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Hematopoiesis
Human erythroid differentiation requires VDAC1-mediated mitochondrial clearance
Martina Moras,1,2,3 Claude Hattab,1,2,3 Pedro Gonzalez-Menendez,3,4 Claudio M. Fader,5,6 Michael Dussiot,3,7 Jerome Larghero,8 Caroline Le Van Kim,1,2,3 Sandrina Kinet,3,4 Naomi Taylor,3,4,9 Sophie D. Lefevre1,2,3# and Mariano A. Ostuni1,2,3#
1Université de Paris, UMR_S1134, BIGR, Inserm, Paris, France; 2Institut National de Transfusion Sanguine, Paris, France; 3Laboratoire d’Excellence GR-Ex, Paris, France; 4Institut de Génétique Moléculaire de Montpellier, Université de Montpellier, CNRS, Montpellier, France; 5Laboratorio de Biología Celular y Molecular, Instituto de Histología y Embriología (IHEM), Universidad Nacional de Cuyo, CONICET, Mendoza, Argentina; 6Facultad de Odontología, Universidad Nacional de Cuyo, Mendoza, Argentina; 7Université de Paris, UMR_S1163, Laboratory of Cellular and Molecular Mechanisms of Hematological Disorders and Therapeutical Implication, INSERM, Paris, France; 8AP-HP, Hôpital Saint-Louis, Unité de Thérapie Cellulaire, Paris, France and 9Pediatric Oncology Branch, Center for Cancer Research (CCR), National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, MD, USA
#SDL and MAO contributed equally as co-senior authors
ABSTRACT
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 accel- erates 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-ery- throid cells, VDAC1 was identified as a target for Parkin-mediated ubiq- uitination 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.
Introduction
Mature erythrocytes result from a finely regulated process called erythropoiesis, producing two million erythrocytes every second in healthy human adults.1 In mammals, during the late stages of terminal erythroid differentiation, erythrob- lasts expel their nuclei and lose their organelles including the Golgi apparatus, endoplasmic reticulum (ER), ribosomes and mitochondria.2 Organelles can be eliminated by the general process of macro-autophagy. This process is initiated by the formation of a double membrane structure called phagophore, engulfing cyto- plasmic material to form the autophagosome which fuses with a lysosome for degradation.3 Alternatively, mitochondria can be eliminated by a selective autophagic process called mitophagy, in which outer mitochondrial membrane (OMM) proteins act as signals to recruit the phagophore membrane.4 In erythroid progenitors, much work has shown that autophagy is essential for the organelle removal that occurs during reticulocyte maturation.5,6 Notably though, the major- ity of these studies were performed in human progenitors that had already reached the reticulocyte stage of differentiation or in genetic mouse models that
Ferrata Storti Foundation
Haematologica 2022 Volume 107(1):167-177
Correspondence:
MARIANO A. OSTUNI
mariano.ostuni@inserm.fr
SOPHIE D. LEFEVRE sophie.lefevre@inserm.fr
Received: April 29, 2020. Accepted: December 21, 2020. Pre-published: January 7, 2021.
https://doi.org/10.3324/haematol.2020.257121 ©2022 Ferrata Storti Foundation
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