P53 and Parkin co-regulate mitophagy in bone marrow mesenchymal stem cells to promote the repair of early steroid-induced osteonecrosis of the femoral head
P53 and Parkin co-regulate mitophagy in bone marrow mesenchymal stem cells to promote the repair of early steroid-induced osteonecrosis of the femoral head
复制标题
P53和Parkin共同调控骨髓间充质干细胞线粒体自噬促进早期激素性股骨头坏死的修复
DOI：
10.1038/s41419-020-2238-1
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发表时间：
2020-01-20
影响因子：
9
通讯作者：
Xie, Zhihong
中科院分区：
文献类型：
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作者：
Zhang, Fei;Peng, Wuxun;Xie, Zhihong
骨髓间充质干细胞（BMSCs）在骨坏死区的存活和干细胞化在早期激素性股骨头坏死（ONFH）的治疗中尤为重要。我们以前曾使用BMSCs修复早期激素诱导的ONFH，但移植的BMSCs在股骨头坏死区的氧化应激（OS）微环境中经历了大量的应激诱导的凋亡和老化，这限制了它们的功效。我们后续的研究表明，在OS下，细胞内大量受损线粒体的积累是导致应激诱导的BMSCs凋亡和衰老的重要因素。这种积累的主要原因是OS导致蛋白53（P53）的上调，其抑制帕金的线粒体易位和帕金的E3泛素连接酶的活化，这降低了线粒体自噬的水平并导致细胞不能有效地去除受损的线粒体。然而，P53下调可以有效地逆转这一过程。因此，我们在BMSCs中上调Parkin并下调P53。我们发现这显著增强了BMSCs的线粒体自噬，减少了细胞内受损线粒体的积累，有效地对抗了应激诱导的BMSCs凋亡和衰老，提高了BMSCs移植对激素诱导的早期ONFH的疗效。
Survival and stemness of bone marrow mesenchymal stem cells (BMSCs) in osteonecrotic areas are especially important in the treatment of early steroid-induced osteonecrosis of the femoral head (ONFH). We had previously used BMSCs to repair early steroid-induced ONFH, but the transplanted BMSCs underwent a great deal of stress-induced apoptosis and aging in the oxidative-stress (OS) microenvironment of the femoral-head necrotic area, which limited their efficacy. Our subsequent studies have shown that under OS, massive accumulation of damaged mitochondria in cells is an important factor leading to stress-induced apoptosis and senescence of BMSCs. The main reason for this accumulation is that OS leads to upregulation of protein 53 (P53), which inhibits mitochondrial translocation of Parkin and activation of Parkin’s E3 ubiquitin ligase, which decreases the level of mitophagy and leads to failure of cells to effectively remove damaged mitochondria. However, P53 downregulation can effectively reverse this process. Therefore, we upregulated Parkin and downregulated P53 in BMSCs. We found that this significantly enhanced mitophagy in BMSCs, decreased the accumulation of damaged mitochondria in cells, effectively resisted stress-induced BMSCs apoptosis and senescence, and improved the effect of BMSCs transplantation on early steroid-induced ONFH.