Biología Celular y Molecular, Instituto de Histología y Embriología (IHEM), Universidad Nacional de Cuyo, CONICET, Mendoza, Argentina; Facultad de Odontología, Universidad Nacional de Cuyo, Mendoza
Michael Dussiot
Laboratoire d’Excellence GR-Ex, F-75015, Paris, France; Université de Paris, UMR_S1163, Laboratory of Cellular and Molecular Mechanisms of Hematological Disorders and Therapeutical Implication, Inserm, F-75014 Paris
Jerome Larghero
AP-HP, Hôpital Saint-Louis, Unité de Thérapie cellulaire, Paris
Caroline Le Van Kim
Université de Paris, UMR_S1134, BIGR, Inserm, F-75015 Paris, France; Institut National de Transfusion Sanguine, F-75015 Paris, France; Laboratoire d’Excellence GR-Ex, F-75015, Paris
Sandrina Kinet
Laboratoire d’Excellence GR-Ex, F-75015, Paris, France; Institut de Génétique Moléculaire de Montpellier, Univ Montpellier, CNRS, Montpellier
Naomi Taylor
Laboratoire d’Excellence GR-Ex, F-75015, Paris, France; Institut de Génétique Moléculaire de Montpellier, Univ Montpellier, CNRS, Montpellier, France; Pediatric Oncology Branch, Center for Cancer Research (CCR), National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, Maryland
Sophie D. Lefevre
Université de Paris, UMR_S1134, BIGR, Inserm, F-75015 Paris, France; Institut National de Transfusion Sanguine, F-75015 Paris, France; Laboratoire d’Excellence GR-Ex, F-75015, Paris
Mariano A. Ostuni
Université de Paris, UMR_S1134, BIGR, Inserm, F-75015 Paris, France; Institut National de Transfusion Sanguine, F-75015 Paris, France; Laboratoire d’Excellence GR-Ex, F-75015, Paris
Erythroblast maturation in mammals is dependent on organelle clearance throughout terminal erythropoiesis. We studied the role of the outer mitochondrial membrane protein voltage-dependent anion channel-1 (VDAC1) in human terminal erythropoiesis. We show that short hairpin (shRNA)-mediated downregulation of VDAC1 accelerates erythroblast maturation. Thereafter, erythroblasts are blocked at the orthochromatic stage, exhibiting a significant decreased level of enucleation, concomitant with an increased cell death. We demonstrate that mitochondria clearance starts at the transition from basophilic to polychromatic erythroblast, and that VDAC1 downregulation induces the mitochondrial retention. In damaged mitochondria from non-erythroid cells, VDAC1 was identified as a target for Parkin-mediated ubiquitination to recruit the phagophore. Here, we showed that VDAC1 is involved in phagophore’s membrane recruitment regulating selective mitophagy of still functional mitochondria from human erythroblasts. These findings demonstrate for the first time a crucial role for VDAC1 in human erythroblast terminal differentiation, regulating mitochondria clearance.