1. Downregulation of Mitochondrial TSPO Inhibits Mitophagy and Reduces Enucleation During Human Terminal Erythropoiesis
- Author
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Naomi Taylor, Claude Hattab, Suella Martino, Mariano A. Ostuni, Sophie D. Lefevre, Martina Moras, Pedro Gonzalez-Menendez, Jérôme Larghero, Sandrina Kinet, Caroline Le Van Kim, KARLI, Mélanie, Biologie Intégrée du Globule Rouge (BIGR (UMR_S_1134 / U1134)), Institut National de la Transfusion Sanguine [Paris] (INTS)-Université de La Réunion (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pointe-à-Pitre/Abymes [Guadeloupe] -Université des Antilles (UA)-Université Paris Cité (UPCité), Institut National de la Transfusion Sanguine [Paris] (INTS), Laboratoire d'Excellence : Biogenèse et pathologies du globule rouge (Labex Gr-Ex), Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Hematopoïèse et Immunothérapie, Institut de Génétique Moléculaire de Montpellier (IGMM), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), CIC - Biotherapie - Saint Louis ((CIC-BT 301)), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut National de la Transfusion Sanguine [Paris] (INTS)-Université de La Réunion (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pointe-à-Pitre/Abymes [Guadeloupe] -Université des Antilles (UA)-Université de Paris (UP), Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), and Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)
- Subjects
Mitochondrion ,MESH: Benzodiazepinones ,MESH: Down-Regulation ,lcsh:Chemistry ,0302 clinical medicine ,MESH: RNA, Small Interfering ,Mitophagy ,Erythropoiesis ,RNA, Small Interfering ,lcsh:QH301-705.5 ,Spectroscopy ,0303 health sciences ,Benzodiazepinones ,[SDV.MHEP] Life Sciences [q-bio]/Human health and pathology ,MESH: Kinetics ,biology ,VDAC ,Chemistry ,Cell Differentiation ,General Medicine ,Computer Science Applications ,Cell biology ,Mitochondria ,Phenotype ,MESH: Receptors, GABA ,030220 oncology & carcinogenesis ,enucleation ,MESH: Cell Differentiation ,MESH: Cell Nucleus ,Voltage-dependent anion channel ,MESH: Mitochondria ,MESH: Mitophagy ,Down-Regulation ,PINK1 ,MESH: Phenotype ,Catalysis ,Article ,Inorganic Chemistry ,03 medical and health sciences ,Downregulation and upregulation ,Receptors, GABA ,Erythroblast ,Translocator protein ,Humans ,Physical and Theoretical Chemistry ,Molecular Biology ,030304 developmental biology ,Cell Nucleus ,MESH: Humans ,MESH: Erythropoiesis ,Organic Chemistry ,Kinetics ,lcsh:Biology (General) ,lcsh:QD1-999 ,biology.protein ,[SDV.MHEP]Life Sciences [q-bio]/Human health and pathology ,TSPO1 - Abstract
International audience; Translocator protein (TSPO) and voltage dependent anion channels (VDAC) are two proteins forming a macromolecular complex in the outer mitochondrial membrane that is involved in pleiotropic functions. Specifically, these proteins were described to regulate the clearance of damaged mitochondria by selective mitophagy in non-erythroid immortalized cell lines. Although it is well established that erythroblast maturation in mammals depends on organelle clearance, less is known about mechanisms regulating this clearance throughout terminal erythropoiesis. Here, we studied the effect of TSPO1 downregulation and the action of Ro5-4864, a drug ligand known to bind to the TSPO/VDAC complex interface, in ex vivo human terminal erythropoiesis. We found that both treatments delay mitochondrial clearance, a process associated with reduced levels of the PINK1 protein, which is a key protein triggering canonical mitophagy. We also observed that TSPO1 downregulation blocks erythroblast maturation at the orthochromatic stage, decreases the enucleation rate, and increases cell death. Interestingly, TSPO1 downregulation does not modify reactive oxygen species (ROS) production nor intracellular adenosine triphosphate (ATP) levels. Ro5-4864 treatment recapitulates these phenotypes, strongly suggesting an active role of the TSPO/VDAC complex in selective mitophagy throughout human erythropoiesis. The present study links the function of the TSPO/VDAC complex to the PINK1/Parkin-dependent mitophagy induction during terminal erythropoiesis, leading to the proper completion of erythroid maturation.
- Published
- 2020