Nuclear receptor coactivator 4-mediated ferritinophagy drives proliferation of dental pulp stem cells in hypoxia

• Published in: Biochemical and biophysical research communications Vol. 554; pp. 123 - 130
• Main Authors: Yang, Andi, Wang, Lulu, Jiang, Ke, Lei, Lang, Li, Houxuan
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 21.05.2021
• Subjects: Autophagy; Ferritin; Mesenchymal stem cells; Nuclear receptor coactivator 4; Nuclear receptor coactivator 4; Autophagy; Ferritin; Mesenchymal stem cells
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1016/j.bbrc.2021.03.075

Nuclear receptor coactivator 4 (NCOA4)-mediated ferritinophagy has been implicated in the ferroptosis in cancer cells and hematopoiesis in the bone marrow. However, the role of iron metabolism, especially NCOA4-mediated degradation of ferritin, has not been explored in the proliferation of mesenchymal stem cells. The present study was designed to explore the role of NCOA4-mediated ferritinophagy in hypoxia-treated dental pulp stem cells (DPSCs). Hypoxia treatment increased ROS generation, boosted cytosolic labile iron pool, increased expression of transferrin receptor 1 and NCOA4. Moreover, colocalization of LC3B with NCOA4 and ferritin was observed in hypoxia-treated DPSCs, indicating the development of ferritinophagy. Hypoxia promoted the proliferation of DPSCs, but not ferroptosis, under normal serum supplement and serum deprivation. NCOA4 knock-down reduced ferritin degradation and inhibited proliferation of DPSCs under hypoxia. Furthermore, the activation of hypoxia inducible factor 1α and p38 mitogen-activated protein kinase signaling pathway was involved in the upregulation of NCOA4 in hypoxia. Therefore, our present study suggested that NCOA4-mediated ferritinophagy promoted the level of labile iron pool, leading to enhanced iron availability and elevated cell proliferation of DPSCs. Our present study uncovered a physiological role of ferritinophagy in the proliferation and growth of mesenchymal stem cells under hypoxia. •NCOA4-mediated ferritinophagy enhanced the labile iron pool in DPSCs.•Hypoxia promoted proliferation with no significant cell death in DPSCs.•TFR-promoted iron import and NCOA4-mediated ferritin degradation collectively fulfilled the iron demand in hypoxia.