Downregulation of Mitochondrial TSPO Inhibits Mitophagy and Reduces Enucleation During Human Terminal Erythropoiesis
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 se...
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MDPI AG
2020-11-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/21/23/9066 |
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| author | Martina Moras Claude Hattab Pedro Gonzalez-Menendez Suella Martino Jerome Larghero Caroline Le Van Kim Sandrina Kinet Naomi Taylor Sophie D. Lefevre Mariano A. Ostuni |
| author_facet | Martina Moras Claude Hattab Pedro Gonzalez-Menendez Suella Martino Jerome Larghero Caroline Le Van Kim Sandrina Kinet Naomi Taylor Sophie D. Lefevre Mariano A. Ostuni |
| author_sort | Martina Moras |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-10T14:28:13Z |
| format | Article |
| id | doaj.art-75526b71cb094dbf850da50ca55c1367 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T14:28:13Z |
| publishDate | 2020-11-01 |
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| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-75526b71cb094dbf850da50ca55c13672023-11-20T22:47:16ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672020-11-012123906610.3390/ijms21239066Downregulation of Mitochondrial TSPO Inhibits Mitophagy and Reduces Enucleation During Human Terminal ErythropoiesisMartina Moras0Claude Hattab1Pedro Gonzalez-Menendez2Suella Martino3Jerome Larghero4Caroline Le Van Kim5Sandrina Kinet6Naomi Taylor7Sophie D. Lefevre8Mariano A. Ostuni9Inserm, BIGR, UMR_S1134, Université de Paris, F-75015 Paris, FranceInserm, BIGR, UMR_S1134, Université de Paris, F-75015 Paris, FranceInstitut de Génétique Moléculaire de Montpellier, University of Montpellier, CNRS, F-34293 Montpellier, FranceInserm, BIGR, UMR_S1134, Université de Paris, F-75015 Paris, FranceUnité de Thérapie cellulaire, AP-HP, Hôpital Saint-Louis, F-75010 Paris, FranceInserm, BIGR, UMR_S1134, Université de Paris, F-75015 Paris, FranceInstitut de Génétique Moléculaire de Montpellier, University of Montpellier, CNRS, F-34293 Montpellier, FranceInstitut de Génétique Moléculaire de Montpellier, University of Montpellier, CNRS, F-34293 Montpellier, FranceInserm, BIGR, UMR_S1134, Université de Paris, F-75015 Paris, FranceInserm, BIGR, UMR_S1134, Université de Paris, F-75015 Paris, FranceTranslocator 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.https://www.mdpi.com/1422-0067/21/23/9066erythropoiesisTSPO1VDACmitophagyPINK1enucleation |
| spellingShingle | Martina Moras Claude Hattab Pedro Gonzalez-Menendez Suella Martino Jerome Larghero Caroline Le Van Kim Sandrina Kinet Naomi Taylor Sophie D. Lefevre Mariano A. Ostuni Downregulation of Mitochondrial TSPO Inhibits Mitophagy and Reduces Enucleation During Human Terminal Erythropoiesis International Journal of Molecular Sciences erythropoiesis TSPO1 VDAC mitophagy PINK1 enucleation |
| title | Downregulation of Mitochondrial TSPO Inhibits Mitophagy and Reduces Enucleation During Human Terminal Erythropoiesis |
| title_full | Downregulation of Mitochondrial TSPO Inhibits Mitophagy and Reduces Enucleation During Human Terminal Erythropoiesis |
| title_fullStr | Downregulation of Mitochondrial TSPO Inhibits Mitophagy and Reduces Enucleation During Human Terminal Erythropoiesis |
| title_full_unstemmed | Downregulation of Mitochondrial TSPO Inhibits Mitophagy and Reduces Enucleation During Human Terminal Erythropoiesis |
| title_short | Downregulation of Mitochondrial TSPO Inhibits Mitophagy and Reduces Enucleation During Human Terminal Erythropoiesis |
| title_sort | downregulation of mitochondrial tspo inhibits mitophagy and reduces enucleation during human terminal erythropoiesis |
| topic | erythropoiesis TSPO1 VDAC mitophagy PINK1 enucleation |
| url | https://www.mdpi.com/1422-0067/21/23/9066 |
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